B7-H3 and B7-H4 are type I transmembrane proteins belonging to the B7 family. Their abnormal expression is associated with many diseases such as colon cancer, breast cancer, liver cancer, and lung cancer, making them novel targets for immunotherapy.
Clinical research on B7-H3/B7-H4 ADC products
Antibody-drug conjugate (ADC) is a type of targeted therapy designed to treat cancer using biologics. It is a three-component system comprising an effective cytotoxic anticancer agent linked to an antibody via a biodegradable linker. The antibody binds to certain markers (antigens or receptors) attached to the surface of cancer cells. Inside the cancer cells, the entire antibody-drug conjugate is internalized, its linker degraded, and the active drug released.
ADCs are one of the hottest research fields in recent years since they selectively transport cytotoxins to tumor cells, thereby improving efficacy and safety. The research on ADC products targeting B7-H3 and B7-H4 is increasing, including MGC018 and DS-7300a targeting B7-H3 (phase II), as well as AZD8205 targeting B7-H4 (phase I/II).
Representative B7-H3/B7-H4 ADC compounds
MGC018 is an ADC that targets B7-H3, developed by MacroGenics, which can deliver the DNA alkylating agent duocarmycin to tumor cells expressing B7-H3. Duocarmycin can disrupt the DNA of dividing and non-dividing cells, leading to cell death. The average drug-to-antibody ratio (DAR) is ~2.7. MGC018 is currently being evaluated in phase I/II dose-expansion study in patients with metastatic castration-resistant prostate cancer (mCRPC), non-small cell lung cancer (NSCLC), squamous cell carcinoma of head and neck (SCCHN), and melanoma.
DS-7300a is a novel B7-H3-targeted antibody-drug conjugate with an effective DNA topoisomerase I inhibitor and in vitro features, pharmacokinetic features, safety profile, and in vivo antitumor activity in nonclinical species. DS-7300a specifically binds to B7-H3, inhibiting the growth of cancer cells expressing B7-H3 in vitro, while not inhibiting the growth of B7-H3-negative cancer cells. At the ESMO congress last year, DS-7300a showed remarkable efficacy, particularly in the most difficult-to-treat small cell lung cancer. Of the nine patients in the study, six were confirmed to have partial response, with one partial response pending confirmation. The disease control rate reached 77.8%.
Mirzotamab clezutoclax (ABBV-155) is a B7-H3 ADC developed by AbbVie, comprising a monoclonal antibody, linker, and BCL-XL inhibitor, intended for the treatment of advanced solid tumors. ABBV-155 has already progressed to the phase I clinical trial, which includes dose escalation and dose expansion phases to evaluate the safety, PK, and preliminary efficacy of ABBV-155 alone and in combination with paclitaxel or docetaxel in adult patients with relapsed and/or refractory solid tumors.
HS-20093 is a humanized IgG1 antibody-drug conjugate (ADC) specifically binding to B7-H3, a widely expressed target on solid tumor cells. In September 2021, Johnson & Johnson’s biologic class 1 injection HS-20093 was approved for clinical use (acceptance number: CXSL2101192) for the treatment of advanced malignant solid tumors.
AZD8205 is a B7-H4-targeted ADC drug developed by AstraZeneca using cleavable linker technology. By conjugating the B7-H4 monoclonal antibody INT016 with a novel topoisomerase I inhibitor (TOP1i) AZ’0132 via a cleavable linker, the drug can selectively deliver AZ’0132 to B7-H4-positive cells, causing DNA damage and cell apoptosis.
XMT-1660 is a Dolasynthen antibody-drug conjugate targeting B7-H4 and carrying the DolaLock effective payload with controlled bystander effects. XMT-1660 is based on the Dolasynthen platform, combining various attributes, including site-specific bioconjugation and precise control of the drug-to-antibody ratio (DAR). Each antibody of XMT-1660 (DAR-6) contains six DolaLock auristatin F-hydroxypropylamide (AF-HPA) anti-tubulin payloads.
Future Prospects
In recent years, the research on ADCs has been very active, but no ADC products targeting B7-H3 or B7-H4 have been approved for marketing yet. The fastest progress is being made by MacroGenics’ MGC018, Daiichi Sankyo’s DS-7300a, and AstraZeneca’s AZD8205. It is believed that the first anti-B7-H3 or anti-B7-H4 ADC product will be approved for marketing soon.
Reference
1. Ayechew Adera Getu, Abiye Tigabu, Ming Zhou, Jianrong Lu, Øystein Fodstad and Ming Tan, New frontiers in immune checkpoint B7-H3 (CD276) research and drug development, Molecular Cancer (2023) 22:43.
2. WEI SHI, YIN WANG, Immune checkpoint B7-H3 is a therapeutic vulnerability in prostate cancer harboring PTEN and TP53 deficiencies, Sci. Transl. Med. 15, eadf6724 (2023).
3. Kenneth Peuker, et.al, Microbiota-dependent activation of the myeloid calcineurin-NFAT pathway inhibits B7H3- and B7H4-dependent anti-tumor immunity in colorectal cancer, Immunity 2022 Apr 12;55(4):701-717.e7.
4. Krista Kinneer, Philipp Wortmann, et.al, Design and Preclinical Evaluation of a Novel B7-H4 Directed Antibody–Drug Conjugate, AZD8205, Alone and in Combination with the PARP1-Selective Inhibitor AZD5305, Clin Cancer Res 2023;29:1086–101
5. _620P ESMO MGC018 Poster.pdf (macrogenics.com)
6. 453O – DS-7300 (B7-H3 DXd antibody-drug conjugate [ADC]) shows durable antitumor activity in advanced solid tumors: Extended follow-up of a phase I/II study
7. A first-in-human study of mirzotamab clezutoclax as monotherapy and in combination with taxane therapy in relapsed/refractory solid tumors: Dose escalation results. | Journal of Clinical Oncology (ascopubs.org)
8. ARTEMIS-001: Phase 1 study of HS-20093, a B7-H3–targeting antibody-drug conjugate, in patients with advanced solid tumor. | Journal of Clinical Oncology (ascopubs.org)
9. Antitumor effect of XMT-1660, a B7-H4 targeting antibody-drug conjugate, in an unselected panel of patient-derived xenograft models of breast cancer (mersana.com)