B7-H3 (CD276)
An Actionable Therapeutic Target
B7-homologue 3 ( B7-H3 or CD276 and B7RP-2), is a type 1 transmembrane glycoprotein with two isoforms comprised of an extracellular V- and C-like Ig domain. It is a member of the B7 family of immune checkpoint proteins and is a key player in cancer progression.
B7-H3 is selectively expressed in both tumor cells and immune cells within the tumor microenvironment. In addition to its immune checkpoint function, B7-H3 has been linked to tumor cell proliferation, metastasis, and therapeutic resistance.
Numerous B7-H3-based ADCs have demonstrated potent antitumor activity and acceptable safety profiles in preclinical models. [1][2]
Here is an overview:
| Drug | Company Notes | Payload | Key Trial |
| Vobramitamab duocarmazine, also known as MGC018 and AEX4089DC1 [3][4] | MacroGenics linker-drug technology licensed from Byondis | Seco-duocarmycin hydroxybenzamide azaindole (DUBA) | A phase 2 (Tamarack-study) in mCRPC
|
| Ifinatamab deruxtecan, also known as DS-7300A [5] | Daiichi Sankyo in collaboration with Merck & Co/MSD In October 2023 Merck & Co signed a development agreement with Daiichi Sankyo for US $1.5bn upfront | Deruxtecan | A phase 2 Ideate-01 in SCLC
|
| HS-20093, also known as GSK5764227 or GSK’227 [6] | Hansoh Pharma in collaboration with GSK In December 2023 GSK signed a licensing agreement US $185m upfront. | Undisclosed topoisomerase inhibitor | Artemis-001 in solid tumors; various ongoing (Chinese) phase 2 studies
|
| MHB088C | Minghui Pharmaceutical | A Proprietary SuperTopoiTM (topoisomerase inhibitor) payload (approx. 5 to 10 times more potent than DXd) | A phase 1/2 in solid tumors
|
| IBI-129 / IBI129 | Innovent Biologics | Undisclosed | A phase 1/2 in solid tumors |
| DB-1311 /BNT234 | DualityBio in collaboration with BioNTech. In April 2023 BioNTech licensed signed a development agreement worth $170 M upfront. | A topoisomerase I inhibitor | A phase 1/2 in solid tumors
|
| 7MW3711 | Mabwell Bioscience | Mtoxin™ (MF6), a novel, proprietary, topoisomerase I inhibitor payload | Two Phase 1/2 studies trials in solid tumors |
| Mirzotamab clezutoclax (ABBV-155; Mirzo-C) [7] | AbbVie | BCL-XL inhibitor | A phase 1 in solid tumors
|
| BAT8009 | Bio-Thera Solutions | A topoisomerase I inhibitor | A phase 1 study (China)
|
| YL201 | MediLink Therapeutics | YL0010014 (topoisomerase I inhibitor) | A phase 1 in solid tumors
|
Reference
[1] Zhou WT, Jin WL. B7-H3/CD276: An Emerging Cancer Immunotherapy. Front Immunol. 2021 Jul 19;12:701006. doi: 10.3389/fimmu.2021.701006. PMID: 34349762; PMCID: PMC8326801.
[2] Getu AA, Tigabu A, Zhou M, Lu J, Fodstad Ø, Tan M. New frontiers in immune checkpoint B7-H3 (CD276) research and drug development. Mol Cancer. 2023 Mar 2;22(1):43. doi: 10.1186/s12943-023-01751-9. PMID: 36859240; PMCID: PMC9979440.
[3] Scribner JA, Brown JG, Son T, Chiechi M, Li P, Sharma S, Li H, De Costa A, Li Y, Chen Y, Easton A, Yee-Toy NC, Chen FZ, Gorlatov S, Barat B, Huang L, Wolff CR, Hooley J, Hotaling TE, Gaynutdinov T, Ciccarone V, Tamura J, Koenig S, Moore PA, Bonvini E, Loo D. Preclinical Development of MGC018, a Duocarmycin-based Antibody-drug Conjugate Targeting B7-H3 for Solid Cancer. Mol Cancer Ther. 2020 Nov;19(11):2235-2244. doi: 10.1158/1535-7163.MCT-20-0116. Epub 2020 Sep 23. PMID: 32967924.
[4] Brignole C, Calarco E, Bensa V, Giusto E, Perri P, Ciampi E, Corrias MV, Astigiano S, Cilli M, Loo D, Bonvini E, Pastorino F, Ponzoni M. Antitumor activity of the investigational B7-H3 antibody-drug conjugate, vobramitamab duocarmazine, in preclinical models of neuroblastoma. J Immunother Cancer. 2023 Sep;11(9):e007174. doi: 10.1136/jitc-2023-007174. PMID: 37775116; PMCID: PMC10546160.
[5] Belluomini L, Sposito M, Avancini A, Insolda J, Milella M, Rossi A, Pilotto S. Unlocking New Horizons in Small-Cell Lung Cancer Treatment: The Onset of Antibody-Drug Conjugates. Cancers (Basel). 2023 Nov 10;15(22):5368. doi: 10.3390/cancers15225368. PMID: 38001628; PMCID: PMC10670928.
[6] Fabrizio FP, Muscarella LA, Rossi A. B7-H3/CD276 and small-cell lung cancer: What's new? Transl Oncol. 2024 Jan;39:101801. doi: 10.1016/j.tranon.2023.101801. Epub 2023 Oct 20. PMID: 37865049; PMCID: PMC10728701.
[7] Negi A, Voisin-Chiret AS. Strategies to Reduce the On-Target Platelet Toxicity of Bcl-xL Inhibitors: PROTACs, SNIPERs and Prodrug-Based Approaches. Chembiochem. 2022 Jun 20;23(12):e202100689. doi: 10.1002/cbic.202100689. Epub 2022 Mar 19. PMID: 35263486; PMCID: PMC9311450.
