Abstract 1898: LNCB74 is a potent and safe next-generation antibody-drug-conjugate utilizing a cancer selective linker for the treatment of B7-H4 expressing cancers

Abstract

Abstract The B7 family protein B7-H4 is highly expressed on a range of solid tumors including breast, ovarian, and endometrial cancers, where it may play a role in immune evasion. In non-cancerous tissues, B7-H4 expression is limited, suggesting it may be a potential target for an antibody drug conjugate (ADC). LNCB74 is a human IgG1 antibody conjugated to the potent microtubule disrupting payload monomethyl auristatin E (MMAE) with a drug-to-antibody ratio of 4 (DAR4). The ADC employs a highly selective B7-H4 antibody based upon NextCure’s expertise in B7-H4 tumor biology coupled with a glucuronidase-cleavable, site-specific linkage to an engineered cysteine in the antibody light chain via LegoChem Biosciences’ ConjuAllTM technology. This improves the safety profile and therapeutic index of the agent by a) increasing stability in circulation, b) selectively releasing payload in tumor cells, and c) reducing payload release in off-target cells. LNCB74 was further engineered with a “LALA”-mutant Fc region to minimize uptake and toxicity to immune cells. In a nonhuman primate (NHP) toxicity study, LNCB74 was well tolerated for repeat dosing and provides evidence for a superior safety profile without noticeable side effects. LNCB74 is rapidly internalized by B7-H4-expressing tumor cells, and demonstrates potent, target-specific cytotoxicity on multiple cancer cell lines. In vivo studies demonstrate a strong bystander effect following a single dose administration of LNCB74. A rapid and durable anti-tumor response has been demonstrated in multiple cell-line derived (CDX) and patient-derived xenograft (PDX) tumor models. In summary, LNCB74 is a promising ADC enabling specific targeting of B7-H4 positive cancers across a spectrum of indications. Citation Format: Daniel P. Fitzgerald, Duc N. Doan, Riley B. Peacock, Shannon M. Kahan, Suvendu Lomash, Stephen Slocum, Kwang Hwa Jung, Hwanhee Oh, Ingrid Meza, Yanira Manzanarez, Shanmugam Selvam, Dallas B. Flies, Chul-Woong Chung, Sol Langermann. LNCB74 is a potent and safe next-generation antibody-drug-conjugate utilizing a cancer selective linker for the treatment of B7-H4 expressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1898.