The U.S. Food and Drug Administration (FDA) has cleared an investigational new drug (IND) application for OBI-992 (also known as BSI-992), to conduct a Phase 1/2 study of its novel antibody-drug conjugate (ADC) cancer therapy targeting TROP2 being developed OBI Pharma and its partner Biosion.

The targeting antibody was discovered through Biosion’s SynTracer® High Throughput Endocytosis Platform and was licensed to OBI Pharma in December 2021. OBI Pharma owns ex-China commercial rights for OBI-992 (BSI-992) , and Biosion owns China rights.

The investigational agent is a human trophoblast cell-surface antigen 2 (TROP2-) targeted antibody-drug-conjugate (ADC) that carries a potent topoisomerase I inhibitor payload to kill solid tumors.

TROP2 Targeting ADC
TROP2 is a transmembrane glycoprotein and calcium signal transducer with limited expression in normal human tissues. It is, however, consistently overexpressed in a variety of solid tumors such as lung, breast, ovarian, and gastric cancer. TROP2 also plays a major role in several oncogenic signaling pathways that lead to tumor development, invasion, and metastasis. As a result, TROP2 has become an ideal therapeutic target for the treatment of cancer. [1][2

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Today, sacituzumab govitecan (Trodelvy™, Gilead) is the only anti-TROP2 antibody-drug conjugate approved to treat metastatic triple-negative breast cancer (TNBC), while datopotamab deruxtecan (Dato-DXd, DS-1062a), which includes a potent DNA topoisomerase I inhibitor (DXd), is being developed by Daiichi Sankyo.[3][4]

TROP2 is also targeted by SKB264 (also known as MK-2870), an ADC being developed by KLUS Pharma (a subsidiary of Kelun Pharmaceuticals, Sichuan Chengdu, China) in collaboration with Merck & Co/MSD for the treatment of select patients with a variety of advanced solid tumors. SKB264 is novel anti-TROP2 ADC developed using sulfonyl pyrimidine-CL2A-carbonate linker to conjugate its payload, a belotecan-derivative topoisomerase I inhibitor, to achieve an average Drug-to-antibody Ratio (DAR) of 7.4.[5]

Pre-clinical studies
OBI-992 (BSI-992) uses a differentiated hydrophilic, enzyme-cleavable linker that is stable in circulation but releases the cytotoxic payload inside tumor cells. OBI-992 (BSI-992 demonstrates remarkable antitumor efficacy, improved pharmacokinetic characteristics, and a favorable safety profile in animal models. The anti-TROP-2 targeting antibody was discovered and developed by Biosion, OBI Pharma owns ex-China commercial rights for OBI-992 (BSI-992).

“We are very pleased to see OBI Pharma receive FDA clearance for OBI-992 (BSI-992),” noted Hugh M. Davis, Ph.D., Chief Business & Development Officer, and President of Biosion USA, Inc.

“OBI-992 demonstrated superiority over other TROP2 ADCs in pre-clinical studies. It is a solid validation of the unique advantages of Biosion’s SynTracer® platform to identify fit-for-purpose antibodies for the development of novel ADC therapies. We are excited about this innovative treatment and making a meaningful difference for patients worldwide.”

OBI Pharma plans to enroll patients with advanced solid tumors, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and gastric cancer (GC), although several other cancers are also potential targets.

“The clinical trial intends to evaluate the safety, pharmacokinetics, and preliminary efficacy of OBI-992, a novel anti-TROP2 ADC with best-in-class potential. We look forward to dosing the first patient in our Phase 1/2 clinical study of OBI-992, which is expected to begin in early 2024,” said OBI Pharma’s Chief Medical Officer, Wayne Saville, M.D.

“OBI-992 is a novel anti-TROP2 ADC designed and engineered by OBI Pharma. It demonstrates outstanding preclinical efficacy, favorable safety, and high stability in numerous in-vivo studies compared to other TROP2 ADCs. We are excited to commence the first-in-human clinical trial of OBI-992. OBI Pharma strives to advance our promising therapeutics to the clinic for cancer patients,” Heidi Wang, Ph.D., OBI Pharma’s Chief Executive Officer, concluded.

Highlights of prescribing information
Sacituzumab govitecan (Trodelvy™, Gilead) [Prescribing Information]

[1] Liu X, Deng J, Yuan Y, Chen W, Sun W, Wang Y, Huang H, Liang B, Ming T, Wen J, Huang B, Xing D. Advances in Trop2-targeted therapy: Novel agents and opportunities beyond breast cancer. Pharmacol Ther. 2022 Nov;239:108296. doi: 10.1016/j.pharmthera.2022.108296. Epub 2022 Oct 5. Erratum in: Pharmacol Ther. 2023 Mar;243:108336. PMID: 36208791.
[2] Wen Y, Ouyang D, Zou Q, Chen Q, Luo N, He H, Anwar M, Yi W. A literature review of the promising future of TROP2: a potential drug therapy target. Ann Transl Med. 2022 Dec;10(24):1403. doi: 10.21037/atm-22-5976. PMID: 36660684; PMCID: PMC9843409.
[3] Okajima D, Yasuda S, Maejima T, Karibe T, Sakurai K, Aida T, Toki T, Yamaguchi J, Kitamura M, Kamei R, Fujitani T, Honda T, Shibutani T, Muramatsu S, Nakada T, Goto R, Takahashi S, Yamaguchi M, Hamada H, Noguchi Y, Murakami M, Abe Y, Agatsuma T. Datopotamab Deruxtecan, a Novel TROP2-directed Antibody-drug Conjugate, Demonstrates Potent Antitumor Activity by Efficient Drug Delivery to Tumor Cells. Mol Cancer Ther. 2021 Dec;20(12):2329-2340. doi: 10.1158/1535-7163.MCT-21-0206. Epub 2021 Aug 19. PMID: 34413126; PMCID: PMC9398094.
[4] Nelson BE, Meric-Bernstam F. Leveraging TROP2 Antibody-Drug Conjugates in Solid Tumors. Annu Rev Med. 2023 Sep 27. doi: 10.1146/annurev-med-071322-065903. Epub ahead of print. PMID: 37758237.
[5] Cheng Y, Yuan X, Tian Q, Huang X, Chen Y, Pu Y, Long H, Xu M, Ji Y, Xie J, Tan Y, Zhao X, Song H. Preclinical profiles of SKB264, a novel anti-TROP2 antibody conjugated to topoisomerase inhibitor, demonstrated promising antitumor efficacy compared to IMMU-132. Front Oncol. 2022 Dec 23;12:951589. doi: 10.3389/fonc.2022.951589. Erratum in: Front Oncol. 2023 Dec 07;13:1334938. PMID: 36620535; PMCID: PMC9817100.

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