Abstract 2613: Treatment of solid tumors with antibody drug conjugates targeting aberrant O-glycoproteins

Abstract

Abstract The lack of antibodies with sufficient cancer selectivity is currently limiting the treatment of solid tumors by immunotherapies. Many solid tumors display aberrant glycosylation that results in the expression of tumor-associated carbohydrate antigens (TACAs) distinct from healthy tissues. Targeting aberrantly glycosylated glycopeptide epitopes provides the cancer selectivity needed for immunotherapy of solid tumors. However, only a few such glycopeptide epitopes have been targeted to date. We have developed a strategy to predict, design, and produce cancer-specific antibodies targeting novel O-glycoprotein epitopes with exquisite cancer specificity. Our mAbs avoid on-target off-tumor toxicity due to the specificity of aberrant glycosylation, and cover a broad range of cancer indications, including breast, lung, colon, pancreatic, and ovarian cancer. Additionally, our antibodies can be used as an IHC companion diagnostic and can be functionalized across a number of modalities, including next-generation CAR-T, T-cell bispecifics, and antibody-drug-conjugates (ADCs).Here, we present two novel antibodies, GO-08 and GO-013, selectively targeting cancer-specific Tn-glycosylated proteins in a site-specific manner with low nanomolar affinities. GO-008 and GO-013 were collectively shown to be highly cancer-selective by immunohistochemistry of sections from a large array of different squamous and adenocarcinomas, including triple-negative breast cancer, lung cancer, gastric cancer, ovarian cancer, pancreatic, and colorectal cancer. The two antibodies were functionalized utilizing ConjuAllTM technology, conjugating the microtubule disrupting payload MMAE via a site-specific beta-glucuronidase cleavable linker. ConjuAllTM functions as a plasma stable, tumor labile linkage, and due to the minimal expression pattern of beta-glucuronidase in healthy tissues, reduces both off- and on-target toxicity due to the minimization of release of free payload in non-tumor tissues. The ADCs based on GO-08 and GO-013 (LCB45A and LCB22A) demonstrated target-specific cytotoxicity invitro and in vivo with tumor elimination in breast and lung PDX models. GO-013 conjugated to MMAE (LCB22A) was well tolerated in cynomolgus monkey toxicity studies. Moreover, the ADCs selectively kill target cells in a human mixed organotypic cancer model without affecting healthy cells, indicating tolerability and safety. The combination of specificity of TACA targeting to differentiate ADC binding from healthy tissue and ConjuAll’s tumor selective payload release promises to enable an excellent anti-cancer therapy. Citation Format: Aaron C. Groen, Nisha Shrestha, Boris Klebanov, Byeongjun Yu, BeomYong Lee, Chul-Woong Chung, Changsik Park, Mikkel K. Aasted, Sally Dabelsteen, Hans H. Wandall. Treatment of solid tumors with antibody drug conjugates targeting aberrant O-glycoproteins [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 2613.