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Frontiers of Medicine

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Front. Med.    2024, Vol. 18 Issue (4) : 597-621    https://doi.org/10.1007/s11684-024-1072-8
Unlocking the potential of bispecific ADCs for targeted cancer therapy
Hongye Zeng, Wenjing Ning, Xue Liu(), Wenxin Luo(), Ningshao Xia
State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China
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Abstract

Antibody–drug conjugates (ADCs) are biologically targeted drugs composed of antibodies and cytotoxic drugs connected by linkers. These innovative compounds enable precise drug delivery to tumor cells, minimizing harm to normal tissues and offering excellent prospects for cancer treatment. However, monoclonal antibody-based ADCs still present challenges, especially in terms of balancing efficacy and safety. Bispecific antibodies are alternatives to monoclonal antibodies and exhibit superior internalization and selectivity, producing ADCs with increased safety and therapeutic efficacy. In this review, we present available evidence and future prospects regarding the use of bispecific ADCs for cancer treatment, including a comprehensive overview of bispecific ADCs that are currently in clinical trials. We offer insights into the future development of bispecific ADCs to provide novel strategies for cancer treatment.
Keywords antibody–drug conjugate      bispecific antibody      bispecific ADC      cancer     
Corresponding Author(s): Xue Liu,Wenxin Luo   
Just Accepted Date: 27 June 2024   Online First Date: 22 July 2024    Issue Date: 30 August 2024
 Cite this article:   
Hongye Zeng,Wenjing Ning,Xue Liu, et al. Unlocking the potential of bispecific ADCs for targeted cancer therapy[J]. Front. Med., 2024, 18(4): 597-621.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-024-1072-8
https://academic.hep.com.cn/fmd/EN/Y2024/V18/I4/597
Drug (INN) Target Antibody isotype Linker Payload DAR Indications Characteristics Initial approval References
Gemtuzumab ozogamicina CD33 IgG4 Hydrazone Calicheamicin 2.5 CD33-positive acute myeloid leukemia (AML) First ADC approved for clinical use; heterogeneity; low potency payload; unstable hydrazone linker; high immunogenicity of antibody moiety 2000.05 FDA [14]
Brentuximab vedotin CD30 IgG1 Val-Cit dipeptide MMAE 4 Hodgkin lymphoma Stable dipeptide linker; potent payload MMAE 2011.08 FDA [15]
Trastuzumab emtansine HER2 IgG1 SMCC; noncleavable DM1 3.5 HER2-positive breast cancer First ADC approved for solid tumor treatment; no bystander effect; HER2 signal inhibition; ADCC; CDC effects 2013.02 FDA [16–18]
Inotuzumab ozogamicin CD22 IgG4 Hydrazone Calicheamicin 2.5 Acute lymphoblastic leukemia (ALL) Humanized antibody; similar linker and payload to those of gemtuzumab ozogamicin 2017.08 FDA [19, 20]
Moxetumomab pasudotoxb CD22 Mouse Fv Hydrazone Pseudomonas exotoxin A, PE38 NA Hairy cell leukemia (HCL) First new drug approved for HCL treatment 2018.09 FDA [21]
Polatuzumab vedotin CD79β IgG1 Val-Cit dipeptide MMAE 4 Diffuse large B cell lymphoma (DLBCL) First ADC for the treatment of DLBCL 2019.06 FDA [22]
Enfortumab vedotin Nectin-4 IgG1 Val-Cit dipeptide MMAE 4 Urothelial malignancies Fully human anti-nectin-4 antibody; serious skin reactions in some patients; prolonged median OS (12.9 months) compared to chemotherapy (9 months) 2019.12 FDA [23, 24]
Trastuzumab deruxtecan HER2 IgG1 GGFG tetrapeptide Dxd 8 HER2-positive breast cancer, gastric or gastresophageal junction adenocarcinoma Novel topoisomerase I inhibitor payload (DXd); stable tetrapeptide-based linker; improved DAR of 7-8; superior PFS and ORR compared to T-DM1 2019.12 FDA [25–27]
Sacituzumab govitecan Trop2 IgG1 CL2A; pH sensitivity SN38 7.6 Triple-negative breast cancer Potent payload SN38; pH-sensitive stable linker; median PFS 4.8 months vs. 1.7 months for chemotherapy; median OS 11.8 months vs. 6.9 months for chemotherapy 2020.04 FDA [28]
Belantamab mafodotinc BCMA IgG1 MC; noncleavable MMAF 4 Multiple myeloma No bystander effect; noncleavable linker and impermeable payload MMAF; BCMA-targeted therapy for multiple myeloma 2020.08 FDA [29, 30]
Cetuximab saratolacan EGFR IgG1 NA IRDye700DX NA Head and neck cancer Photosensitizing dye-based payload; laser-activated cancer cell-killing mechanism; approved by PMDA in Japan 2020.09 PMDA [31]
Loncastuximab tesirine CD19 IgG1 Val-Ala dipeptide PBD 2.3 DLBCL High-potency payload PBD 2021.04 FDA [32]
Disitamab vedotin HER2 IgG1 Val-Cit dipeptide MMAE 4 HER2-positive gastric cancer Approved by NMPA in China; third HER2-targeted ADC on the market; patients received disitamab vedotin 2.5 mg/kg and ORR was 18.1% 2021.06 NMPA [33]
Tisotumab vedotin TF IgG1 Val-Cit dipeptide MMAE 4 Cervical cancer Fully humanized anti-TF antibody; ADCC and ADCP effects; first TF-targeted ADC 2021.09 FDA [34, 35]
Mirvetuximab soravtansine FRα IgG1 sulfo-SPDB DM4 3.5 FRα-positive epithelial ovarian, fallopian tube or primary peritoneal cancer First FRα-targeted ADC; novel cleavable sulfo-SPDB linker; efficacy in patients with high FRα expression 2022.11 FDA [36]
Tab.1  Current ADCs approved worldwide
Fig.1  Timeline of major advances in bispecific ADCs.
Drugs (INN) Target Mechanism Indications First approval time References
Catumaxomab CD3/EpCAM To redirect cytotoxic T cells to tumor cells, ADCC, ADCP Malignant ascites; various solid tumors 2009.04 EMA (delisting announced in 2017) [52]
Blinatumomab CD3/CD19 To redirect cytotoxic T cells to tumor cells ALL 2014.12 FDA [53]
Emicizumab Factor X/factor IXa To combine activated factors IX and X to restore the function of activated factor VIII, which is deficient in hemophilia patients Hemophilia A 2017.11 FDA [54]
Amivantamab-vmjw EGFR/cMet To block the binding of EGFR and cMet to ligands EGFR-mutated non-small cell lung cancer (NSCLC) 2021.05 FDA [55]
Tebentafusp CD3/gp100 To redirect cytotoxic T cells to tumor cells Uveal melanoma 2022.01 FDA [56]
Faricimab Ang2/VEGF To block the binding of Ang2 and VEGF to ligands Diabetic macular edema, age-related macular degeneration 2022.01 FDA [57, 58]
Mosunetuzumab CD3/CD20 To redirect cytotoxic T cells to tumor cells Follicular and marginal zone lymphoma 2022.06 EMA [59]
Cadonilimab PD-1/CTLA-4 To cause immune checkpoint inhibition Various solid tumors 2022.06 NMPA [60]
Teclistamab CD3/BCMA To redirect cytotoxic T cells to tumor cells Multiple myeloma 2022.08 EMA [61]
Ozoralizumab TNF-α/HSA To block TNF-α and improve serum half-life of nanobody Rheumatoid arthritis 2022.09 PMDA [62]
Epcoritamab CD3/CD20 To redirect cytotoxic T cells to tumor cells Large B cell lymphoma 2023.05 FDA [63]
Glofitamab CD3/CD20 To redirect cytotoxic T cells to tumor cells Large B cell lymphoma 2023.03 Health Canada [64]
Elranatamab CD3/BCMA To redirect cytotoxic T cells to tumor cells Multiple myeloma 2023.08 FDA [65]
Talquetamab CD3/GPRC5D To redirect cytotoxic T cells to tumor cells Multiple myeloma 2023.08 FDA [66]
Tab.2  Bispecific antibodies approved worldwide
Monoclonal antibody?drug conjugates Bispecific antibody?drug conjugates
Schematic diagram
Antibody structure Traditional bivalent IgG antibodies that target a single antigen Can be symmetric or asymmetrical and can target two different antigen binding sites; antibody valency ranges from bivalent to tetravalent or even more
Indications May not be as effective for patient populations with low antigen expression Dual-targeting broadens the range of indications and helps overcome tumor resistance
Toxic side effects Targets a single antigen, which may be expressed in healthy tissues causing on-target off-tumor toxicity Simultaneously targets two different antigens, promoting antigen cross-linking and reducing on-target off-tumor effects
Design and production Relatively easy to design and produce Increased molecular complexity presents challenges to design and production
Clinical and market status Fifteen monoclonal ADCs have been approved, and over one hundred ADCs are in various stages of clinical trials No bispecific ADCs have been approved yet; BL-B01D1 and JSKN003 are the most advanced in phase III clinical trials (China)
Tab.3  Differences between monoclonal and bispecific ADCs
Fig.2  Structure and mechanism of action of bispecific ADCs. (A) Bispecific ADCs comprise three key elements: a bispecific antibody moiety that binds to multiple antigens or different epitopes expressed on the tumor cell surface; a cytotoxic drug that induces tumor cell apoptosis; and a chemical linker that ensures that the payload is released within tumor cells and is not prematurely released in the bloodstream. (B) Bispecific ADCs counteract drug resistance by simultaneously blocking multiple signaling pathways. (C) A dual targeting strategy increases the selectivity for tumor cells, reducing off-target toxicity in healthy tissues. (D) Biparatopic ADCs boost receptor cross-linking and clustering. (E) The cytotoxicity of bispecific ADCs requires key sequential steps: binding to multiple epitopes or antigens; internalization of the bispecific ADC–antigen complex; lysosomal degradation of the bispecific antibody portion; release of the cytotoxic drug; and induction of tumor cell apoptosis. Through the bystander effect, a fraction of the payload may be released into the extracellular environment, where it can kill neighboring cells.
Fig.3  Main characteristics of bispecific ADCs in clinical trials. The similarities and differences among clinical bispecific ADCs. Various formats of bispecific antibodies have been designed to recognize two different antigen binding sites (shown in purple and green). Most bispecific antibodies are built on IgG1 scaffolds that confer extended half-life and high solubility while minimizing nonspecific immunogenicity. Linkers are shown in gray. In the payload, tubulin binders are shown in yellow, and topoisomerase I inhibitors in red. The values given for the payloads represent the DARs.
Drugs Target Payload Design Phase (clinical registration date) Indications ClinicalTrial.gov identifier
JSKN-003 HER2/HER2 Topoisomerase I inhibitor DAR: 4
Linker: dibenzocyclooctyne tetrapeptide linker
Platform: enzyme catalyzed and click chemistry based glycan-specific conjugation; charge repulsion induced bispecific (CRIB); knobs-into-holes(KIH)		 III (2023.09.22) Low-HER2, unresectable and/or metastatic breast cancer NCT06079983
BL-B01D1 EGFR/HER3 Topoisomerase I inhibitor (ED04) DAR: 8
Linker: cleavable linker
Platform: IgG-scFv		 III (2023.10.25) Recurrent or metastatic nasopharyngeal carcinoma (NPC) NCT06118333
TQB2102 HER2/HER2 Topoisomerase I inhibitor DAR: 5.8
Linker: cleavable linker MC-GGFG
Platform: KIH; scFv-Fab		 II (2023.12.27) Breast cancer NCT06198751
REGN5093-M114 cMet/cMet Maytansine derivative (M24) DAR: 3.2
Linker: cleavable linker M114
Platform: Veloci-Bi; VelociNator; common light chain strategy and modification of protein A binding avidity		 I/II (2021.07.20) cMet-overexpressing NSCLC; advanced cancer NCT04982224
MEDI4276a HER2/HER2 Tubulysin variant (AZ13599185) DAR: 4
Linker: protease-cleavable peptide-based maleimidocaproyl linker
Platform: scFv-(H)IgG		 I (2015.09.28) HER2-expressing advanced solid tumors NCT02576548
ZW49 HER2/HER2 N-acyl sulfonamide auristatin payload (ZD02044) DAR: 2
Linker: protease cleavable linker
Platform: Azymetric; ZymeLink; scFv-Fab		 I (2019.01.28) Locally advanced or metastatic HER2-expressing cancers NCT03821233
M1231 MUC1/EGFR Hemiasterlin-related microtubule inhibitor DAR: 4
Linker: cleavable linker ValCit-PABA
Platform: strand-exchange engineered domain (SEED); Xpress CF+ for site-specific conjugation; scFv-Fab		 I (2021.01.04) Solid tumors, metastatic NSCLC, esophageal squamous cell carcinoma NCT04695847
IMGN151 FRα/FRα Maytansinoid derivative (DM21) DAR: 3.5
Linker: cleavable peptide linker AAA
Platform: KIH; scFv-Fab		 I (2022.08.23) Endometrial cancer, high grade serous adenocarcinoma of ovary, primary peritoneal carcinoma, fallopian tube cancer NCT05527184
AZD9592 EGFR/cMet Topoisomerase I inhibitor (AZ14170132) DAR: 6
Linker: cleavable linker
Platform: DuetMab; KIH		 I (2022.11.18) Advanced solid tumors, NSCLC, head and neck neoplasms NCT05647122
Tab.4  Clinical trials of bispecific ADCs
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