Presented at AACR Annual Meeting 2022
Hyunkyung Yu1, Nathalie Bellocq2, Youngeun Ha1, Hyunuk Kim1, Yunyeon Kim1, Bu-Nam Jeon1, Léo Marx2, Mathilde Pantin2, Hyunjin Yoo1, Seungmin Byun1, Joo-Yeon Chung1, Gyeongyeon Kim1, Mi Young Cha1, Patrick Garrouste2, Frédéric Lévy2
1Genome & Company, Korea
2Debiopharm International SA, Lausanne, Switzerland
Antibody-drug conjugates (ADCs) are promising cancer treatment modalities that combine the selectivity of antibodies and the cytotoxic properties of payloads using chemical linkers.
However, despite their success, ADCs still suffer from drawbacks such as systemic toxicity, limiting their potential clinical applications. The systemic toxicity of ADCs is mainly related to its linker’s stability and its antibody’s selectivity towards the targeted antigen expressed on cancer cells. Lu/BCAM (Lutheran/basal cell adhesion molecule) is a member of the immunoglobulin superfamily and is a receptor for laminin, a protein that facilitates cell adhesion, migration, and invasion. A growing number of studies show that BCAM plays an essential role in tumor progression and is overexpressed on epithelial cancers, e.g., skin cancer (Schön et al., J Invest Dermatol, 2000). Moreover, BCAM has been introduced as a promising ADC target for breast cancer (Kikkawa et al., Sci Rep, 2018).
We describe the ADC GENA-111-Multilink™-auristatin F (hereafter GENA-111-AF), wherein the GENA-111 antibody has been armed with an auristatin F derivative using Debiopharm’s Multilink™ technology and a stabilized thiol maleimide conjugation. Multilink™ technology comprises a cleavable peptidic sequence that facilitates multidrug attachment and the production of ADCs with high Drug Antibody Ratio (DAR). In this presentation, GENA-111-AF was prepared with one auristatin F per linker at a DAR of 4.26. We investigated the antitumor effects of GENA-111-AF on several cancer cell lines expressing both BCAM and HER2 at different levels, and compared it with the efficacy of trastuzumab-MultilinkTM-DM1 prepared in-house (hereafter trastuzumab-DM1) as a positive control for HER2-positive cancer cell lines.
We show here that BCAM is highly expressed in various cancer cell lines, including breast cancer, and GENA-111-AF has significant cytotoxic activity against BCAM expressing cell lines even in the cells not responding to trastuzumab-DM1. In addition, GENA-111-AF shows complete remissions in A431, BCAM-positive human skin cancer, xenograft model.