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
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.
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
Fig.1
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
Advanced solid tumors, NSCLC, head and neck neoplasms
NCT05647122
Tab.4
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