Combining a homogenous KIM-1-DM1 antibody drug conjugate with sunitinib in renal cell carcinoma

Résumé fourni par la source

Renal cell carcinoma (RCC) is the most common form of kidney cancer. It is also one of deadliest cancers, with a 5-year survival rate of less than 20% in advanced cancer patients with distant metastasis. Current treatments rely on targeted therapies, such as sunitinib, which are limited in efficacy. Recently, antibody drug conjugates (ADCs) have emerged as a promising treatment modality by delivering cytotoxic payloads specifically to cancer cells. Here, we describe the engineering of a novel ADC (LT-025), where the antibody targets the kidney injury molecule (KIM) -1 receptor over-expressed on RCC cells to deliver a toxic maytansinoid (DM1) payload. Unlike prior attempts to engineer a KIM-1 targeted ADC that were limited by a heterogenous product, here we used a microbial transglutaminase (MTGase)-based conjugation strategy, which achieved a site-specific conjugation of the drug-linker to the antibody, resulting in a homogenous ADC with a drug-to-antibody ratio (DAR) of 2. The ADC exhibited prolonged stability, excellent antigen-binding capability, and KIM-1 expression-dependent cellular internalization and cytotoxicity in RCC, including in sunitinib-resistant RCC. Excitingly, LT-025 was well tolerated in vivo, and combining LT-025 and sunitinib exhibited a synergistic antitumor efficacy in a RCC mouse model. Combining an ADC with a targeted therapeutic could emerge as a paradigm shift in the management of advanced RCC.

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