Abstract 328: LCB84, a TROP2-targeted ADC, for treatment of solid tumors that express TROP-2 using the hu2G10 tumor-selective anti-TROP2 monoclonal antibody, a proprietary site-directed conjugation technology and plasma-stable tumor-selective linker chemistry

Abstract

LCB84 is a human Trop-2-targeting antibody drug conjugate (ADC) composed of monomethyl auristatin E (MMAE) as payload and the Hu2G10 (by Mediterranea Theranostic) humanized IgG1 antibody that selectively targets the ADAM10-activated Trop-2 protein selectively expressed in transformed cancer cells (1). LCB84 was prepared using ConjuAll࣪, a proprietary site-directed conjugation technology of LegoChem Biosciences, which incorporates a conjugation ‘handle’ joined by enzymatic prenylation to a specifically engineered recognition sequence (CaaX) on antibody light chains. This conjugation handle facilitates simple versatile chemical conjugation to the linker-payload. A proprietary plasma-stable cleavable linker that is recognized and cleaved by a cancer-associated lysosomal enzyme, β-glucuronidase, was used to enable efficient and traceless payload release in a cancer-specific manner. LCB84 has been evaluated for anti-tumor activity and showed superior anticancer efficacy in triple-negative breast cancer (TNBC), pancreatic ductal adenocarcinoma (PDAC), gastric cancer and non-small cell lung cancer (NSCLC) cell line-derived xenograft (CDX) models compared to the ADC competitors Trodelvy and DS-1062. The LCB84 treatments were well tolerated, with no changes in body weight compared to control animals, for all dosing groups. LCB84 has robust cross-reactivity against primate Trop-2, which allows rigorous toxicity studies in monkeys. Remarkably, preliminary toxicity studies using cynomolgus monkeys showed that LCB84 is well tolerated, with calculated therapeutic index (TI, MTD/MED) of ~30 for single dosing and ~40 for repeat dosing. In conclusion, LCB84 is highly effective against Trop-2-positive CDX models in mice at doses that are well tolerated in mice and in primate models. Use of this proprietary plasma-stable cancer-selective linker technology and the Hu2G10 anti-Trop-2 monoclonal antibody that targets cancer-activated Trop-2 has led to a greatly improved next generation ADC for the treatment of various Trop-2-positive solid cancers including TNBC, PDAC, NSCLC and gastric cancer. Citation Format: Hyejung Kim, Emanuela Guerra, Eunji Baek, Yeojin Jeong, Hyogeun You, Byeongjun Yu, Taeik Jang, Alberti Saverio, Chul-Woong Chung, Changsik Park. LCB84, a TROP2-targeted ADC, for treatment of solid tumors that express TROP-2 using the hu2G10 tumor-selective anti-TROP2 monoclonal antibody, a proprietary site-directed conjugation technology and plasma-stable tumor-selective linker chemistry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 328.

Trop2-targeted therapies in solid tumors: advances and future directions

“…It consists of monomethyl auristatin E (MMAE) as the payload and a humanized IgG1 mAb (Hu2G10) that can selectively target ADAM10-activated Trop2 on transformed tumor cells 36 . LegoChem Biosciences engineered LCB84 with a plasma-stable cleavable linker to allow for efficient and traceless payload release in a cancer-specific manner 37 . Compared with SG and Dato-DXd, LCB84 exhibited significantly enhanced in vivo antitumor activity in multiple CDX models, such as those for TNBC, NSCLC, and pancreatic ductal adenocarcinoma (PDAC).…”

“…Humanized 2G10 (Hu2G10) binds cancer-specific, cleaved/activated Trop2 with a high affinity (K D < 10 -12 M), and effectively suppresses the growth of Trop2-positive tumors in vivo , including breast, colon, and prostate cancers 36 , 57 . The ADC version of Hu2G10, known as LCB84, is being evaluated in an FIH phase 1/2 clinical trial (NCT05941507) 37 . Given that the combination of two mAbs, binding non-overlapping epitopes, could offer complementary MOAs and lead to synergistic therapeutic efficacy, Alberti's team explored the combined in vivo activity of 2G10 and 2EF-an anti-Trop2 mAb recognizing N-terminal epitopes of Trop2-ECD with proven antitumor activity across multiple tumor models 58 .…”

Progress and Innovative Combination Therapies in Trop-2-Targeted ADCs

“…The cancer-specific antibody Hu2G10, developed based on this finding, exhibits a significantly higher affinity for cancer-specific Trop-2 compared to wtTrop-2. In vivo studies demonstrate that the naked Hu2G10 antibody effectively inhibits the growth of breast cancer, colon cancer, ovarian cancer, and prostate cancer, thereby enhancing anti-cancer efficacy and paving the way for the next generation of ADCs [76][77][78][79]. Furthermore, exploring the heterogeneity of Trop-2 is expected to lead to the development of antibodies with improved affinity.…”

Targeting Trop2 in solid tumors: a look into structures and novel epitopes

“…No systemic toxicity was observed following Hu2G10 treatment. The ACD setting of Hu2G10, namely LCB84, demonstrated potent effectiveness against multiple Trop2-positive cell-line derived xenograft (CDX) models, including triple-negative breast cancer (TNBC), pancreatic ductal adenocarcinoma (PDAC), GC and NSCLC ( 59 ). This novel 2G10-based strategy, which recognizes tumor-specific Trop2, possesses the potential to improve the clinical outcome of next-generation Trop2-targeted therapies.…”