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bioRxiv · 10.64898/2026.01.12.699160

A strategically designed homogeneous antibody-drug conjugate improves safety and therapeutic index in renal cell carcinoma

Thurakkal, L.·Velayutham, K.·Sarkar, B.·Kalyan, A.·Sengupta, S.·Saha, T.
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Abstract

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 eHicacy. 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 eHicacy 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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Thurakkal, L., Velayutham, K., Sarkar, B., Kalyan, A., Sengupta, S., Saha, T.. 2026-01-13. A strategically designed homogeneous antibody-drug conjugate improves safety and therapeutic index in renal cell carcinoma. https://doi.org/10.64898/2026.01.12.699160

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