Application and future prospects of bispecific antibodies in the treatment of non-small cell lung cancer

Application and future prospects of bispecific antibodies in the treatment of non-small cell lung cancer

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Junxu Wen, Wenxing Cui, Xiaoyan Yin, Yu Chen, Ailing Liu, Qian Wang, Xiangjiao Meng

Cancer Biology & Medicine | 2025, 22(4) : 348 - 375

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Cancer Biology & Medicine | 2025, 22(4): 348-375

• Review •

Application and future prospects of bispecific antibodies in the treatment of non-small cell lung cancer

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Junxu Wen, Wenxing Cui, Xiaoyan Yin, Yu Chen, Ailing Liu, Qian Wang, Xiangjiao Meng

Affiliations

¹Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China

About Author:

*These authors contributed equally to this work.

Author contributions

Conceived and designed the analysis: Xiangjiao Meng.

Collected the data: Junxu Wen and Wenxing Cui.

Contributed data or analysis tools: Xiaoyan Yin, Yu Chen, Ailing Liu, and Qian Wang.

Performed the analysis: Junxu Wen, Wenxing Cui, and Xiaoyan Yin.

Wrote the paper: Junxu Wen and Wenxing Cui.

Published: 2025-04-15 doi: 10.20892/j.issn.2095-3941.2024.0470

Outline

Abstract

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As the leading cause of cancer-related deaths, lung cancer remains a noteworthy threat to human health. Although immunotherapies, such as immune checkpoint inhibitors (ICIs), have significantly increased the efficacy of lung cancer treatment, a significant percentage of patients are not sensitive to immunotherapies and patients who initially respond to treatment can quickly develop acquired drug resistance. Bispecific antibodies (bsAbs) bind two different antigens or epitopes simultaneously and have been shown to enhance antitumor efficacy with suitable safety profiles, thus attracting increasing attention as novel antitumor therapies. At present, in addition to the approved bsAb, amivantamab, three novel bsAbs (KN046, AK112, and SHR-1701) are being evaluated in phase 3 clinical trials and many bsAbs are being evaluated in phase 1/2 clinical trials for patients with non-small cell lung cancer (NSCLC). Herein we present the structure, classification, and mechanism of action underlying bsAbs in NSCLC and introduce related clinical trials. Finally, we discuss challenges, potential solutions, and future prospects in the context of cancer treatment with bsAbs.

Key words

Bispecific antibody / non-small cell lung cancer / novel antitumor therapy / structure / challenges

Cite this Article

Junxu Wen, Wenxing Cui, Xiaoyan Yin, Yu Chen, Ailing Liu, Qian Wang, Xiangjiao Meng. Application and future prospects of bispecific antibodies in the treatment of non-small cell lung cancer[J]. Cancer Biology & Medicine, 2025 , 22 (4) : 348 -375 . DOI: 10.20892/j.issn.2095-3941.2024.0470

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Introduction

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Lung cancer, the leading cause of cancer-related deaths, is one of the most significant threats to human health. Non-small cell lung cancer (NSCLC) is the most prevalent subtype, accounting for nearly 85% of all lung cancer cases. Although targeted therapy and immunotherapy have improved the efficacy of NSCLC treatment, therapeutic resistance and poor patient response indicate the urgent need to find more effective therapies¹. Bispecific antibodies (bsAbs) were first proposed by Nisonoff in the 1960s and are defined as antibodies that simultaneously bind two different antigens or epitopes². BsAbs have shown encouraging efficacy as late-line treatment in numerous clinical trials, indicating that bsAbs may be effective treatments for overcoming resistance to existing targeted therapies and immunotherapies. Given the high overall response rate (ORR) and durable response demonstrated in a phase 1 trial (NCT02609776/CHRYSALIS), amivantamab was first approved in the US on 21 May 2021 for medical intervention in adult patients with locally advanced or metastatic NSCLC and epidermal growth factor receptor (EGFR) exon 20 insertion mutations that have progressed during or after platinum-based chemotherapy³. According to data from ClinicalTrials.gov, numerous bsAbs are being assessed in clinical trials for patients with NSCLC. However, the existing reviews concerning the use of bsAbs for the treatment of lung cancer have failed to describe the relevant bsAbs and clinical trials completely⁴. This article briefly introduces bsAbs, discusses the mechanisms of action and application in NSCLC treatment, and reviews related clinical trials in detail.

Production and classification of bsAbs

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BsAbs refer to antibodies that bind two different antigens or epitopes simultaneously, which can enhance antibody targeting and cancer treatment efficacy. BsAbs were first proposed in the 1960s by Nisonoff² (Figure 1). BsAbs were mainly constructed using hybridoma or chemical recombination technology in the early stage. Hybridoma technology involves the formation of a quadroma by somatic fusing two different antibody-producing hybridoma cell lines to generate bsAbs⁵. Hybridoma cell A expressing mAb A and hybridoma cell B expressing mAb B were fused to generate a quadroma expressing bsAbs containing immunoglobulin heavy and light chains inherited from both parents (Figure 2A). However, this approach faced several challenges, including low yields of the desired bsAbs and immune side effects caused by misassembling heavy and light chains². The stochastic pairing of two distinct heavy and light chains each can theoretically generate up to 10 possible molecular configurations, of which only 1 molecular configuration forms a functional bsAb⁶.

Chemical recombination technology refers to the chemical reassociation of fragments derived from two different mAbs (Figure 2B)⁷. The initial chemical recombination strategies relied on manipulating the disulfide arrangements. With the advances in increasingly sophisticated antibody modification techniques, the number of available chemical crosslinkers increased, such as a bis-sulfone crosslinker, bis-maleimide chemistry, dibromomaleimide crosslinker, and pyridazinedione⁸. However, this method often led to the inactivation, unfolding, or aggregation of bsAbs². With the development of bioconjugation and click chemistry-based technologies, chemical recombination technology has had a vital role in the construction of bispecific antibody‒drug conjugates (bsADCs) with better yields in recent years, producing stable and homogeneous bsAbs⁸.

The development of bsAbs has been significantly hindered due to limitations of these two strategies. The rapid advances in genetic engineering technologies have provided a promising alternative to overcome the limitations of hybridoma and chemical recombination technology, which could also make the antibody less immunogenic and better tolerated⁹. Genetic engineering technologies enhance specific activities, such as improving antigen affinity, modulating pharmacokinetics, and optimizing effector functions¹⁰. Gene recombination and protein engineering are the primary genetic engineering technologies used to construct bsAbs (Figure 2C)^11,12. A second wave of bsAb production emerged due to advances in genetic engineering technologies². Most of the bsAbs that are approved or in clinical trials are constructed by genetic engineering technologies.

BsAbs can be categorized into two distinct groups based on structure: IgG-like bsAbs containing Fc fragments; and non-IgG-like bsAbs without Fc fragments¹³ (Figure 2C). IgG-like bsAbs are based on intact IgG structures and have better solubility and stability and a longer half-life than non-IgG-like bsAbs because IgG-like bsAbs contain Fc fragments. Moreover, IgG-like bsAbs also enhance tumor-killing effects by achieving antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cell phagocytosis (ADCP). The strategies used to construct IgG subtype bsAbs include CrossMab, Knobs-into-Holes (KiH), Triomab quadroma, Duo body, and dual variable domain-immunoglobulin (DVD-Ig). IgG-like bsAbs can be further classified into symmetric and asymmetric types, with the majority being asymmetric⁶. Symmetric bsAbs are designed by fusing two identical antibody fragments or conjugating single-chain variable fragments (scFvs) or single-variable domains to conventional antibodies via linker molecules. These constructs typically adopt a tetravalent structure with four binding sites, ensuring balanced antigen targeting while mitigating the risk of improper chain association. In contrast, asymmetric bsAbs incorporate distinct antigen-binding arms, forming heterodimers that offer enhanced flexibility in target selection¹⁴. Non-IgG-like bsAbs are based on scFvs, which are characterized by small size and strong permeability. The lack of an Fc fraction means that non-IgG-like bsAbs have many disadvantages, such as a short half-life, unstable structure, and low expression. The strategies used to construct bsAbs of this subtype include dual-affinity re-targeting proteins (DART), bispecific T-cell engager (BiTE), tandem diabodies (TandAbs), and bi-Nanobody^15,16. The characteristics and relevant bsAbs of different platforms are listed in Table 1.

Mechanisms of action underlying bsAbs

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BsAbs can be split into the following two groups: bsAbs for immunotherapy; and bsAbs for targeted therapy. The mechanisms of action underlying bsAbs in the context of NSCLC treatment and relevant clinical trials are introduced herein. The framework of this review is shown in Figure 3.

BsAbs for immunotherapy

Moderating the immune response by binding multiple immunomodulatory molecules

The most well-known immunomodulators are immune checkpoints, which have a role in tumor immune evasion and can be divided into two categories: inhibitory checkpoints; and costimulatory checkpoints. Common inhibitory checkpoints include programmed death-1/programmed death-ligand 1 (PD-1/PD-L1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), T-cell immunoglobulin and mucin domain-containing protein (TIM-3) and lymphocyte activation gene 3 (LAG-3). Immune checkpoint inhibitors (ICIs) have undoubtedly been the paramount accomplishment in tumor treatment over the past decade, revolutionizing the field of oncology¹⁷. Unfortunately, the ORR of patients with NSCLC receiving ICIs is only 20%¹⁸. Many NSCLC patients develop resistance over time and relapse, indicating that single mAb therapy has limited efficacy. Although combination therapy can increase the response rate, combination therapy may result in an increased number of treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs)¹⁹, thus forming the basis for the use of bsAbs to simultaneously target two checkpoint proteins. BsAbs modulate the immune response by binding multiple immunomodulatory molecules to enhance antitumor efficacy (Figure 4A).

BsAbs targeting two checkpoints

Inhibitory checkpoints, the “brakes” of the immune system, are vital for the maintenance of self-tolerance. Inhibitory checkpoints decrease the intensity of the immune response and terminate continued activation to alleviate or prevent host damage caused by chronic inflammation and autoimmunity under normal physiologic conditions²⁰. ICIs blocking inhibitory checkpoints induce an effective antitumor immune response²¹ and markedly increase the survival rate and ORR of NSCLC patients²². Although > 100 mAbs are approved for clinical application by the Food and Drug Administration (FDA), patients have an enduring response to only a few mAbs, indicating the limited efficacy of mAbs²³. Through the upregulation of alternative inhibitory checkpoints, mAbs may result in incomplete blockage, leading to ICI resistance²⁴. This shortcoming can be overcome by developing bsAbs that bind two inhibitory checkpoints simultaneously to achieve an enhanced antitumor effect.

PD-1/PD-L1 × CTLA-4

PD-1, which is upregulated on effector T cells after activation, restrict the activity of T cells in the context of the inflammatory response²⁵. The major PD-1 ligand is PD-L1, which is expressed in NSCLC cells and may inhibit the antitumor immune response²⁶. Blocking the PD-1/PD-L1 axis can inhibit tumor growth and restore the functional activity and number of CD8+ T cells²⁷. CTLA-4 was the first targeted immune checkpoint²⁵. CD28 receptors located on T cells that bind to CD80 or CD86 costimulatory molecules on antigen-presenting cells (APCs) are crucial for effectively activating T cells²⁸. CTLA-4 and CD28 have common ligands, and compared to CD28, CTLA-4 has greater overall binding affinities to CD80 and CD86²⁹. By strongly binding to CD80 and CD86, CTLA-4 decreases the activation of T cells and actively delivers inhibitory signals. CTLA-4 and PD-1 are usually co-expressed in tumor-infiltrating lymphocytes (TILs). Although combining anti-PD-1 and anti-CTLA-4 antibodies is the most effective and powerful combination therapy for numerous malignancies to date, combining anti-PD-1 and anti-CTLA-4 antibodies also significantly increases immune-mediated toxicity, which may reduce the opportunity for combination with other therapies. Compared to the combination of two monoclonal antibodies, bsAbs that simultaneously target two inhibitory checkpoints can achieve maximum clinical therapeutic effects while minimizing toxicity³⁰.

KN046

KN046, a novel bsAb that is fused with the human wild-type IgG1 Fc fragment, can simultaneously bind to PD-L1 and CTLA-4 with increased affinity for PD-L1, which enables KN046 to target tumors expressing high levels of PD-L1. A phase 2 trial (NCT03838848) that evaluated KN046 in metastatic NSCLC patients as second-line treatment, revealed an ORR of 14.1%, a median progression-free survival (mPFS) of 3.7 months, and a median overall survival (mOS) of 18.4 months among 64 patients. The incidence of grade ≥ 3 TRAEs was 42.2%. The most frequent TRAEs were infusion reactions (10.9%), hepatic dysfunction (4.7%), and pneumonia (3.1%). KN046 was shown to be effective and relatively safe for advanced NSCLC as a second-line treatment³¹.

Cadonilimab/AK104

Cadonilimab, also known as AK104, is a human symmetric IgG1 tetravalent bsAb that targets PD-1 and CTLA-4. Cadonilimab has distinctly lower toxicity in the clinical setting because cadonilimab does not bind Fc receptors, thereby minimizing ADCC, ADCP, and interleukin-6 (IL-6)/IL-8 release^32,33. The effect of AK104 on patients with selected advanced solid tumors was evaluated in the NCT04172454 phase 1b/2 study. Among the 53 evaluable patients previously treated for advanced NSCLC, the ORR was 5.7% and the disease control rate (DCR) was 35.8%. TRAEs occurred in 39 patients (73.6%) and grade ≥ 3 TRAEs occurred in 6 patients (11.3%). The most frequent TRAEs were increased aspartate aminotransferase (AST) levels (22.6%), increased alanine transaminase (ALT) levels (18.9%), and weight loss (13.2%; Table 2)³⁴. Cadonilimab was approved for use in China for patients with recurrent or metastatic cervical cancer who have received or are receiving platinum-based chemotherapy in June 2022³⁵. We look forward to more supportive research results to promote the use of cadonilimab in the treatment of NSCLC. A range of studies investigating the therapeutic efficacy of cadonilimab in NSCLC, such as NCT05816499, NCT05812534, and NCT05377658, are ongoing.

As the most common and promising targets, PD-(L)1 and CTLA-4 have crucial roles in NSCLC immunotherapy. The efficacy and safety of anti-PD-(L)1 and anti-CTLA-4 combination therapy were evaluated. However, TRAEs occurred in 78.0% of patients and grade ≥ 3 TRAEs occurred in 34.0% patients of patients receiving nivolumab and ipilimumab³⁶. BsAbs simultaneously binding PD-(L)1 and CTLA-4 were developed to enhance anti-tumor efficacy and reduce toxicity and TRAEs. TRAEs occurred in 73.6% of patients and grade ≥ 3 TRAEs occurred in 11.3% of patients receiving AK104. The incidence of grade ≥ 3 TRAEs was clearly reduced compared to combination nivolumab and ipilimumab. However, the incidence of grade ≥ 3 TRAEs was 42.2% in patients receiving KN046. In addition, investigation of biomarkers warrants further study. A recent study showed that CD74 can be used as a biomarker to predict the treatment response to AK104. Patients with high expression of CD74 protein had superior progression-free survival (PFS) and overall survival (OS)³⁷. In addition, among receiving KN046, those with high CD8 expression had a longer median (m)OS and combination PD-L1 and CD8 had the potential to predict the KN046 response³⁸.

PD-1/PD-L1 × TIM-3

TIM-3, encoded by HAVCR2, is a marker of dysfunctional CD8+ T cells³⁹. Antibodies targeting TIM-3 promote an antitumor immune response that relies on T cells and IFN-γ⁴⁰. Alternative immune inhibitory molecules, especially TIM-3, might lead to adaptive resistance in patients receiving anti-PD-1 therapy by increasing expression; resistance is prevented when anti-PD-1 antibodies are combined with anti-TIM-3 antibodies⁴¹. Co-blocking PD-1 and TIM-3 can lead to regression of tumors in preclinical models and enhance the antitumor T-cell response in patients with advanced tumors. Nearly 60% of regulatory T cells (Tregs) in lung cancer patients express TIM-3³⁹.

AZD7789

AZD7789 is a novel IgG1 bsAb that simultaneously binds PD-1 and TIM-3. AZD7789 may overcome anti-PD-1 resistance. The safety and preliminary efficacy results of a phase 1/2 clinical trial (NCT04931654) were presented at 2023 European Society for Medical Oncology (ESMO). Among 39 patients with stage IIIB-IV NSCLC receiving previous anti-PD-(L)1 treatment, 82% experienced TEAEs, 23% of which were grade ≥ 3. TRAEs occurred in 41% of patients and no grade ≥ 3 TRAEs were observed. The most common TRAE was asthenia, which occurred in 8% of patients. Among all 18 patients evaluated, 7 had stable disease⁴².

TIM-3 is a biomarker of exhausted T cells and the potential mechanism of adaptive resistance. However, few bsAbs targeting PD-(L)1 and TIM-3 have been developed for NSCLC treatment. Researchers have developed an experimental system to predict the response of bsAbs targeting PD-(L)1 and TIM-3 based on multi-omic analyses⁴³, which may help more accurately select the population most likely to benefit.

PD-1/PD-L1 × LAG-3

LAG-3/CD223 is a type Ⅰ transmembrane protein expressed on CD4+ and CD8+ T cells, natural killer (NK) cells, and natural killer T (NKT) cells. LAG-3/CD223 is constitutively expressed on plasmacytoid dendritic cells (pDCs) and Tregs. LAG-3 can be cleaved to form soluble LAG-3 (sLAG-3), which is positively correlated with T cell antitumor activity and DC migration. LAG-3 is expressed on TILs in 41.5% of NSCLC patients⁴⁴. LAG-3 expression in NSCLC cells was not reported until a study in 2020 revealed that LAG-3 is expressed in lung cancer cell lines and that LAG expression is associated with the NSCLC clinical stage⁴⁵. LAG-3 expression correlates with recurrence-free survival (RFS), PD-1 expression on TILs, and PD-L1 expression on tumor cells in patients with NSCLC⁴⁶. LAG-3 enhances the ability of Tregs to exert inhibitory effects and inhibits CD8+ effector T cell function²⁵. Dual blockade of the LAG-3 and PD-1 pathways can achieve a more effective antitumor response compared to blocking LAG-3 or PD-1/PD-L1 alone⁴⁷.

MGD013/tebotelimab

MGD013, also known as tebotelimab, is a first-in-class PD-1 × LAG-3 bsAb containing an Fc fragment that enhances the antitumor T-cell response compared to anti-PD-1 and anti-LAG-3 antibodies alone or in combination and can restore the function of exhausted T cells^48,49. NCT03219268, a phase 1 study, was conducted to evaluate the efficacy of MGD013 in patients with unresectable or metastatic neoplasms. Among 29 NSCLC patients, the ORR was 17.2% and the DCR was 58.6%. The incidence of grade ≥ 3 TRAEs was 18% and the most common TRAEs were fatigue (15.6%), rash (8.3%), and hypothyroidism (7.8%)⁵⁰.

LAG-3 is expressed on exhausted T cells and targeting LAG-3 may reinvigorate antitumor immunity⁵¹. A recent study revealed that LAG-3^hiPD-1^hi memory CD4+ T cells are potential biomarkers for predicting the response to PD-1 × LAG-3 bsAb⁵². MGD013 showed a satisfactory safety profile with 18% grade ≥ 3 TRAEs in NSCLC treatment. However, the paucity of enrolled patients and the dearth of relevant clinical trials both point to the importance of further research.

BsAbs targeting checkpoints and non-checkpoints

Several non-checkpoint molecules, such as growth factors (GFs) and cytokines, also affect the intensity of the antitumor immune response in addition to immune checkpoints. GFs and cytokines exert pro- or anti-tumor effects on the initiation and progression of malignancies. Numerous antibodies targeting GFs or cytokines are approved for monotherapy or combination therapy with ICIs for several cancer types²³.

PD-1/PD-L1 × vascular endothelial growth factor (VEGF)

VEGF (also referred to as VEGFA) has crucial roles in vascular homeostasis in various tissues, the progression and metastasis of several cancers, and retinopathologic changes in eye diseases that cause blindness. VEGF is correlated with invasion, metastasis, recurrence, and prognosis in the majority of human cancers⁵³. MAbs that target VEGF, such as bevacizumab, have shown potent antitumor effects in several human cancer types.

AK112/ivonescimab

AK112 (also known as ivonescimab) is a novel IgG1 tetravalent PD-1 × VEGF bsAb that is designed to overcome PD-1-mediated immunosuppression and concurrently suppress tumor angiogenesis in the TME. AK112 was developed via TETRABODY technology. AK112 exhibits enhanced binding affinity and antitumor effects⁵⁴. According to the results presented at the 2024 WCLC from NCT05499390, a phase 3 trial testing AK112 in patients with PD-L1-positive advanced NSCLC, AK112 exhibited excellent antitumor ability and tolerable toxicity. Among all 398 enrolled patients, 198 received AK112 and 200 received pembrolizumab. Notably, among patients who received AK112, the ORR was 50% and the DCR was 89.9%. The mPFS was 11.14 months. Among patients who received pembrolizumab, the ORR was 38.5% and the DCR was 70.5%. The mPFS was 5.82 months. Among patients who received AK112, TRAEs occurred in 89.9% and grade ≥ 3 TRAEs occurred in 29.4%. The most common TRAEs were proteinuria (31.5%), increased aspartate aminotransferase activity (19.8%), and hypercholesterolemia (16.2%). AK112 significantly improved the mPFS compared to pembrolizumab (11.14 months vs. 5.82 months) and showed tolerable toxicity.

PM8002

PM8002 is an IgG1 bsAb that targets PD-L1 and VEGFA. The tolerance, safety, PK, and antitumor efficacy of PM8002 have been evaluated in patients with advanced solid tumors in a phase 1/2a clinical trial (ChiCTR2000040552). Among the 263 enrolled patients, the overall ORR was 15.2% and the DCR was 75.4%. Among 27 patients with NSCLC, the ORR was 18.5%. TRAEs occurred in 181 (68.8%) patients, 48 (18.3%) of whom were grade ≥ 3. The most frequent TRAEs were proteinuria (17.5%), hypertriglyceridemia (11.4%), and increased aspartate transaminase (AST) levels (9.9%)⁵⁵. In addition, according to the results of the clinical trial, NCT05918445, which was presented at the 2024 American Society of Clinical Oncology (ASCO) meeting, among 36 evaluable EGFR-T790M-positive NSCLC patients the ORR with PM8002 was 19.4% and the DCR was 69.4%. Among all 61 enrolled patients, TRAEs occurred in 85.2% and grade ≥ 3 TRAEs occurred in 19.7%. The most common TRAEs were proteinuria (54.1%), hypertension (24.6%), hypothyroidism (21.3%), and hypoalbuminemia (19.7%).

The combination of AK112 and chemotherapy was first approved in May 2024 for the treatment of NSCLC patients who progressed after tyrosine kinase inhibitor (TKI) therapy⁵⁶. We will discuss this combination in more detail in the combination therapy section. However, studies on biomarkers for bsAbs targeting PD-(L)1 and VEGF are inadequate.

PD-1/PD-L1 × transforming growth factor β (TGF-β)

TGF-β is a multifunctional polypeptide cytokine that has a complex and paradoxical role in tumors at different phases of tumor progression. TGF-β exerts tumor-inhibiting effects in the early stage and tumor-promoting effects in the late stage⁵⁷. In addition to supporting tumor growth, metastasis, invasion, and therapy resistance, recent research has revealed that TGF-β regulates cancer metabolic reprogramming and drives tumor metabolism in the tumor microenvironment (TME)⁵⁸. TGF-β facilitates lung cancer cell invasion and metastasis by reducing SH2B3 to increase anoikis resistance and epithelial‒mesenchymal transition (EMT)⁵⁹. Although TGF-β seems to be a promising therapeutic target and anti-TGF-β antibodies have been evaluated in several clinical experiments, anti-TGF-β therapy has not achieved satisfactory results because of adverse systemic effects. PD-1/PD-L1 and TGF-β activate immunosuppressive signaling pathways in the TME and inhibiting TGF-β is helpful for restoring sensitivity to anti-PD-L1 therapy. BsAbs that simultaneously target PD-1/PD-L1 and TGF-β exhibit superior antitumor activity⁶⁰.

Bintrafusp alfa (BA)/M7824

BA, also known as M7824, is a novel bsAb that fuses the extracellular domain of human TGF-β receptor Ⅱ (TGF-βRⅡ) to the C-terminus of heavy chains in the IgG1 anti-PD-L1 antibody to sequester TGF-β more effectively in the TME. BA enhances T-cell activity and increases the number of TILs to exert better antitumor effects through increased affinity-based binding to TGF-β and increased sequestration of TGF-β by targeting PD-L1 on the cell surface and co-localization⁶¹. BA shows promising antitumor efficacy and manageable tolerability according to the results of NCT02517398, a phase 1 trial evaluating BA in patients with metastatic or locally advanced solid tumors. The ORR was 17.5% in patients receiving a 500-mg dose and 25.0% in patients receiving a 1200-mg dose. The ORR was 21.3% in all 80 patients. TRAEs occurred in 55 patients (68.8%) and 23 (28.8%) were grade ≥ 3. The most common TRAEs were pruritus (21.3%), maculopapular rush (18.8%), and decreased appetite (12.5%)⁶². In addition, the results for advanced NSCLC patients who progressed to primary refractory or acquired resistance to anti-PD-L1 therapy after chemotherapy have recently been published. Among 62 patients, the ORR was 4.8%, the mPFS was 1.4 months, and the mOS was 7.3 months. TRAEs occurred in 73.5% of patients, 22.9% of whom had grade ≥ 3 TRAEs. The most common TRAEs were asthenia (27.7%), pruritus (22.9%), and decreased appetite (16.9%; Table 2)⁶³. However, according to the results of a phase 3 trial (NCT03631706) that compared the efficacy of M7824 and pembrolizumab in PD-L1+ NSCLC patients, those treated with M7824 had a shorter mOS (21.1 months vs. 22.1 months) and more TRAEs⁶⁴.

SHR-1701

SHR-1701 is a novel PD-L1 × TGF-β bsAb that fuses an anti-PD-L1 mAb with the TGF-βRⅡ extracellular domain. NCT03774979 is an open-label, phase 1 study that was conducted in 2021 to investigate the safety, tolerability, and clinical activity of SHR-1701 in patients with metastatic or locally advanced solid tumors. According to the results presented at the 2021 ASCO meeting, in the cohort consisting of EGFR+ NSCLC patients TRAEs occurred in 50.3% of patients, grade 3 TRAEs occurred in 7.4% of patients, and no grade 4 or 5 TRAEs occurred among all 27 enrolled patients. The most common TRAEs were increased ALT levels (14.8%), fatigue (11.1%), anemia (11.1%), and anorexia (11.1%). Among the 24 evaluable patients, the ORR was 16.7% and the DCR was 50.0% (Table 2).

Given the high-level expression of PD-(L)1 and TGF-β in the TME⁶⁵, bsAbs that simultaneously target PD-(L)1 and TGF-β to precisely enrich the TME and reduce side effects were developed. The two bsAbs showed encouraging antitumor effects and manageable tolerability with < 30.0% developing grade ≥ 3 TRAEs. However, the latest results of the relevant trials have not been published and the exploration of biomarkers was inadequate. In addition, a phase 2 trial (NCT04580498) is underway to explore the efficacy and safety of SHR-1701 as neoadjuvant therapy, the latest results of which are promising⁶⁶.

Connection between immune cells and tumor cells

CD3 is a critical surface molecular marker of T cells. BsAbs can simultaneously bind CD3 on the surface of T cells and tumor-associated antigens (TAAs) or tumor-specific antigens (TSAs) on the surface of tumor cells, thereby redirecting T cells to tumor cells and facilitating binding (Figure 4B). This binding can lead to T-cell activation and immune synapse formation⁶⁷, through which activated T cells secrete perforin and other granzymes, eventually leading to tumor cell lysis⁶⁸. These bsAbs are also called T-cell engagers, which can overcome tumor immune evasion caused by loss of MHC class I expression⁶⁹. In addition, bsAbs linking other molecules on the surface of T cells, such as PD-1, to TAAs/TSAs can also redirect T cells and facilitate binding with tumor cells⁷⁰. In addition to targeting CD3 to recruit an extensive range of T cells, several effector cells or immune cell subtypes, such as γδ T cells, NK cells, and invariant natural killer T (iNKT) cells, can be promising targets for bsAbs engaging immune and tumor cells⁷¹.

CD3 × epithelial cell adhesion molecule (EpCAM)

EpCAM is a 39–42 kDa L-type transmembrane glycoprotein consisting of 314 amino acids that are encoded by the TACSTD1 gene. EpCAM is often overexpressed in many tumors, such as rectal cancer, NSCLC, esophageal cancer, and prostate cancer^72,73. EpCAM directly affects the cell cycle and cell proliferation and can upregulate the proto-oncogenes, c-myc and cyclin A/E⁷⁴. Therefore, the inhibition of EpCAM can restrain the growth of tumor cells.

Catumaxomab

Catumaxomab is a quadroma bsAb targeting CD3 and EpCAM that was approved for the treatment of patients with EpCAM-positive malignant ascites by the European Union in 2009 and is also the first bsAb approved for marketing⁷⁵. Although catumaxomab was withdrawn from the market for commercial reasons in 2017; relevant studies are still ongoing. Because 86.5% of NSCLC patients express EpCAM⁷⁶, we believe that CD3 × EpCAM bsAbs may be effective for treating NSCLC. Unfortunately, the results of a phase 1 study assessing the safety and tolerability of intravenous catumaxomab treatment in NSCLC patients were disappointing⁷⁷.

CD3 × carcinoembryonic antigen (CEA)

CEA is a common tumor biomarker that is overexpressed in several solid tumors, such as colorectal carcinoma (CRC), pancreatic carcinoma (PanCa), gastric carcinoma (GC), NSCLC, and other carcinomas⁷⁸. CEA is a 180 kDa glycoprotein that is anchored to the cell surface via glycosylphosphatidylinositol (GPI) and belongs to the CEA-related cell adhesion molecules (CEACAMs) immunoglobulin family. CEA is involved in endothelial cell functions, such as cell proliferation, adhesion, and migration.

CEA TCB/RO686889

CEA TCB is a novel IgG-based bsAb that binds the CD3 epsilon chain (CD3e) located on T cells and to the CEA located on tumor cells. CEA TCB is characterized by a longer circulatory half-life, T-cell activity within tumors, and killing of tumor cells independent of immune cell activation in the peripheral blood. The CEA TCB molecule is characterized by monovalent binding to CD3e, owing to a novel Fc fraction that abrogates binding to complement components and Fc gamma receptors (FcγRs). The level of CEA expression is the best indicator for predicting the activity of CEA TCB and 10,000 CEA binding sites/cells is the threshold for the activity of CEA receptors. Moreover, CEA-TCB efficiently affects poorly infiltrated and non-inflamed T cells and can alleviate the immunosuppressive TME by converting immune-cold, PD-L1-negative tumors to immune-hot, PD-L1-positive tumors⁷⁹. A phase 1/2 study (NCT03337698) focusing on the effects of several combination immunotherapy-based therapies, including CEA TCB, on patients with metastatic NSCLC is ongoing.

In addition to the above TAAs/TSAs, several other tumor markers are targeted by bsAbs to bind immune and tumor cells. An increasing number of new drugs, such as GEN1044 (5T4 × CD3) and CC-1 (PSMA × CD3), are currently in preclinical or clinical trials. Although numerous encouraging results have been reported, several clinical trials evaluating bsAbs for NSCLC have not published any results. The relevant clinical trials are listed in Table 3.

In this section we introduce the use of bsAbs for immunotherapy in NSCLC patients. Most bsAbs exert the antitumor effects by binding dual immunomodulatory molecules and few bsAbs connect immune and tumor cells. Although most of these drugs exhibit encouraging efficacy and acceptable safety profiles, studies of biomarkers are inadequate. Therefore, we expect more studies involving biomarkers to help select the population most likely to benefit more precisely.

BsAbs for targeted therapy

BsAbs that block two signaling pathways

Targeted therapies, such as those that inhibit signaling pathways by targeting receptor tyrosine kinases (RTKs), also have crucial roles in the treatment of malignancies. RTKs constitute a cell-surface receptor family that have a critical role in modulating cell proliferation, differentiation, migration, survival, and metabolism. RTK mutations and abnormal activation of intracellular signaling pathways are important pathogenic mechanisms of numerous cancers under pathologic conditions. Blocking or attenuating RTK activity is a promising treatment strategy⁶². Several TKIs and monoclonal antibodies, such as trastuzumab, cetuximab, and cabozantinib, have exhibited potent antitumor activity. However, drug resistance resulting from the activation of alternative signaling pathways or other mutations severely limits the application of TKIs⁸⁰. BsAbs that simultaneously target two signaling pathways may enhance the antitumor response and overcome drug resistance (Figure 4C).

EGFR × cellular-mesenchymal epithelial transition (c-MET)

EGFR, a member of the ERBB receptor tyrosine kinase superfamily, is one of the most essential RTKs and has crucial roles in the proliferation, angiogenesis, and metastasis of cancer cells. Moreover, EGFR mutations have crucial roles in lung cancers, especially NSCLC, among which 15% of patients present with EGFR mutations⁸⁰. c-MET, a member of the RTK family, is a proto-oncogene that promotes several biological processes, such as the proliferation, development, migration, and invasion of cells under physiologic conditions, and can lead to oncogenesis and tumor progression, especially in NSCLC. Interestingly, in patients with acquired resistance, the MET gene copy number (GCN) is increased and the combination of MET and EGFR inhibition can restore drug sensitivity⁸¹. This phenomenon suggests that simultaneously blocking EGFR and MET may enhance antitumor effects.

Amivantamab

Amivantamab, a fully human monoclonal IgG1 bsAb developed via the Genmab DuoBody^® technology platform, exerts antitumor effects by simultaneously binding EGFR and c-MET to inhibit downstream signaling cascades. Amivantamab has an enhanced ability to bind to FcγRIIIa and enhances antitumor activity through several mechanisms, such as Fc-mediated ADCC via interactions with Fcγ receptors on NK cells and cytokine production and phagocytosis via interactions with Fcγ receptors on monocytes and macrophages³. A phase 1 study, NCT02609776 (CHRYSALIS), evaluated the safety, PK and preliminary efficacy of amivantamab in advanced NSCLC patients. Among 39 response-evaluable patients with EGFR exon 20 insertion mutations, the ORR was 36%, and the clinical benefit rate was 67.0%. Among all 50 patients, 36.0% had grade ≥ 3 TRAEs. The most common AEs were rash (72.0%), infusion-related reactions (60.0%), and paronychia (34.0%)⁸². Based on the results of the CHRYSALIS trial, the FDA approved amivantamab on 21 May 2021 for the treatment of adult NSCLC patients with EGFR exon 20 insertion mutations that progressed during or after platinum-based chemotherapy. In addition, researchers updated the results concerning the therapeutic effects of amivantamab on NSCLC patients with MET exon 14 skipping mutations in the MET-2 cohort of CHRYSALIS at the 2022 ASCO meeting. Among 36 patients with ≥ 1 baseline disease assessment, the overall ORR was 33.3% and the clinical benefit rate was 58.3%⁸³. Amivantamab shows encouraging antitumor activity in patients with MET exon 14 skipping mutations, including patients who have received prior MET inhibitor treatment. In addition to intravenous formulations, a subcutaneous (SC) formulation of amivantamab was developed via the Halozyme Therapeutics ENHANZE™ technology. The safety and PK of amivantamab SC administration were evaluated in a phase 1b study (NCT04606381/PALOMA).

MCLA-129

MCLA-129 is a novel ADCC-enhanced human EGFR × c-MET biclonic bsAb that was developed to overcome c-MET signaling-independent EGFR TKI resistance. MCLA-129 exerts antitumor effects via several mechanisms, such as ADCC and ADCP, and inhibits downstream signaling of EGFR and c-MET. MCLA-129 was shown to inhibit EGFR and c-MET activity in NSCLC cell lines to induce tumor regression and overcome c-MET signaling-independent EGFR TKI resistance⁸⁴. According to the results of an open-label, dose-escalation, and expansion phase 1/2 study (NCT04868877), which evaluated MCLA-129 in patients with advanced NSCLC and other solid tumors, MCLA-129 showed preliminary antitumor activity and a favorable safety profile. Among the 13 evaluable patients, the DCR was 38.5% and no dose-limiting toxicity was observed⁸⁵. In addition, a phase 1/2 study (NCT04930432) is underway to evaluate the safety, pharmacokinetics (PK), and antitumor effects of MCLA-129 in patients with advanced NSCLC and other solid tumors.

The above two bsAbs, which target EGFR and c-MET, both showed satisfactory antitumor efficacy. Amivantamab is undoubtedly one of the most widely used bsAbs in NSCLC treatment. Although amivantamab improves PFS compared to standard osimertinib, amivantamab also causes increased toxicity⁸⁶. Importantly, structural complexity may increase immunogenicity and increase side effects. Amivantamab caused an infusion-related reaction in 69.0% of patients when administered for the first time. Researchers have tried to maintain antitumor efficacy and decrease side effects by optimizing the dosage forms. For example, subcutaneous amivantamab maintained efficacy and reduced administration time to improve tolerability in the PALOMA-3 study⁸⁷. In addition, the exploration of biomarkers is worthy of attention. A recent study revealed that a high level of amphiregulin (AREG) expression is related to better amivantamab activity. AREG is a potential biomarker for predicting the response to amivantamab⁸⁸.

MET × MET

REGN5093

REGN5093 inhibits the growth of MET-driven tumor cells by concurrently binding two distinct epitopes of MET. NCT04077099 is a phase 1/2 study that evaluated the efficacy of REGN5093 in patients with MET-altered advanced NSCLC. Among the 36 patients who received the 2000-mg dose, a partial response occurred in 6 patients (16.7%). Among all 44 enrolled patients, 11 (25.0%) experienced grade ≥ 3 TEAEs⁸⁹.

Although MET plays a significant role in NSCLC progression, therapies targeting MET are not satisfactory because of the lack of predictive biomarkers⁹⁰. Although the results revealed therapeutic effects and a manageable safety profile of REGN5093 in patients with MET-altered advanced NSCLC, additional clinical trials are needed.

HER2 × HER3

ERBB is a transmembrane RTK family consisting of ERBB1 (EGFR), ERBB2 (HER2), ERBB3 (HER3), and ERBB4 (HER4). Although HER3 has relatively weak tyrosine kinase activity owing to its ability to activate the signaling pathways of oncogenic EGFR and HER2, HER3 has still been linked to cancer⁹¹. Furthermore, HER3 expression is significantly associated with neuregulin-1 gene (NRG1) fusion in patients with lung cancer. NRG1 proteins, the ligands of HER3, induce HER3 to heterodimerize with HER2 to activate downstream ERBB-mediated signaling pathways. NRG1 fusions are uncommon in different kinds of cancers with an incidence of ≤ 1%, but in patients with invasive mucinous adenocarcinomas (IMAs) the incidence of NRG1 fusion is 10%–30%. Treatments targeting REBB are potential therapies for patients harboring NRG1 fusions⁹².

Zenocutuzumab/MCLA-128

Zenocutuzumab, also known as MCLA-128, is a full-length human IgG1 biclonic bsAb that concurrently targets HER2 and HER3 and inhibits HER3 signaling at supramaximal NRG1 concentrations via a special “dock and block” mechanism. The arm targeting HER2 “docks” HER2 at the surface of tumor cells to increase the HER3 Fab concentration and the arm targeting HER3 “blocks” HER3 binding to NRG1 to prevent the formation of signaling dimers and downstream oncogenic signaling⁹³. According to the results of NCT02912949, a phase 1/2 study evaluating the efficacy of zenocutuzumab in patients with solid tumors harboring an NRG1 fusion (eNRGy), zenocutuzumab showed encouraging antitumor efficacy and a well-tolerated safety profile. Among all 71 patients with measurable NRG fusions, the overall ORR was 34.0% and the ORR was 35.0% among 40 patients with NRG+ NSCLC. Among 208 patients who received zenocutuzumab monotherapy in phase 2, grade ≥ 3 adverse events occurred in < 5.0% of patients.

The prognosis of NSCLC patients with NRG1 fusion is not favorable because of the poor response to standard therapies⁹⁴. Although NRG1 is a potential therapeutic target for NSCLC patients, the development of new drugs is not satisfactory. BsAbs targeting HER2 and HER3 exhibited encouraging efficacy in patients with NRG+ NSCLC, with a 35.0% ORR. Therefore, we look forward to more promising results.

BsADCs

BsADCs are novel antitumor drugs composed of an mAb conjugated to a cytotoxic agent via a chemical linker. ADCs combine the specific targeting ability of antibodies with the potent tumor killing effect of cytotoxic drugs to achieve superior antitumor efficacy⁹⁵. BsADCs show more robust selectivity, enhanced internalization, and accelerated downstream cascades to exert greater antitumor activity and minimize toxicity compared to monospecific ADCs⁹⁶ (Figure 4D).

EGFR × HER3

BL-B01D1

BL-B01D1 is a novel EGFR × HER3 bsADC generated by attaching an EGFR × HER3 bsAb (SI-B001) to a novel inhibitor of topoisomerase Ⅰ (Ed-01) via a stable cathepsin B cleavable linker. BL-B01D1 has superior tumor inhibitory effects in xenograft models compared to parental monospecific ADCs⁹⁷. Based on results of NCT05194982, a phase 1 clinical study evaluating safety of BL-B01D1, PK and preliminary antitumor efficacy of BL-B01D1 in patients with locally advanced or metastatic solid tumors presented at the 2023 ESMO, BL-B01D1 showed encouraging antitumor efficacy and an adequate safety profile. Among 38 patients with EGFR mutant (EGFRmut) NSCLC, the ORR was 63.2% and the DCR was 89.5%. In addition, among 49 patients with EGFR wild-type (EGFRwt) NSCLC, the ORR was 44.0% and the DCR was 94.0%. The mPFS of patients with EGFRmut NSCLC and patients with EGFRwt NSCLC was 6.9 and 5.2 months, respectively. Among all 114 enrolled patients, the most common TRAEs were anemia (59.0%), leukopenia (59.0%), neutropenia (51.0%), and thrombocytopenia (48.0%)⁹⁸. These promising results in patients with NSCLC indicate that BL-B01D1 may be an effective drug for treating NSCLC.

Folate receptor alpha (FRα) × transient receptor potential vanilloid 6 (TRPV6)

CBP-1008

CBP-1008 is a novel bsADC that simultaneously targets FRα and TRPV6 and exhibits greater binding affinity to FRα than to TRPV6⁹⁹. The safety, tolerance, and PK of CBP-1008 were assessed in patients with advanced solid tumors in a phase 1a/1b study (NCT04740398). Among all 178 enrolled patients, most AEs were mild-to-moderate. The most common grade ≥ 3 TRAEs were neutropenia (n = 85), decreased leukocyte count (n = 49) and anemia (n = 10). Among 82 evaluable platinum-resistant ovarian cancer (PROC) patients, the ORR was 25.6% and the DCR was 62.2%. According to the most recent results, CBP-1008 exhibited a manageable safety profile and antitumor efficacy in PROC patients¹⁰⁰. We look forward to more clinical trials evaluating CBP-1008 in NSCLC patients because FRα and TRPV6 are highly expressed in lung cancer.

ADC is a novel and promising antitumor therapy. However, tumor heterogeneity, drug resistance, and TRAEs limit the use of ADCs. BsADCs could address the heterogeneity and resistance and maintain superior antitumor efficacy¹⁰¹. The exploration of the use of bsADCs in the treatment of NSCLC has been inadequate, and few results have been reported. Insufficient research on biomarkers has also limited the use of bsADCs.

In this section we introduce the use of bsAbs for targeted therapy in NSCLC patients. However, numerous clinical trials evaluating the use of bsAbs for targeted therapy in patients with NSCLC or other solid tumors have not published the results. The relevant clinical trials are listed in Table 4. EGFR is one of the most important targets for the targeted therapy of NSCLC. Although there are three generations of TKIs, drug resistance cannot be ignored. BsAbs targeting EGFR are potential ways to overcome drug resistance. In addition to monotherapy, combined therapy with bsAbs also exhibit promising efficacy and an acceptable safety profile. In May 2024 the combination of ivonescimab/AK112, pemetrexed, and carboplatin was first approved for patients with locally advanced or metastatic non-squamous NSCLC with EGFR mutations who progressed after TKI treatment⁵⁶. In the next section we introduce combination bsAb therapies for the treatment of NSCLC.

Combination bsAb therapies

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BsAbs + chemotherapy

SI-B001 + chemotherapy

SI-B001 is a novel EGFR × HER3 IgG-(scFv)2 bsAb that shows encouraging antitumor efficacy and a favorable safety profile when used alone or in combination with chemotherapy¹⁰². Docetaxel, a semisynthetic taxane, is one of the most important antitumor agents used in chemotherapy and can bind to β tubulin to arrest the cell cycle or induce apoptosis¹⁰³. NCT05020457 is a phase 2 study that was conducted to evaluate the safety and efficacy of SI-B001 plus chemotherapy in patients with locally advanced or metastatic EGFR wild-type ALK wild-type NSCLC. According to the results presented at the 2023 ASCO meeting, among 22 evaluable patients in Schedule 2 of Cohort B who received SI-B001 in combination with docetaxel as second-line treatment after prior first-line anti-PD-(L)1 therapy plus platinum-based chemotherapy, the ORR was 45.5%, and the DCR was 68.2%. Among the 18 of 22 patients without actionable genomic alterations (AGA), the ORR was 50.0% and the DCR was 72.2%. Among all 55 enrolled patients, the most common grade ≥ 3 TRAEs were bone marrow suppression (17.0%), neutropenia (15.0%), and leukopenia (12.0%)¹⁰⁴.

AK112 + chemotherapy

AK112 is a novel bsAb that targets PD-1 and VEGF. Researchers presented work at the 2022 ASCO meeting that supported the promising antitumor efficacy and superior safety profile of AK112 in combination with chemotherapy. NCT04736823 is a phase 2 clinical trial that evaluated the efficacy of AK112 plus chemotherapy in NSCLC patients. The patients were divided into the following 3 cohorts: untreated NSCLC patients with wild-type EGFR/ALK (cohort 1); patients with EGFR mutations who failed prior anti-EGFR treatment or osimertinib treatment (cohort 2); and patients whose disease progressed after anti-PD-(L)1 therapy and platinum-based chemotherapy (cohort 3). The ORRs (DCRs) of cohorts 1, 2, and 3 were 53.5% (100%), 68.4% (94.7%), and 40.0% (80.0%), respectively. Among all 133 enrolled patients, TRAEs occurred in 115 patients (86.5%) and grade ≥ 3 TRAEs occurred in 38 patients (28.6%; Table 5)¹⁰⁵. The latest results of a phase 3 trial (HARMONi-A) that evaluated AK112 plus chemotherapy in patients with EGFR-mutant non-squamous NSCLC were presented at the 2024 ASCO meeting. The ORR was 35.4% and the DCR was 83.2% in 161 patients who received placebo plus chemotherapy. The ORR was 50.6% and the DCR was 93.1% in 161 patients who received AK112 plus chemotherapy. TRAEs occurred in 98.1% of patients and grade ≥ 3 TRAEs occurred in 54.0% of patients. The most common TRAEs were leukopenia (65.2%), anemia (60.2%), neutropenia (60.2%), and thrombocytopenia (47.8%).

Several clinical trials, such as Impower150, are underway to evaluate the efficacy and safety of atezolizumab plus bevacizumab and chemotherapy in NSCLC patients. According to the results posted for Impower150, TRAEs were observed in 94.1% patients and grade ≥ 3 TRAEs were observed in 60.4% patients¹⁰⁶. Although grade ≥ 3 TRAEs occurred in 54.0% of patients receiving AK112 plus chemotherapy, which was lower than that patients receiving atezolizumab plus bevacizumab and chemotherapy, reducing toxicity must still be considered. The combination of AK112, pemetrexed, and carboplatin was first approved in May 2024 for patients with locally advanced or metastatic non-squamous NSCLC with EGFR mutations who had progressed after TKI treatment. However, the TRAEs cannot be ignored, with 98.1% of patients experiencing TRAEs and 54.0% with grade ≥ 3 TRAEs.

KN046 + chemotherapy

KN046 is a novel PD-L1 × CTLA-4 bsAb. NCT04054531 is a phase 2 clinical trial that was conducted to evaluate KN046 plus chemotherapy as a first-line treatment for NSCLC. Combined therapy with KN046 and platinum-based doublet chemotherapy exhibited promising antitumor activity and was tolerated according to the posted results. TRAEs occurred in 92.0% and grade ≥ 3 TRAEs occurred in 25.3% of the 87 enrolled patients. The most common grade ≥ 3 TRAEs were diarrhea (5.7%), increased ALT levels (4.6%), infusion-related reactions (3.4%), and rash (3.4%). Among 82 evaluable patients, the overall ORR was 50.6%, and the DCR was 87.7%¹⁰⁷. In addition, according to the 2-year NCT04054531 follow-up results the mOS in both cohorts was > 2 years, showing that combining KN046 and chemotherapy as first-line treatment for NSCLC patients has promising clinical benefits and is well-tolerated¹⁰⁸. NCT03838848 is a phase 2 study that was conducted to evaluate KN046 in patients with advanced NSCLC. According to the results presented at the 2023 ESMO, the ORR was 26.9%, the DCR was 80.8%, the mPFS was 5.52 months, and the mOS was 12.68 months among all 29 enrolled patients. The most common grade ≥ 3 TRAEs were infusion reaction (23.1%), decreased platelet cell count (15.4%), and anemia (11.5%; Table 5)¹⁰⁹.

Amivantamab + chemotherapy

Amivantamab was shown to have outstanding performance as a monotherapy and encouraging performance as a combination therapy. NCT04538664 is a phase 3 study that assesses amivantamab plus chemotherapy in patients with locally advanced or metastatic NSCLC and EGFR exon 20 insertion mutations. According to the results presented at 2023 ESMO, the ORR was 73.0%, the DoR was 13.5 months, and the mPFS was 12.9 months among 153 patients receiving amivantamab plus chemotherapy. In contrast, the ORR was 43.0%, the DoR was 6.8 months, and the mPFS was 6.9 months in patients who received chemotherapy. TRAEs occurred in all patients and grade ≥ 3 TRAEs occurred in 75.0% of the patients. The most common TRAEs were neutropenia, paronychia, rash, anemia, and infusion-related reactions¹¹⁰. NCT04988295 is a phase 3 clinical trial evaluating amivantamab as a combined therapy in patients with locally advanced or metastatic NSCLC with the EGFR exon 19del or exon 21 L858R substitution after failing osimertinib therapy. According to the results posted by the 2023 ESMO, the ORR was 64.0% and the mPFS was 6.3 months among 131 patients receiving amivantamab plus chemotherapy. In contrast, the ORR was 36.0% and the mPFS was 4.2 months in patients receiving chemotherapy. TRAEs occurred in all patients and grade ≥ 3 TRAEs occurred in 72.0% of patients¹¹¹. Notably, amivantamab plus chemotherapy achieved robust antitumor efficacy with a relatively high incidence of TRAEs.

SHR-1701 + chemotherapy

According to the results of NCT04580498 presented at the 2024 ASCO meeting, SHR-1701 plus chemotherapy has shown promising potential as a neoadjuvant therapy for NSCLC patients. The ORR was 58.0% among 97 patients who received SHR-1701 plus chemotherapy as neoadjuvant therapy. TRAEs occurred in 97.0% of patients and grade ≥ 3 TRAEs occurred in 73.0% of patients. The most common TRAEs were leukopenia (77.0%), anemia (70.0%), neutropenia (70.0%), and thrombocytopenia (53.0%).

BsAbs + targeted therapy

AK104 + anlotinib

Anlotinib is a novel TKI that targets multiple RTKs and inhibits the proliferation and angiogenesis of tumors¹¹². AK104 (a PD-1 × CTLA-4 bsAb) and anlotinib combination therapy was evaluated in patients with NSCLC in a phase 1b/2 study (NCT04646330). This combination therapy showed promising antitumor efficacy and an acceptable safety profile. Among all 18 enrolled NSCLC patients with PD-L1 TPSs ≥ 1.0%, grade 3 TRAEs occurred in 1 patient (6.0%) and no grade 4 or 5 TRAEs were observed. The ORR was 62.5% and the DCR was 100% among the 8 evaluable patients. Notably, the ORR was 80.0% among 5 evaluable patients with non-squamous NSCLC¹¹³.

Amivantamab + lazertinib

Lazertinib is a novel third-generation TKI that was approved for the treatment of NSCLC in January 2021¹¹⁴. NCT02609776 is a phase 1 study that evaluated the safety, PK, and preliminary antitumor efficacy of amivantamab as monotherapy and in combination with lazertinib in patients with advanced NSCLC. According to the results presented at the 2021 ASCO meeting, ORR was 36.0% among 45 chemotherapy-naïve NSCLC patients who relapsed with osimertinib¹¹⁵. NCT04487080 is a phase 3 study that evaluated amivantamab plus lazetinib in patients with locally advanced or metastatic NSCLC. The latest results were presented at the 2023 ESMO. The ORR was 86.0% and the mPFS was 23.7 months among the 429 patients who received amivantamab plus lazetinib. TRAEs occurred in all patients and grade ≥ 3 TRAEs occurred in 75.0% of the patients. The most recent results from CHRYSALIS-2 were presented at the 2024 ASCO meeting. The ORR was 52.0% and the mPFS was 11.1 months among 105 atypical EGFR-mutated advanced NSCLC patients (Table 5).

Amivantamab + osimertinib

Osimertinib is an approved third-generation TKI that targets EGFR in NSCLC patients with acquired EGFR T790M resistance mutations¹¹⁶. NCT05801029 is a phase 2 study that was conducted to assess the efficacy and safety of amivantamab plus osimertinib as a first-line treatment in patients with EGFR mutations or locally advanced or metastatic NSCLC. This clinical trial was initiated on 18 July 2023 and we look forward to seeing the results.

BsAbs + immunotherapy

REGN7075 + cemiplimab

REGN7075 is a costimulatory bsAb that simultaneously targets EGFR and CD28. Cemiplimab is a monoclonal antibody against PD-1. Combination therapy with REGN7075 and cemiplimab is being evaluated in a phase 1/2 clinical trial (NCT04626635) in patients with advanced solid tumors. According to preliminary results for a dose-escalation cohort (up to 30 mg of REGN7075), TRAEs occurred in 14 (78.0%) patients and no grade ≥ 3 TRAEs were observed among all 18 enrolled patients. The most common TRAEs were fatigue (17.0%), increased AST levels (11.0%), diarrhea (11.0%), hypothyroidism (11.0%), pyrexia (11.0%), and maculopapular rash (11.0%)¹¹⁷. The antitumor efficacy has not been assessed due to the inadequate number of patients.

In this section we introduce combination therapies involving bsAbs and other therapies (chemotherapy, targeted therapy, and immunotherapy). The combination of bsAbs and chemotherapy is the most frequently used combination therapy. However, the results of clinical trials exploring the combination of bsAbs and radiotherapy (RT) are inadequate. Combination therapy has shown improved antitumor efficacy compared to monotherapy with bsAbs. However, the TRAEs also significantly increased.

Challenges and future prospects

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Although bsAbs have exhibited superior antitumor efficacy and safety profiles compared to two mAb combination therapies, several challenges remain. We propose several methods to overcome these challenges.

Increased side effects caused by “on-target off-tumor” toxicity

Some solid tumor TAAs, which are also expressed in normal cells, may cause “on-target off-tumor” toxicity and increase side effects^118,119. With advances in our understanding of tumor and immune cells, an increasing number of new targeting molecules, such as receptor tyrosine kinase-like orphan receptor (ROR1) and Notch signaling pathway members, have been discovered or used to generate novel bsAb forms for NSCLC treatment^120,121. We expect more effective targets for the development of bsAbs to be discovered in the future. In addition to finding more effective targets that are abundantly expressed on tumor cells but scarcely expressed on normal cells, a novel “masking technology” is also a promising approach to alleviate toxicity through use of antibodies to reduce side effects in normal cells^122–124. For example, bsAbs with XTEN masks that can be released by proteases within the TME can achieve more precise activation of bsAbs in tumors and reduce the effects on normal cells¹²⁵. In addition, several drugs based on masking technology, such as CX-904, JANX008, TAK-186, and TAK-280, are being evaluated in phase 1 clinical trials (NCT05387265, NCT05783622, NCT04844073, and NCT05220098, respectively).

Insufficient infiltration of TILs and the immunosuppressive microenvironment limit bsAb efficacy

Insufficient infiltration of TILs in the TME and local immunosuppressive microenvironment may limit the efficacy of bsAbs^118,119. RT has the potential to transform immune cell insufficient-infiltrating (immune-cold) tumors into immune cell sufficient-infiltrating (immune-hot) tumors. A recent study of pancreatic ductal adenocarcinoma showed that the use of a bsAb in combination with RT had greater antitumor effects compared to monotherapy¹²⁶. In murine models with Lewis lung carcinoma lacking sufficient TILs, which respond poorly to anti-PD-(L)1 treatment, BA plus RT induced more significant tumor inhibition than BA or RT monotherapy did and prolonged survival¹²⁷. Unfortunately, combination therapies involving bsAbs and RT for NSCLC treatment have not been thoroughly investigated. We encourage an increasing number of researchers to pay more attention to these types of combination strategies. Therefore, the combination with RT may be a promising therapy for patients with insufficient immune cell infiltration in the future. In addition, combining bsAbs with anti-PD-(L)1 ICIs can reverse the locally immunosuppressive environment to achieve better outcomes¹¹⁹.

Increased TRAEs caused by increased immunogenicity

Although bsAbs can enhance antitumor effects by simultaneously binding two targets, both monotherapy and combination therapy cause increased toxicity. One of the main reasons is that the bsAb structure may increase immunogenicity. Neoantigens or the exposure of cryptic epitopes, a dysregulated immune system caused by anti-drug antibodies (ADAs) and the complexity of the bsAb structure could increase immunogenicity, which may trigger more TRAEs¹²⁸. To address this question, optimizing the dosage forms and exploring the best route for administration are necessary. For example, infusion-related reactions (IRRs) were observed in patients who received amivantamab. Subcutaneous amivantamab can maintain efficacy and improve tolerability, with only 13.0% IRRs⁸⁷. In addition, developing a reliable immunogenicity risk assessment system to guide the selection of bsAbs and formats in the clinic is necessary.

Explorations of biomarkers are insufficient

Inadequate research on biomarkers has hindered the selection of beneficial populations. In this review the exploration of the mentioned bsAb biomarkers was introduced, but the relevant studies were in the initial stage. The complexity of intratumoral heterogeneity was one of the determining factors for the patient response to bsAbs¹²⁹. The development of spatial multiomics could help us to describe the TME more thoroughly and find predictive biomarkers of bsAbs. In addition, the levels of EGFR ligand expression correlated with the response to amivantamab, suggesting that monitoring the ligand expression levels of targets in peripheral blood could also help us identify biomarkers of bsAbs. We call for more research on prognostic biomarkers of bsAbs, which can promote the development of precision oncology.

Resistance to bsAbs failed to receive due attention

Although bsAbs have shown superior antitumor efficacy, drug resistance is still an unavoidable problem¹³⁰. The stimulation of bsAbs may aggravate the exhaustion of T cells, which may lead to drug resistance to bsAbs¹³¹. In addition, the local immunosuppressive microenvironment is also an important reason for bsAb resistance¹³². There are several studies involving the mechanisms of drug resistance to bsAbs in hematologic malignancies. Owing to the lack of long-term follow-up data, relevant studies on NSCLC treatment are rare. More evidence from evidence-based medicine and relevant clinical trials is needed for further studies about bsAb resistance in NSCLC patients. Recently, the development of trispecific antibodies (tsAbs) has experienced rapid growth. tsAbs may be able to alleviate drug resistance to bsAbs.

More evidence-based medical evidence is needed to verify the superiority of bsAbs

Although combination therapies of two mAbs can enhance antitumor efficacy, the increased toxicity limits the use of combination toxicity. BsAbs are among the most promising novel antitumor therapies for the treatment of NSCLC and are expected to improve antitumor efficacy and reduce toxicity. For example, compared with the combination of nivolumab (anti-PD-1) and ipilimumab (anti-CTLA), the incidence of grade ≥ 3 TRAEs was clearly lower in patients receiving AK104 (11.3% vs. 34.0%). In patients receiving AK112 plus chemotherapy, grade ≥ 3 TRAEs occurred in 54.0% of patients, which was lower than patients receiving atezolizumab (anti-PD-L) plus bevacizumab (anti-VEGF) and chemotherapy (60.4%)¹⁰⁶. However, there are no clinical trials comparing the use of bsAbs with the combination of two matching drugs. More clinical trials and adequate mature data are needed to verify the superiority of the use of bsAbs over the combination of two drugs. The follow-up data and in-depth analysis of novel drugs are insufficient. The precise clinical and biological observations of the therapeutic benefits and adverse effects of bsAbs are expected to be popular research topics in the coming years.

Conclusions

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With the development of immunotherapies for the treatment of NSCLC, the survival of patients with NSCLC has increased significantly. Unfortunately, only a few patients respond to treatment and many of these patients rapidly develop acquired resistance. BsAbs are promising therapies that may overcome acquired resistance and improve the therapeutic outcomes of NSCLC patients. In this review the application of bsAbs in the treatment of NSCLC was introduced and the related challenges, corresponding solutions, and future prospects were discussed. Although the use of bsAbs in solid tumors is limited compared to hematologic malignancies and only one bsAb has been approved for the treatment of NSCLC, the results from numerous clinical trials have shown that bsAbs may be a promising first- or later-line treatment for NSCLC patients. For many reasons, the research and development of bsAbs for solid tumors remain limited. BsAb, RT, and tsAb combined therapies are not thoroughly studied and merit more attention. We are confident that the use of bsAbs will change the treatment of NSCLC going forward.

Funding

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This work was supported by the National Natural Science Foundation of China (Grant No. 82272845) and the Natural Science Foundation of Shandong (Grant No. ZR2023LZL001).

References

Less

Wang M,Herbst RS,Boshoff C.Toward personalized treatment approaches for non-small-cell lung cancer.Nat Med. 2021; 27: 1345–56.

Li H,Er Saw P,Song E.Challenges and strategies for next-generation bispecific antibody-based antitumor therapeutics.Cell Mol Immunol. 2020; 17: 451–61.

Syed YY.Amivantamab: first approval.Drugs. 2021; 81: 1349–53.

Khosla AA,Jatwani K,Singh R,Reddy A,Jaiyesimi I,Desai A.Bispecific antibodies in lung cancer: a state-of-the-art review.Pharmaceuticals (Basel). 2023; 16: 1461.

Köhler G,Milstein C.Continuous cultures of fused cells secreting antibody of predefined specificity.Nature. 1975; 256: 495–7.

Brinkmann U,Kontermann RE.The making of bispecific antibodies.MAbs. 2017; 9: 182–212.

Brennan M,Davison PF,Paulus H.Preparation of bispecific antibodies by chemical recombination of monoclonal immunoglobulin G1 fragments.Science. 1985; 229: 81–3.

Szijj P,Chudasama V.The renaissance of chemically generated bispecific antibodies.Nat Rev Chem. 2021; 5: 78–92.

Sanz L,Blanco B,Alvarez-Vallina L.Antibodies and gene therapy: teaching old ‘magic bullets’ new tricks.Trends Immunol. 2004; 25: 85–91.

10.

Arlotta KJ,Owen SC.Antibody and antibody derivatives as cancer therapeutics.Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2019; 11: e1556.

11.

Tiller KE,Tessier PM.Advances in antibody design.Annu Rev Biomed Eng. 2015; 17: 191–216.

12.

Suurs FV,Lub-de Hooge MN,de Vries EGE,de Groot DJA.A review of bispecific antibodies and antibody constructs in oncology and clinical challenges.Pharmacol Ther. 2019; 201: 103–19.

13.

Garber K.Bispecific antibodies rise again.Nat Rev Drug Discov. 2014; 13: 799–801.

14.

Herrera M,Pretelli G,Desai J,Garralda E,Siu LL,Steiner TM, et al.Bispecific antibodies: advancing precision oncology.Trends Cancer. 2024; 10: 893–919.

15.

Ayyar BV,Arora S,O’Kennedy R.Coming-of-age of antibodies in cancer therapeutics.Trends Pharmacol Sci. 2016; 37: 1009–28.

16.

Kang J,Sun T,Zhang Y.Immunotherapeutic progress and application of bispecific antibody in cancer.Front Immunol. 2022; 13: 1020003.

17.

Robert C.A decade of immune-checkpoint inhibitors in cancer therapy.Nat Commun. 2020; 11: 3801.

18.

Ribas A,Wolchok JD.Cancer immunotherapy using checkpoint blockade.Science. 2018; 359: 1350–5.

19.

Li L,Li G,Rao B,Dong AH,Liang W,Zhu JX, et al.Landscape of immune checkpoint inhibitor-related adverse events in Chinese population.Sci Rep. 2020; 10: 15567.

20.

Rothlin CV,Ghosh S.Lifting the innate immune barriers to antitumor immunity.J Immunother Cancer. 2020; 8: e000695.

21.

D’Errico G,Machado HL,Sainz B Jr.A current perspective on cancer immune therapy: step-by-step approach to constructing the magic bullet.Clin Transl Med. 2017; 6: 3.

22.

Keating GM.Nivolumab: a review in advanced nonsquamous non-small cell lung cancer.Drugs. 2016; 76: 969–78.

23.

Zhang T,Lin Y,Gao Q.Bispecific antibodies targeting immunomodulatory checkpoints for cancer therapy.Cancer Biol Med. 2023; 20: 181–95.

24.

Rohatgi A,Kirkwood JM.Beyond PD-1: the next frontier for immunotherapy in melanoma.Front Oncol. 2021; 11.

25.

Pardoll DM.The blockade of immune checkpoints in cancer immunotherapy.Nat Rev Cancer. 2012; 12: 252–64.

26.

Konishi J,Yamazaki K,Azuma M,Kinoshita I,Dosaka-Akita H,Nishimura M.B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression.Clin Cancer Res. 2004; 10: 5094–100.

27.

Wei SC,Duffy CR,Allison JP.Fundamental mechanisms of immune checkpoint blockade therapy.Cancer Discov. 2018; 8: 1069–86.

28.

Vasilevko V,Ghochikyan A,Holterman MJ,Agadjanyan MG.CD80 (B7-1) and CD86 (B7-2) are functionally equivalent in the initiation and maintenance of CD4+ T-cell proliferation after activation with suboptimal doses of PHA.DNA Cell Biol. 2002; 21: 137–49.

29.

Linsley PS,Greene JL,Brady W,Bajorath J,Ledbetter JA,Peach R.Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors.Immunity. 1994; 1: 793–801.

30.

Burton EM,Tawbi HA.Bispecific antibodies to PD-1 and CTLA4: doubling down on T cells to decouple efficacy from toxicity.Cancer Discov. 2021; 11: 1008–10.

31.

Zhou C,Xiong A,Fang J,Li X,Fan Y,Zhuang W, et al.1022P: A phase II study of KN046 (a bispecific anti-PD-L1/CTLA-4) in patients with metastatic non-small cell lung cancer (NSCLC) who failed first line treatment.Ann Oncol. 2022; 33: S1022.

32.

Huang Z,Pang X,Zhong T,Chen N,He X,Xia D, et al.289: Cadonilimab, an anti-PD1/CTLA4 bi-specific antibody with Fc effector null backbone.J Immunother Cancer. 2021; 9: A313–4.

33.

Pang X,Huang Z,Zhong T,Zhang P,Wang ZM,Xia M, et al.Cadonilimab, a tetravalent PD-1/CTLA-4 bispecific antibody with trans-binding and enhanced target binding avidity.MAbs. 2023; 15: 2180794.

34.

Zhao Y,Ma Y,Fan Y,Zhou J,Yang N,Yu Q, et al.A multicenter, open-label phase Ib/II study of cadonilimab (anti PD-1 and CTLA-4 bispecific antibody) monotherapy in previously treated advanced non-small-cell lung cancer (AK104-202 study).Lung Cancer. 2023; 184: 107355.

35.

Keam SJ.Cadonilimab: first approval.Drugs. 2022; 82: 1333–9.

36.

Paz-Ares LG,Ciuleanu TE,Pluzanski A,Lee JS,Gainor JF,Otterson GA, et al.Safety of first-line nivolumab plus ipilimumab in patients with metastatic NSCLC: a pooled analysis of CheckMate 227, CheckMate 568, and CheckMate 817.J Thorac Oncol. 2023; 18: 79–92.

37.

Wang J,Li X,Xiao G,Desai J,Frentzas S,Wang ZM, et al.CD74 is associated with inflamed tumor immune microenvironment and predicts responsiveness to PD-1/CTLA-4 bispecific antibody in patients with solid tumors.Cancer Immunol Immunother. 2024; 73: 36.

38.

Ma Y,Xue J,Zhao Y,Zhang Y,Huang Y,Yang Y, et al.Phase I trial of KN046, a novel bispecific antibody targeting PD-L1 and CTLA-4 in patients with advanced solid tumors.J Immunother Cancer. 2023; 11: e006654.

39.

Wolf Y,Anderson AC,Kuchroo VK.TIM3 comes of age as an inhibitory receptor.Nat Rev Immunol. 2020; 20: 173–85.

40.

Ngiow SF,von Scheidt B,Akiba H,Yagita H,Teng MW,Smyth MJ.Anti-TIM3 antibody promotes T cell IFN-γ-mediated antitumor immunity and suppresses established tumors.Cancer Res. 2011; 71: 3540–51.

41.

Romero D.Immunotherapy: PD-1 says goodbye, TIM-3 says hello.Nat Rev Clin Oncol. 2016; 13: 202–3.

42.

Besse B,Italiano A,Cousin S,Ruiter G,Felip E,Castanon Alvarez E, et al.1313MO: Safety and preliminary efficacy of AZD7789, a bispecific antibody targeting PD-1 and TIM-3, in patients (pts) with stage IIIB–IV non-small-cell lung cancer (NSCLC) with previous anti-PD-(L)1 therapy.Ann Oncol. 2023; 34: S755.

43.

Natoli M,Hatje K,Gulati P,Junker F,Herzig P,Jiang Z, et al.Deciphering molecular and cellular ex vivo responses to bispecific antibodies PD1-TIM3 and PD1-LAG3 in human tumors.J Immunother Cancer. 2022; 10: e005548.

44.

Datar I,Sanmamed MF,Wang J,Henick BS,Choi J,Badri T, et al.Expression analysis and significance of PD-1, LAG-3, and TIM-3 in human non-small cell lung cancer using spatially resolved and multiparametric single-cell analysis.Clin Cancer Res. 2019; 25: 4663–73.

45.

Ma C,Sun X,Shen D,Sun Y,Guan N,Qi C.Ectopic expression of LAG-3 in non-small-cell lung cancer cells and its clinical significance.J Clin Lab Anal. 2020; 34: e23244.

46.

He Y,Yu H,Rozeboom L,Rivard CJ,Ellison K,Dziadziuszko R, et al.LAG-3: Protein expression in non-small cell lung cancer and its relationship with PD-1/PD-L1 and tumor-infiltrating lymphocytes.J Thorac Oncol. 2017; 12: 814–23.

47.

Nguyen LT,Ohashi PS.Clinical blockade of PD1 and LAG3 – potential mechanisms of action.Nat Rev Immunol. 2015; 15: 45–56.

48.

LaMotte-Mohs R,Shah K,Smith D,Gorlatov S,Ciccarone V,Tamura J, et al.Abstract 3217: MGD013, a bispecific PD-1 × LAG-3 dual-affinity re-targeting (DART^®) protein with T-cell immunomodulatory activity for cancer treatment.Cancer Res. 2016; 76: 3217.

49.

Wang J,Asch AS,Hamad N,Weickhardt A,Tomaszewska-Kiecana M,Dlugosz-Danecka M, et al.A phase 1, open-label study of MGD013, a bispecific DART^® molecule binding PD-1 and LAG-3 in patients with relapsed or refractory diffuse large B-cell lymphoma.Blood. 2020; 136: 21–2.

50.

Sumrow B.A phase 1, first-in-human, open-label, dose escalation study of MGD013, a bispecific DART^® molecule binding PD-1 and LAG-3 in patients with unresectable or metastatic neoplasms.J Clin Oncol. 2020; 38: 3004.

51.

Luke JJ,Patel MR,Blumenschein GR,Hamilton E,Chmielowski B,Ulahannan SV, et al.The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: a phase 1 trial.Nat Med. 2023; 29: 2814–24.

52.

Sung E,Ko M,Won JY,Jo Y,Park E,Kim H, et al.LAG-3xPD-L1 bispecific antibody potentiates antitumor responses of T cells through dendritic cell activation.Mol Ther. 2022; 30: 2800–16.

53.

Apte RS,Chen DS,Ferrara N.VEGF in signaling and disease: beyond discovery and development.Cell. 2019; 176: 1248–64.

54.

Zhong T,Huang Z,Pang X,Jin C,He X,Xia Y.521 AK112, a tetravalent bispecific antibody targeting PD-1 and VEGF, enhances binding avidity and functional activities and elicits potent anti-tumor efficacy in pre-clinical studies.J Immunother Cancer. 2022; 10: A1–603.

55.

Guo Y,Guo J,Cheng Y,Wang Z,Li Y,Lv D, et al.Phase Ib/IIa safety and efficacy of PM8002, a bispecific antibody targeting PD-L1 and VEGF-A, as a monotherapy in patients with advanced solid tumors.J Clin Oncol. 2023; 41: 2536.

56.

Dhillon S.Ivonescimab: first approval.Drugs. 2024; 84: 1135–42.

57.

Peng D,Fu M,Wang M,Wei Y,Wei X.Targeting TGF-β signal transduction for fibrosis and cancer therapy.Mol Cancer. 2022; 21: 104.

58.

Shi X,Yang J,Deng S,Xu H,Wu D,Zeng Q, et al.TGF-β signaling in the tumor metabolic microenvironment and targeted therapies.J Hematol Oncol. 2022; 15: 135.

59.

Wang L-N,Zhang Z-T,Wang L,Wei H-X,Zhang T,Zhang L-M, et al.TGF-β1/SH2B3 axis regulates anoikis resistance and EMT of lung cancer cells by modulating JAK2/STAT3 and SHP2/Grb2 signaling pathways.Cell Death Dis. 2022; 13: 472.

60.

Gulley JL,Schlom J,Barcellos-Hoff MH,Wang XJ,Seoane J,Audhuy F, et al.Dual inhibition of TGF-β and PD-L1: a novel approach to cancer treatment.Mol Oncol. 2022; 16: 2117–34.

61.

Lan Y,Yeung TL,Huang H,Wegener AA,Saha S,Toister-Achituv M, et al.Colocalized targeting of TGF-β and PD-L1 by bintrafusp alfa elicits distinct antitumor responses.J Immunother Cancer. 2022; 10: e004122.

62.

Paz-Ares L,Kim TM,Vicente D,Felip E,Lee DH,Lee KH, et al.Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in second-line treatment of patients with NSCLC: results from an expansion cohort of a phase 1 trial.J Thorac Oncol. 2020; 15: 1210–22.

63.

Barlesi F,Isambert N,Felip E,Cho BC,Lee DH,Peguero J, et al.Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with non-small cell lung cancer resistant or refractory to immune checkpoint inhibitors.Oncologist. 2023; 28: 258–67.

64.

Cho BC,Lee JS,Wu YL,Cicin I,Dols MC,Ahn MJ, et al.Bintrafusp alfa versus pembrolizumab in patients with treatment-naive, programmed death-ligand 1-high advanced NSCLC: a randomized, open-label, phase 3 trial.J Thorac Oncol. 2023; 18: 1731–42.

65.

Li T,Wang X,Niu M,Wang M,Zhou J,Wu K, et al.Bispecific antibody targeting TGF-β and PD-L1 for synergistic cancer immunotherapy.Front Immunol. 2023; 14: 1196970.

66.

Zhou Q,Pan Y,Yang X,Zhao Y,Han G,Pang Q, et al.Neoadjuvant SHR-1701 with or without chemotherapy in unresectable stage III non-small-cell lung cancer: a proof-of-concept, phase 2 trial.Cancer Cell. 2024; 42: 1258–67.e2.

67.

Dagher OK,Schwab RD,Brookens SK,Posey AD Jr.Advances in cancer immunotherapies.Cell. 2023; 186: 1814.e1.

68.

Tian Z,Liu M,Zhang Y,Wang X.Bispecific T cell engagers: an emerging therapy for management of hematologic malignancies.J Hematol Oncol. 2021; 14: 75.

69.

Offner S,Hofmeister R,Romaniuk A,Kufer P,Baeuerle PA.Induction of regular cytolytic T cell synapses by bispecific single-chain antibody constructs on MHC class I-negative tumor cells.Mol Immunol. 2006; 43: 763–71.

70.

Gu C,Zhu HX,Deng L,Meng XQ,Li K,Xu W, et al.Bispecific antibody simultaneously targeting PD1 and HER2 inhibits tumor growth via direct tumor cell killing in combination with PD1/PDL1 blockade and HER2 inhibition.Acta Pharmacol Sin. 2022; 43: 672–80.

71.

Lameris R,de Bruin RC,Schneiders FL,van Bergen en Henegouwen PM,Verheul HM,de Gruijl TD, et al.Bispecific antibody platforms for cancer immunotherapy.Crit Rev Oncol Hematol. 2014; 92: 153–65.

72.

Pak MG,Shin DH,Lee CH,Lee MK.Significance of EpCAM and TROP2 expression in non-small cell lung cancer.World J Surg Oncol. 2012; 10: 53.

73.

Wang C,Chen S,Wu Y,Wu D,Wang J,Li F.The combination therapy with EpCAM/CD3 BsAb and MUC-1/CD3 BsAb elicited antitumor immunity by T-cell adoptive immunotherapy in lung cancer.Int J Med Sci. 2021; 18: 3380–8.

74.

Münz M,Kieu C,Mack B,Schmitt B,Zeidler R,Gires O.The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation.Oncogene. 2004; 23: 5748–58.

75.

Seimetz D,Lindhofer H,Bokemeyer C.Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM×anti-CD3) as a targeted cancer immunotherapy.Cancer Treat Rev. 2010; 36: 458–67.

76.

Went P,Vasei M,Bubendorf L,Terracciano L,Tornillo L,Riede U, et al.Frequent high-level expression of the immunotherapeutic target Ep-CAM in colon, stomach, prostate and lung cancers.Br J Cancer. 2006; 94: 128–35.

77.

Sebastian M,Passlick B,Friccius-Quecke H,Jäger M,Lindhofer H,Kanniess F, et al.Treatment of non-small cell lung cancer patients with the trifunctional monoclonal antibody catumaxomab (anti-EpCAM × anti-CD3): a phase I study.Cancer Immunol Immunother. 2007; 56: 1637–44.

78.

Bacac M,Klein C,Umana P.CEA TCB: a novel head-to-tail 2:1 T cell bispecific antibody for treatment of CEA-positive solid tumors.OncoImmunology. 2016; 5: e1203498.

79.

Bacac M,Fauti T,Sam J,Colombetti S,Weinzierl T,Ouaret D,Bodmer W, et al.A novel carcinoembryonic antigen T-cell bispecific antibody (CEA TCB) for the treatment of solid tumors.Clin Cancer Res. 2016; 22: 3286–97.

80.

Montor WR,Salas AROSE,de Melo FHM.Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitors.Mol Cancer. 2018; 17: 55.

81.

Garon EB,Brodrick P.Targeted therapy approaches for MET abnormalities in non-small cell lung cancer.Drugs. 2021; 81: 547–54.

82.

Park K,John T,Kim S-W,Lee JS,Shu CA,Kim D-W, et al.Amivantamab (JNJ-61186372), an anti-EGFR-MET bispecific antibody, in patients with EGFR exon 20 insertion (exon20ins)-mutated non-small cell lung cancer (NSCLC).J Clin Oncol. 2020; 38: 9512.

83.

Krebs M, et al.Amivantamab in patients with NSCLC with MET exon 14 skipping mutation: updated results from the CHRYSALIS study.J Clin Oncol. 2022; 40: 9008.

84.

de Gorter DJ,Deshiere A,van Rosmalen M,Wohn C,Eppink B,Gallenne T, et al.Abstract 952: The bispecific antibody MCLA-129 impairs NSCLC tumor growth by targeting EGFR and c-MET, inhibiting ligand-induced signaling and promoting ADCC and ADCP.Cancer Res. 2021; 81: 952.

85.

Ou SH,Moreno Garcia V,Gil Bazo I,Prenen H,Moreno I,Johnson M,Castañón Álvarez E, et al.MCLA-129, a human anti-EGFR and anti-c-MET bispecific antibody, in patients with advanced NSCLC and other solid tumors: an ongoing phase 1/2 study.Eur J Cancer. 2022; 174: S122.

86.

EGFR-Mutant NSCLC: spotlight on amivantamab.Cancer Discov. 2023; 13: OF9.

87.

Leighl NB,Akamatsu H,Lim SM,Cheng Y,Minchom AR,Marmarelis ME, et al.Subcutaneous versus intravenous amivantamab, both in combination with lazertinib, in refractory epidermal growth factor receptor-mutated non-small cell lung cancer: primary results from the phase III PALOMA-3 study.J Clin Oncol. 2024; 42: 3593–605.

88.

Rivera-Soto R,Henley B,Pulgar MA,Lehman SL,Gupta H,Perez-Vale KZ, et al.Amivantamab efficacy in wild-type EGFR NSCLC tumors correlates with levels of ligand expression.NPJ Precis Oncol. 2024; 8: 192.

89.

Cho BC,Ahn M-J,Kim TM,Kim C,Shim BY,Han J-Y, et al.1173P: Early safety, tolerability, and efficacy of REGN5093 in patients (pts) with MET-altered advanced non-small cell lung cancer (aNSCLC) from a first in human (FIH) study.Ann Oncol. 2022; 33: S1085.

90.

Wang K,Hsu R.Anti-MET antibody therapies in non-small-cell lung cancer: current progress and future directions.Antibodies. 2024; 13: 88.

91.

Arteaga CL,Engelman JA.ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics.Cancer Cell. 2014; 25: 282–303.

92.

Laskin J,Liu SV,Tolba K,Heining C,Schlenk RF,Cheema P, et al.NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents.Ann Oncol. 2020; 31: 1693–703.

93.

Geuijen CAW,De Nardis C,Maussang D,Rovers E,Gallenne T,Hendriks LJA, et al.Unbiased combinatorial screening identifies a bispecific IgG1 that potently inhibits HER3 signaling via HER2-guided ligand blockade.Cancer Cell. 2018; 33: 922–36.e10.

94.

Gupta B,Gosa Barrett L,Liu SV.NRG1 fusions in NSCLC: being eNRGy conscious.Lung Cancer (Auckl). 2024; 15: 143–8.

95.

Fu Z,Li S,Han S,Shi C,Zhang Y.Antibody drug conjugate: the “biological missile” for targeted cancer therapy.Signal Transduct Target Ther. 2022; 7: 93.

96.

Theocharopoulos C,Lialios P-P,Samarkos M,Gogas H,Ziogas DC.Antibody-drug conjugates: functional principles and applications in oncology and beyond.Vaccines. 2021; 9: 1111.

97.

Wan W,Zhao S,Zhuo S,Zhang Y,Chen L,Li G, et al.Abstract 2642: BL-B01D1, a novel EGFR×HER3-targeting ADC, demonstrates robust anti-tumor efficacy in preclinical evaluation.Cancer Res. 2023; 83: 2642.

98.

Zhang L,Ma Y,Zhao Y,Fang WF Zhao H,Huang Y, et al.1316MO: BL-B01D1, a first-in-class EGFRxHER3 bispecific antibody-drug conjugate, in patients with non-small cell lung cancer: updated results from first-in-human phase I study.Ann Oncol. 2023; 34: S758.

99.

Tan W,Wang W,Bu T,Liu X,Teng Y,Huang B.Abstract 1819: CBP-1008 shows excellent efficacy and desirable drug safety profile in preclinical models.Cancer Res. 2022; 82: 1819.

100.

Gong J,Zhang J,Li N,Shen L,Wu L,Zhang Y, et al.First-in-human, phase I study of CBP-1008, a bi-specific ligand drug conjugate, in patients with advanced solid tumors.J Clin Oncol. 2023; 41: 5577.

101.

Tsuchikama K,Anami Y,Ha SYY,Yamazaki CM.Exploring the next generation of antibody-drug conjugates.Nat Rev Clin Oncol. 2024; 21: 203–23.

102.

Renshaw B,Khalili JS,Xiao S,Zhu Y.Abstract 6309: Anti-tumor efficacy of SI-B001, a novel EGFR × HER3 bispecific antibody, against EGFR-driven epithelial tumors alone or in combination with paclitaxel and carboplatin.Cancer Res. 2023; 83: 6309.

103.

Montero A,Fossella F,Hortobagyi G,Valero V.Docetaxel for treatment of solid tumours: a systematic review of clinical data.Lancet Oncol. 2005; 6: 229–39.

104.

Zhao Y,Zhang L,Fang W,Yang Y,Huang Y,Zou W, et al.SI-B001 plus chemotherapy in patients with locally advanced or metastatic EGFR/ALK wild-type non-small cell lung cancer: a phase II, multicenter, open-label study.J Clin Oncol. 2023; 41: 9025.

105.

Zhao Y,Fang W,Yang Y,Chen J,Zhuang L,Du Y, et al.A phase II study of AK112 (PD-1/VEGF bispecific) in combination with chemotherapy in patients with advanced non-small cell lung cancer.J Clin Oncol. 2022; 40: 9019.

106.

Socinski MA,Nishio M,Jotte RM,Cappuzzo F,Orlandi F,Stroyakovskiy D, et al.IMpower150 final overall survival analyses for atezolizumab plus bevacizumab and chemotherapy in first-line metastatic nonsquamous NSCLC.J Thorac Oncol. 2021; 16: 1909–24.

107.

Yang Y,Fang W,Huang Y,Li X,Huang S,Wu J, et al.A phase 2, open-label, multicenter study to evaluate the efficacy, safety, and tolerability of KN046 in combination with chemotherapy in subjects with advanced non-small cell lung cancer.J Clin Oncol. 2021; 39: 9060.

108.

Zhao Y,Chen G,Li X,Wu J,Chang B,Hu S, et al.1029P: Two-year follow-up from KN046 in combination with platinum doublet chemotherapy as first-line (1L) treatment for NSCLC: an open-label, multi-center phase II trial.Ann Oncol. 2022; 33: S1025–6.

109.

Zhou C,Xiong A,Fang J,Li X,Xie Q,Yu Q, et al.1034P: A phase II study of KN046 (a bispecific anti-PD-L1/CTLA-4) in patients with metastatic non-small cell lung cancer (NSCLC) who failed prior EFGR-TKIs.Ann Oncol. 2022; 33: S1028.

110.

Girard N,Park K,Tang K,Cho BC,Paz-Ares L,Cheng S, et al.LBA5: Amivantamab plus chemotherapy vs chemotherapy as first-line treatment in EGFR exon 20 insertion-mutated advanced non-small cell lung cancer (NSCLC): primary results from PAPILLON, a randomized phase III global study.Ann Oncol. 2023; 34: S1304.

111.

Passaro A,Cho BC,Wang Y,Melosky B,Califano R,Lee S-H, et al.LBA15: Amivantamab plus chemotherapy (with or without lazertinib) vs chemotherapy in EGFR-mutated advanced NSCLC after progression on osimertinib: MARIPOSA-2, a phase III, global, randomized, controlled trial.Ann Oncol. 2023; 34: S1307.

112.

Shen G,Zheng F,Ren D,Du F,Dong Q,Wang Z, et al.Anlotinib: a novel multi-targeting tyrosine kinase inhibitor in clinical development.J Hematol Oncol. 2018; 11: 120.

113.

Wu L,Chen B,Yao W,Li X,Xiao Z,Liu H,Kong Y, et al.1300P: A phase Ib/II trial of AK104 (PD-1/CTLA-4 bispecific antibody) in combination with anlotinib in advanced NSCLC.Ann Oncol. 2021; 32: S1006.

114.

Dhillon S.Lazertinib: first approval.Drugs. 2021; 81: 1107–13.

115.

Bauml J,Cho BC,Park K,Lee KH,Cho EK,Kim D-W, et al.Amivantamab in combination with lazertinib for the treatment of osimertinib-relapsed, chemotherapy-naïve EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC) and potential biomarkers for response.J Clin Oncol. 2021; 39: 9006.

116.

Remon J,Steuer CE,Ramalingam SS,Felip E.Osimertinib and other third-generation EGFR TKI in EGFR-mutant NSCLC patients.Ann Oncol. 2018; 29: i20–7.

117.

Johnson M,Lakhani N,Girda E,Olszanski A,Fong L,Han H, et al.735: A phase 1/2 study of REGN7075 (EGFRxCD28 costimulatory bispecific antibody) in combination with cemiplimab (anti-PD-1) in patients with advanced solid tumors: initial dose-escalation results.J Immunother Cancer. 2022; 10: A766–7.

118.

Middelburg J,Kemper K,Engelberts P,Labrijn AF,Schuurman J,van Hall T.Overcoming challenges for CD3-bispecific antibody therapy in solid tumors.Cancers. 2021; 13: 287.

119.

Edeline J,Houot R,Marabelle A,Alcantara M.CAR-T cells and BiTEs in solid tumors: challenges and perspectives.J Hematol Oncol. 2021; 14: 1–12.

120.

Wang Y,Zhang Y,Sun H,Chen J,Yang H,Zhong Z, et al.Antitumor activity of a ROR1 × CD3 bispecific antibody in non-small cell lung cancer.Int Immunopharmacol. 2023; 123: 110686.

121.

Fu W,Li G,Lei C,Qian K,Zhang S,Zhao J, et al.Bispecific antibodies targeting EGFR/Notch enhance the response to talazoparib by decreasing tumour-initiating cell frequency.Theranostics. 2023; 13: 3641–54.

122.

Song SH,Ghosh T,You DG,Joo H,Lee J,Lee J, et al.Functionally masked antibody to uncouple immune-related toxicities in checkpoint blockade cancer therapy.ACS Nano. 2023; 17: 10065–77.

123.

Tao J,Dhanjee HH,Gribble MW Jr,Kottisch V,Rodriguez J,Brown JS, et al.Site-specific antibody prodrugs via S-arylation: a bioconjugation approach toward masked tyrosine analogues.J Am Chem Soc. 2024; 146: 20080–85.

124.

Shen M,Chen C,Guo Q,Wang Q,Liao J,Wang L, et al.Systemic delivery of mPEG-masked trispecific T-cell nanoengagers in synergy with STING agonists overcomes immunotherapy resistance in TNBC and generates a vaccination effect.Adv Sci (Weinh). 2022; 9: e2203523.

125.

Cattaruzza F,Nazeer A,To M,Hammond M,Koski C,Liu LY, et al.Precision-activated T-cell engagers targeting HER2 or EGFR and CD3 mitigate on-target, off-tumor toxicity for immunotherapy in solid tumors.Nat Cancer. 2023; 4: 485–501.

126.

Piper M,Hoen M,Darragh LB,Knitz MW,Nguyen D,Gadwa J, et al.Simultaneous targeting of PD-1 and IL-2Rβγ with radiation therapy inhibits pancreatic cancer growth and metastasis.Cancer Cell. 2023; 41: 950–69.e6.

127.

Lan Y,Moustafa M,Knoll M,Xu C,Furkel J,Lazorchak A,Yeung TL, et al.Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion.Cancer Cell. 2021; 39: 1388–403.e10.

128.

Zhou Y,Penny HL,Kroenke MA,Bautista B,Hainline K,Chea LS, et al.Immunogenicity assessment of bispecific antibody-based immunotherapy in oncology.J Immunother Cancer. 2022; 10: e004225.

129.

Song X,Xiong A,Wu F,Li X,Wang J,Jiang T, et al.Spatial multi-omics revealed the impact of tumor ecosystem heterogeneity on immunotherapy efficacy in patients with advanced non-small cell lung cancer treated with bispecific antibody.J Immunother Cancer. 2023; 11: e006234.

130.

Anderson KG,Braun DA,Buqué A,Gitto SB,Guerriero JL,Horton B, et al.Leveraging immune resistance archetypes in solid cancer to inform next-generation anticancer therapies.J Immunother Cancer. 2023; 11: e006533.

131.

Philipp N,Kazerani M,Nicholls A,Vick B,Wulf J,Straub T, et al.T-cell exhaustion induced by continuous bispecific molecule exposure is ameliorated by treatment-free intervals.Blood. 2022; 140: 1104–18.

132.

van de Donk NWCJ,Chari A,Mateos MV.Mechanisms of resistance against T-cell engaging bispecific antibodies in multiple myeloma: implications for novel treatment strategies.Lancet Haematol. 2024; 11: e693–707.

133.

Chelius D,Ruf P,Gruber P,Plöscher M,Liedtke R,Gansberger E, et al.Structural and functional characterization of the trifunctional antibody catumaxomab.MAbs. 2010; 2: 309–19.

134.

Holliger P,Prospero T,Winter G.“Diabodies”: small bivalent and bispecific antibody fragments.Proc Natl Acad Sci U S A. 1993; 90: 6444–8.

135.

Merchant AM,Zhu Z,Yuan JQ,Goddard A,Adams CW,Presta LG, et al.An efficient route to human bispecific IgG.Nat Biotechnol. 1998; 16: 677–81.

136.

Yang F,Wen W,Qin W.Bispecific antibodies as a development platform for new concepts and treatment strategies.Int J Mol Sci. 2016; 18: 48.

137.

Cao M,Wang C,Chung WK,Motabar D,Wang J,Christian E, et al.Characterization and analysis of scFv-IgG bispecific antibody size variants.MAbs. 2018; 10: 1236–47.

138.

Kipriyanov SM,Moldenhauer G,Schuhmacher J,Cochlovius B,Von der Lieth CW,Matys ER, et al.Bispecific tandem diabody for tumor therapy with improved antigen binding and pharmacokinetics.J Mol Biol. 1999; 293: 41–56.

139.

Igawa T,Tsunoda H,Kuramochi T,Sampei Z,Ishii S,Hattori K, et al.Engineering the variable region of therapeutic IgG antibodies.MAbs. 2011; 3: 243–52.

140.

Zhou S,Liu M,Ren F,Meng X,Yu J.The landscape of bispecific T cell engager in cancer treatment.Biomarker Res. 2021; 9: 38.

141.

Jakob CG,Edalji R,Judge RA,DiGiammarino E,Li Y,Gu J,Ghayur T.Structure reveals function of the dual variable domain immunoglobulin (DVD-Ig™) molecule.MAbs. 2013; 5: 358–63.

142.

Surowka M,Schaefer W,Klein C.Ten years in the making: application of CrossMab technology for the development of therapeutic bispecific antibodies and antibody fusion proteins.MAbs. 2021; 13: 1967714.

143.

Moore GL,Bautista C,Pong E,Nguyen DH,Jacinto J,Eivazi A, et al.A novel bispecific antibody format enables simultaneous bivalent and monovalent co-engagement of distinct target antigens.MAbs. 2011; 3: 546–57.

144.

Godar M,de Haard H,Blanchetot C,Rasser J.Therapeutic bispecific antibody formats: a patent applications review (1994-2017).Expert Opin Ther Pat. 2018; 28: 251–76.

145.

Labrijn AF,Meesters JI,de Goeij BE,van den Bremer ET,Neijssen J,van Kampen MD, et al.Efficient generation of stable bispecific IgG1 by controlled Fab-arm exchange.Proc Natl Acad Sci U S A. 2013; 110: 5145–50.

146.

Johnson S,Burke S,Huang L,Gorlatov S,Li H,Wang W, et al.Effector cell recruitment with novel Fv-based dual-affinity re-targeting protein leads to potent tumor cytolysis and in vivo B-cell depletion.J Mol Biol. 2010; 399: 436–49.

147.

Oates J,Jakobsen BK.ImmTACs: novel bi-specific agents for targeted cancer therapy.Oncoimmunology. 2013; 2: e22891.

148.

Asano R,Koyama N,Hagiwara Y,Masakari Y,Orimo R,Arai K, et al.Anti-EGFR scFv tetramer (tetrabody) with a stable monodisperse structure, strong anticancer effect, and a long in vivo half-life.FEBS Open Bio. 2016; 6: 594–602.

149.

Vallera DA,Felices M,McElmurry R,McCullar V,Zhou X,Schmohl JU, et al.IL15 Trispecific killer engagers (TriKE) make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function.Clin Cancer Res. 2016; 22: 3440–50.

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Year 2025 volume 22 Issue 4

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doi: 10.20892/j.issn.2095-3941.2024.0470

Receive Date：2024-10-07
Online Date：2026-11-06
Published：2025-04-15

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Received：2024-10-07
Accepted：2025-03-05

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This work was supported by the National Natural Science Foundation of China (Grant No. 82272845) and the Natural Science Foundation of Shandong (Grant No. ZR2023LZL001).

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¹Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China

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Correspondence to: Xiangjiao Meng, E-mail: mengxiangjiao@sina.com

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表12种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Table 1 Characteristics and relevant bsAbs of different platforms

Platform	Construction	Merit	Shortage	Technology	BsAbs in clinical trial	Refs.
Triomab	Triomab is composed of two half-antibodies, each containing one light chain and one heavy chain, derived from the mouse IgG2a isotype and the rat IgG2b isotype. The yields of the desired pair are low.	Addressing issues related to heavy chain and light chain mispairing	Low yields of the desired pair, immunogenic responses and immune side effects	Hybridoma technology	Catumaxomab	¹³³
Diabody	Diabody is constructed in bacteria, slower dissociation kinetics, and an improved affinity for hapten.	Slower dissociation kinetics and an improved affinity for hapten	The formation of non-functional homodimers due to incorrect pairing of the variable domains.	Genetic engineering technology	MGD009	¹³⁴
Knobs-in-Holes	“Knobs-in-Holes” technology facilitates the correct pairing of heavy chains, but does not prevent the incorrect pairing of light chains associated with the two distinct heavy chains.	Correct pairing of heavy chains	It does not prevent the incorrect pairing of light chains associated with the two distinct heavy chains.	Genetic engineering technology	Emicizumab Belantamab KN046	^135,136
scFv-IgG	Cysteine residues are commonly introduced into the heavy- and light-chain regions of the scFv to form an intrachain disulfide bond.	Enhanced stability	Unforeseen molecular heterogeneity	Genetic engineering technology	CDX-527	¹³⁷
TandAb	Two pairs of VL and VH domains are linked in a single polypeptide chain to form a TandAb.	Increased valency, stability, and therapeutic potential	Short half-life and low expression	Genetic engineering technology	Zenocutuzumab	¹³⁸
ART-Ig	Mutations are introduced in the CH3 domains to create altered charge polarity across the Fc interface region.	Addressing the issue of heavy chain/heavy chain mispairing	Short half-life and unstable structure	Genetic engineering technology	AMG 420 REGN1979 AMG 701	¹³⁹
BiTE	BiTE molecules can be rapidly cleared from circulation due to their short half-life. BiTEs bind a T cell-specific molecule and TAAs to redirect T cells.	BiTE can be rapidly cleared from circulation	Activation occurred in a strictly target-dependent manner	Genetic engineering technology	Blinatumomab AMG 596	^71,140
DVD-Ig	DVD-Ig is created by adding additional antigen-binding units to the amino or carboxy termini of either light or heavy chains.	Targeting low-abundance proteins and longer dosing intervals	Enhanced immunogenicity and low yield	Genetic engineering technology	Lutikizumab ABT-981	¹⁴¹
CrossMAb	By utilizing different antibody formats and geometries through domain exchange or crossover.	Proper heavy chain pairing and correct association of light chains with the counterparts	Unrelated side products	Genetic engineering technology	Vanucizumab Faricimab AZD7789	¹⁴²
XmAb	XmAb is a variant generated through structure- and sequence-based approaches to analyze the energetic landscape of paired variant combinations at the CH3 dimer interface.	Potent cytotoxic activity by NK cells and T cells	Enhanced immunogenicity and low yield	Genetic engineering technology	XmAb14045	¹⁴³
Nanobody	Nanobodies, derived from llama and camel heavy-chain-only antibodies, can be easily linked with short linkers, allowing for modulation of antigen-binding valency.	Efficient tissue penetration and enhanced epitope accessibility	Limited half-life	Genetic engineering technology	Ozoralizumab	¹⁴⁴
Fab-scFv-Fc	Fab-scFv-Fc is composed of a light chain, a heavy chain, and a third chain incorporating both the Fc region and scFv.	Efficient manufacturing and purification	Short half-life and enhanced immunogenicity	Genetic engineering technology	MEDI-3902	¹²
DuoBody	DuoBody is engineered by leveraging the CH3/CH3 dimer interface of IgG4, enabling the generation of stable bispecific antibodies in both the IgG4 and IgG1 formats.	DuoBody mimics the natural Fab-arm Exchange process of human IgG4 in vivo	Poor permeability	Genetic engineering technology	Amivantamab Teclistamab Epcoritamab MGD013	¹⁴⁵
DART	Two peptide chains link the opposite fragments, with VLA connected to VHB and VLB connected to VHA, and a disulfide bond at their C-termini that covalently fuses them together.	Improved stability, extended storage and serum stability	Reduced effective tumor penetration	Genetic engineering technology	MGD-009	¹⁴⁶
ImmTAC	A stabilized and soluble T cell receptor is fused with an scFv recognizing CD3 to construct ImmTAC, enabling the targeting of processed antigenic peptides.	Improved affinity and exceptional stability	Activation occurred in a strictly target-dependent manner	Genetic engineering technology	IMCgp100	^12,147
Tetrabody	Fusion of two monoclonal antibodies to form a tetravalent bispecific antibody.	Stable, monodisperse structure, potent anticancer activity, and extended in vivo half-life	Enhanced immunogenicity	Genetic engineering technology	AK104 AK112 AK130	¹⁴⁸
TriKE	TriKE is engineered through the connection of two scFvs by polypeptide linkers, with the incorporation of human IL–15.	Promotion of the survival and proliferation of NKs	Immunogenic responses and immune side effects	Genetic engineering technology	GTB-3500	¹⁴⁹
Biclonics	One residue in a CH3 domain is substituted with a positively charged lysine residue, while one or more residues in the second CH3 domain are substituted with negatively – charged glutamic acid or aspartic acid residues.	Preferential heavy chain heterodimerization	Unstable structure and enhanced immunogenicity	Genetic engineering technology	zenocutuzumab	¹⁴⁴

ART-Ig, asymmetric reengineering technology immunoglobulin; bsAb, bispecific antibody; IgG, immunoglobulin G; BiTE, bispecific T-cell engager; CH3, heavy chain 3; DVD-Ig, dual variable domain-immunoglobulin; DART, dual-affinity re-targeting proteins; Fc, fragment crystallizable; Fab, fragment antigen-binding; ImmTAC, immune-mobilizing monoclonal T-cell receptors against cancer; IL-15, interleukin 15; NK, natural killer; scFv, single-chain fragment variable; TandAb, tandem diabody; TriKE, tri-specific killer engager; VL, variable region of light chain; VH, variable region of heavy chain.

Table 2 Clinical trials of bsAbs for NSCLC as monotherapy that have posted results

NCT number	Phase	Indications	Enrollment	BsAb	Target	Treatment	Outcomes
NCT number	Phase	Indications	Enrollment	BsAb	Target	Treatment	ORR	mPFS	mOS	TRAE	Grade ≥ 3 TRAE
NCT03838848	2	Metastatic NSCLC who failed first line treatment	64	KN046	PD-1 × CTLA-4	KN046	14.1%	3.70 months	18.40 months	NA	42.2%
NCT04172454	1b/2	Patients who had failed previous platinum-based doublet chemotherapy and were immunotherapy naïve	30	AK104	PD-1 × CTLA-4	AK104	10.0%	1.91 months	19.62 months	76.7%	10.0%
NCT02517398	1	Adults with advanced NSCLC that progressed following chemotherapy and was primary refractory or had acquired resistance to anti-PD-(L)1 treatment	62	M7824	PD-L1 × TGF-β	M7824	4.8%	1.40 months	7.30 months	73.5%	22.9%
NCT03774979	1	PD-L1+ advancer/metastatic NSCLC	57	SHR-1701	PD-1 × TGF-β	SHR-1701	44.2%	NA	NA	NA	21.1%
NCT02609776	1	EGFR Exon 20 Insertion–Mutated NSCLC	50	amivantamab	EGFR × c-MET	Amivantamab	40.0%	8.30 months	22.80 months	NA	6.0%
NCT05194982	1	NSCLC (EGFR mut)	40	BL-B01D1	EGFR × HER3	BL-B01D1	67.5%	5.60 months	NA	NA	NA
		NSCLC (EGFRwt)	62				40.3%	5.40 months	NA	NA	NA
NCT04995523	1/2	Advanced NSCLC who had prior CPI treatment and a PD-L1 tumor proportion score ≥ 1%	80	AZD2936	PD-1 × TIGIT	AZD2936	NA	NA	NA	46.3%	5.0%

BsAb, bispecific antibody; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; c-MET, cellular-mesenchymal epithelial transition; HER3, human epidermal growth factor receptor 3; mOS, median overall survival; mPFS, median progression free survival; NSCLC, non-small cell lung cancer; ORR, overall response rate; PD-L1, programmed death-ligand 1; PD-1, programmed death-1; TGF-β, transforming growth factor β; TIGIT, T cell immunoreceptor with Ig and ITIM domains; TRAE, treatment related adverse event.

Table 3 Ongoing clinical trials evaluating bsAbs for immunotherapy in patients with NSCLC or solid tumors

NCT number	Study state	Indications	Treatment	Target	Phase
NCT05585034	Recruiting	Advanced solid tumors	XmAbÂ^®808	B7-H3 × CD28	Phase 1
NCT05607498	Recruiting	Locally advanced/metastatic solid tumors or relapse/refractory lymphoma	EMB07	CD3 × ROR1	Phase 1
NCT05461287	Recruiting	Advanced solid tumor	QLS31904	DLL3 × CD3	Phase 1
NCT05403554	Recruiting	Mesothelin expressing solid cancers	NI-1801	Mesothelin × CD47	Phase 1
NCT05263180	Recruiting	Advanced or metastatic Solid tumors	EMB-09	PD-1 × OX40	Phase 1
NCT05293496	Recruiting	Advanced solid tumors	Lorigerlimab	PD-1 × CTLA-4	Phase 1
NCT05645276	Recruiting	Advanced malignant tumors	AK129	PD-1 × LAG-3	Phase 1
NCT05577182	Recruiting	Advanced malignancies	INCA32459-101	PD-1 × LAG-3	Phase 1
NCT04777084	Recruiting	NSCLC	IBI318	PD-1 × PD-L1	Phase 1
NCT05028556	-	Metastatic or locally advanced solid tumors	Y101D	PD-1 × TGF-β	Phase 1
NCT03809624	Recruiting	Solid tumors	INBRX-105	PD-L1 × 4-1BB	Phase 1
NCT05200013	Recruiting	Advanced solid tumors	BAT7104	PD-L1 × CD47	Phase 1
NCT05101109	Recruiting	Progressive, locally advanced (unresectable) or metastatic solid tumors	BL501	PD-L1 × LAG-3	Phase 1
NCT05638334	Recruiting	Advanced solid tumors	S09501	PD-L1 × OX-40	Phase 1
NCT05537051	Not yet recruiting	Advanced solid tumors	PM8001	PD-L1 × TGF-β	Phase 1
NCT04954456	-	Advanced or metastatic malignancies	QLS31901	PD-L1 × TGF-β	Phase 1
NCT05607563	Recruiting	Advanced tumor	PM1009	TIGIT × PVRIG	Phase 1
NCT05180474	Recruiting	Malignant solid tumors	GEN1047	CD3 × 5T4	Phase 1/2
NCT05543330	Not yet recruiting	Malignant pleural effusions caused by NSCLC	M701	EpCAM × CD3	Phase 1/2
NCT05559541	Recruiting	Advanced solid tumors	AK104	PD-1 × CTLA-4	Phase 1/2
NCT04597541	Active, not recruiting	Advanced solid tumors	Ivonescimab	PD-1 × VEGF	Phase 1/2
NCT05689853	Recruiting	Advanced solid tumors	Ivonescimab	PD-1 × VEGF	Phase 1/2
NCT05229497	Recruiting	Advanced malignant tumors	Ivonescimab	PD-1 × VEGF	Phase 1/2
NCT05214482	Recruiting	Advanced malignant tumors	Ivonescimab	PD-1 × VEGF	Phase 1/2
NCT05159388	Recruiting	Solid tumors	PRS-344/S095012	PD-L1 × 4-1BB	Phase 1/2
NCT05425602	Not yet recruiting	Advanced/metastatic solid tumors	MAX-40279-01	PD-L1 × CTLA-4	Phase 1/2
NCT03440437	Active, not recruiting	Advanced malignancies	FS118	PD-L1 × LAG-3	Phase 1/2
NCT04262466	Recruiting	Select advanced solid tumors	IMC-F106C	PRAME × CD3	Phase 1/2
NCT05102214	Recruiting	Locally advanced or metastatic solid tumors	HLX301	TIGIT × PD-L1	Phase 1/2
NCT05390528	Recruiting	Locally advanced/metastatic solid tumors or lymphoma	HLX301	TIGIT × PD-L1	Phase 1/2
NCT05377658	Not yet recruiting	Resectable NSCLC	AK104	PD-1 × CTLA-4	Phase 2
NCT05215067	Recruiting	Advanced NSCLC	AK104	PD-1 × CTLA-4	Phase 2
NCT05247684	Not yet recruiting	Resectable NSCLC	AK112	PD-1 × VEGF	Phase 2

CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; DLL3, delta-like ligand 3; EpCAM, epithelial cell adhesion molecule; LAG-3, lymphocyte activation gene 3; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; PVRIG, poliovirus receptor-related immunoglobulin domain-containing; PRAME, preferentially expressed antigen in melanoma; PSMA, prostate-specific membrane antigen; ROR1, receptor tyrosine kinase-like orphan receptor 1; TGF-β, transforming growth factor β; TIGIT, T cell immunoreceptor with Ig and ITIM domains; VEGF, vascular endothelial growth factor.

Table 4 Ongoing clinical trials evaluating bsAbs for targeted therapy in patients with NSCLC or solid tumors

NCT number	Study state	Indications	Treatment	Target	Phase
NCT04501770	Not yet recruiting	HER2-positive advanced solid tumors	M802	CD3 × HER2	Phase 1
NCT05442996	Not yet recruiting	Advanced or metastatic solid tumors	HLX35	EGFR × 4-1BB	Phase 1
NCT05360381	Active, not recruiting	Advanced or metastatic solid tumors	HLX35	EGFR × 4-1BB	Phase 1
NCT05150457	Recruiting	Advanced solid tumors	BNA035	EGFR × 4-1BB	Phase 1
NCT05387265	Recruiting	Advanced solid tumors	CX-904	EGFR × CD3	Phase 1
NCT04603287	Recruiting	Locally advanced or metastatic epithelial tumors	SI-B001	EGFR × HER3	Phase 1
NCT03526835	Recruiting	Advanced solid tumors	MCLA-158	EGFR × LGR5	Phase 1
NCT03842085	Recruiting	HER2 positive recurrent or metastatic malignant solid tumor	MBS301	HER2 × HER2	Phase 1
NCT05320874	Not yet recruiting	Advanced HER2-positive or expressing solid tumors	KM257	HER2 × HER2	Phase 1
NCT05380882	Recruiting	Advanced cancers	TQB2930	HER2 × HER2	Phase 1
NCT03650348	-	HER2-positive solid tumors	PRS-343	HER2 × 4-1BB	Phase 1
NCT05076591	Recruiting	HER2-expressing advanced solid tumors	IMM2902	HER2 × SIRPα	Phase 1
NCT04844073	Recruiting	Advanced or metastatic cancer	MVC-101 (TAK-186)	EGFR × CD3	Phase 1/2
NCT04930432	Recruiting	Advanced NSCLC and other solid tumors	MCLA-129	EGFR × c-MET	Phase 1/2
NCT05498389	Not yet recruiting	EGFR mutant lung cancer	EMB-01	EGFR × c-MET	Phase 1/2
NCT05523947	Recruiting	HER2 positive locally advanced or metastatic solid tumor	YH32367	HER2 × 4-1BB	Phase 1/2
NCT05299125	Recruiting	Recurrent/metastatic NSCLC with EGFR mutations	Amivantamab	EGFR × c-MET	Phase 2
NCT05588609	Recruiting	With or without molecularly defined cancers	Zenocutuzumab	HER2 × HER3	Phase 2
NCT05388669	Recruiting	EGFR-mutated advanced or metastatic NSCLC	Amivantamab	EGFR × c-MET	Phase 3
NCT04100694	Available	Advanced NRG1-fusion positive solid tumor	MCLA-128	HER2 × HER3	Not applicable

c-MET, cellular-mesenchymal epithelial transition; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; HER3, human epidermal growth factor receptor 3; LRG5, leucine rich repeat containing G protein-coupled receptor 5; NRG1, neuregulin-1 gene; SIRPα, signal regulatory protein α.

Table 5 Clinical trials of bsAbs for NSCLC as combined therapy that have posted results

NCT number	Phase	Indications	Enrollment	BsAb	Target	Treatment	Outcomes
NCT number	Phase	Indications	Enrollment	BsAb	Target	Treatment	ORR	mPFS	mOS	TRAE	Grade ≥ 3 TRAE
NCT04736823	2	Untreated advanced NSCLC, had no EGFR or ALK gene modifications	43	AK112	PD1 × VEGF	AK112 plus chemotherapy	53.5%	Not reach	NA	92.5%	22.5%
		Advanced NSCLC with EGFR-sensitive mutations, failed previous EGFR-TKI therapy	19			AK112 plus chemotherapy	68.4%	8.5 months	NA	90.7%	30.2%
		Advanced NSCLC who failed systemic platinum-based chemotherapy and anti-PD-1/PD-L1 treatments	20			AK112 plus chemotherapy	40.0%	7.5 months	NA	91.6%	26.5%
NCT04054531	2	Advanced NSCLC	87	KN046	PD-L1 × CTLA-4	KN046 plus chemotherapy	50.6%	5.8 months	26.6 months	92.0%	25.3%
NCT03838848	2	Patients with metastatic NSCLC who failed prior EGFR-TKI(s)	26	KN046	PD-L1 × CTLA-4	KN046 plus chemotherapy	26.9%	5.5 months	20.2 months	92.3%	57.7%
NCT04538664	1	Patients with advanced NSCLC with EGFR exon 20 insertions who had not received previous systemic therapy	153	Amivantamab	EGFR × c-MET	Amivantamab-chemotherapy	73.0%	17.2 months	24.4 months	100%	75.0%
NCT04988295	1	Locally advanced or metastatic EGFR-mutated NSCLC with disease progression on or after osimertinib monotherapy	263	Amivantamab	EGFR × c-MET	Amivantamab-lazertinib-chemotherapy	63.0%	6.3 months	NA	100%	92.0%
			131			Amivantamab-chemotherapy	64.0%	8.3 months	NA	100%	72.0%
NCT04487080	3	Patients with treatment-naïve, EGFR-mutated locally advanced or metastatic NSCLC	429	Amivantamab	EGFR × c-MET	Amivantamab plus lazertinib	86.0%	23.7 months	NA	100%	75.0%
NCT03774979	1	Recurrent or metastatic non-squamous NSCLC who had failed ≤ 2 lines of systemic treatment, driver gene-negative	10	SHR-1701	PD-1 × TGF-β	SHR-1701 plus bevacizumab	10.0%	6.2 months	NA	90.4%	29.4%

BsAb, bispecific antibody; c-MET, cellular-mesenchymal epithelial transition; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; EGFR, epidermal growth factor receptor; mOS, median overall survival; mPFS, median progression free survival; NSCLC, non-small cell lung cancer; ORR, overall response rate; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; TGF-β, transforming growth factor; TRAE, treatment related adverse event; VEGF, vascular endothelial growth factor.

Figure 1 The evolutionary history map of the bsAbs. IgG subtype bispecific antibodies are placed above the timeline and the non-IgG subtype bispecific antibodies are placed below the timeline. Abs, antibodies; ART-Ig, asymmetric reengineering technology immunoglobulin; bsAb, bispecific antibody; BiTE, bispecific T-cell engager; CrossMab, cross-specific monoclonal antibody; DVD-Ig, dual variable domain-immunoglobulin; DART, dual-affinity re-targeting proteins; EGFR, epidermal growth factor receptor; Fab, fragment antigen-binding; Fc, fragment crystallizable; IgG, immunoglobulin G; ImmTAC, immune-mobilizing monoclonal T-cell receptors against cancer; NSCLC, non-small cell lung cancer; scFv, single-chain fragment variable; TandAb, tandem diabody; TKI, tyrosine kinase inhibitor; XmAb, xencor monoclonal antibody.

Figure 2 Three strategies for bsAb construction. (A) Fusing two hybridoma cells to construct bsAbs. Hybridoma cell A expressing mAb A and hybridoma cell B expressing mAb B are fused to generate a quadroma cell which expresses bsAbs. (B) Constructing bsAbs by chemical conjugation. Two mAbs were digested with enzymes to obtain antibody fragments. The fragments from mAb A and mAb B were then reassociated using chemical crosslinkers to construct bsAbs. (C) Constructing bsAbs by genetic engineering. Through genetic engineering technologies, fragments from two distinct mAbs are randomly recombined to construct bsAb in different platforms. The most common genetic engineering technologies used to construct bsAbs are gene recombination and protein engineering. BsAbs can be divided into three types: symmetric IgG subtype; asymmetric IgG subtype; and non-IgG subtype. ART-Ig, asymmetric reengineering technology immunoglobulin; bsAb, bispecific antibody; BiTE, bispecific T-cell engager; CrossMab, cross-specific monoclonal antibody; DVD-Ig, dual variable domain-immunoglobulin; DART, dual-affinity re-targeting proteins; Fab, fragment antigen-binding; Fc, fragment crystallizable; IgG, immunoglobulin G; ImmTAC, immune-mobilizing monoclonal T-cell receptors against cancer; scFv, single-chain fragment variable; TandAb, tandem diabody; TriKE, TriToxin-targeted killer engager; XmAb, xencor monoclonal antibody.

Figure 3 The framework of this review. CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; c-MET, cellular-mesenchymal epithelial transition; CEA, carcinoembryonic antigen; EpCAM, epithelial cell adhesion molecule; EGFR, epidermal growth factor receptor; FRα, folate receptor alpha; HER2, human epidermal growth factor receptor 2; HER3, human epidermal growth factor receptor 3; LAG-3, lymphocyte activation gene 3; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; TIM-3, T-cell immunoglobulin and mucin domain-containing protein 3; TGF-β, transforming growth factor β; TRPV6, transient receptor potential vanilloid 6; VEGF, vascular endothelial growth factor.

Figure 4 Mechanisms of action underlying bsAbs for the treatment of NSCLC. (A) Bridging two immune modulators to recover T-cell activity. After binding to two immune modulators on the T cell surface, bsAbs can restore the activity of exhausted T cells to initiate a tumor-killing immune response. (B) Redirecting T cell to tumor cell. BsAbs can bind the CD3 on the T cell surface and TAA on the tumor cell surface to redirect T cell. Then, T cells will release perforin and granzyme to kill tumor cells. (C) Inhibiting two signaling pathways. The survival of tumor cells relies on multiple signaling pathways. By targeting two receptors on the surface of tumor cells that are integral to these pathways, bsAbs can inhibit downstream signaling, thereby inducing tumor cell death. (D) bsADC with cytotoxic payload. After linking to tumor cells, bsADC release cytotoxic payload to kill tumor cells. bsADC, bispecific antibody-drug conjugate; CD3, cluster of differentiation 3; bsAb, bispecific antibody; TAA, tumor-associated antigen.

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