A first-in-class KIF11 degrader antibody conjugate (DAC) as a potential therapy targeting a broad spectrum of cancers.

Abstract

3092 Background: Kinesin family member 11 (KIF11) plays a critical role in mitotic spindle formation and centrosome separation during cell division, making it an attractive anti-cancer target. Despite its promise, the clinical success of KIF11 inhibitors has been hindered by a narrow therapeutic window, largely due to on-target toxicities, such as myelosuppression. Antibody-drug conjugates present a promising strategy to overcome this limitation by enhancing the therapeutic window of KIF11-targeting therapies. However, creating a KIF11-targeting inhibitor payload with sub-nanomolar potency remains a significant challenge. Using Accutar’s chimeric degrader platform, we developed dKIF976, a first-in-class KIF11 degrader with sub-nanomolar potency. This degrader was further used as payload to create DACs demonstrating potent cell growth inhibition coupled with KIF11 degradation, thereby providing a robust foundation for further in vivo evaluation of novel KIF11-targeting therapy. Methods: dKIF976, a CRBN-based KIF11 degrader, was designed via Accutar’s chimeric degrader platform. Western blot analysis was used to evaluate KIF11 degradation and mitotic arrest, as indicated by Histone H3 phosphorylation, in cancer cell lines. Cell growth inhibition was assessed using ATP-based assays. Mechanism and selectivity of dKIF976 were confirmed through specific cellular assays and proteomic analyses. Cell surface antigen-dependent activity of dKIF976 DACs were evaluated in cell lines with different levels of antigen expression. Results: dKIF976 demonstrated rapid, dose-dependent KIF11 degradation and significant upregulation of p-Histone H3 across all tested cell lines, achieving sub-nanomolar potency. In side-by-side comparisons, dKIF976 displayed significantly greater cell growth inhibition than multiple published KIF11 inhibitors. KIF11 degradation and the resulting cell growth inhibition induced by dKIF976 were confirmed to be dependent on the E3 ligase CRBN and the proteasome. Proteomic analysis via mass spectrometry validated the selective degradation of KIF11. When conjugated to antibodies, dKIF976 DACs exhibited antigen-dependent KIF11 degradation and cell growth inhibition, with enhanced potency observed in cell lines with high target expression. Conclusions: dKIF976 achieves specific and potent KIF11 degradation, inducing mitotic arrest and robust cancer cell growth inhibition. Its superior efficacy and unique mechanism of action establish it as a highly promising payload for antibody conjugates. dKIF976 DACs demonstrated strong antigen-dependent KIF11 degradation and cell growth inhibition. This innovation highlights the potential of using chimeric degraders as payloads for antibody conjugates, offering a promising strategy to enhance the therapeutic window of KIF11-targeted therapies and pave the way for their future success.