Deciphering the Impact of KYM-001: A Pioneering IRAK4 Degrader for MYD88-Mutant ABC DLBCL Therapy

The research evaluated the efficacy of a specific IRAK4 degrader, KYM-001, in targeting human ABC DLBCL cell lines in vitro and in vivo tumor models, both as a standalone treatment and in conjunction with BTK inhibitors. ABC DLBCL, which accounts for about half of DLBCL cases, has a poorer response to R-CHOP chemotherapy than GCB DLBCL. Around 30-40% of ABC DLBCL cases exhibit MYD88 mutations, with L265P being the most common, leading to the continuous activation of the Myddosome. IRAK4 plays a crucial role in the Myddosome's signaling to NFκB and MAPK pathways. Kymera Therapeutics has been developing heterobifunctional IRAK4 degraders, such as KYM-001, to treat MYD88-driven lymphomas.

The study employed immunoassays and targeted MS/MS to measure IRAK4 levels in human PBMCs, ABC DLBCL cell lines, and xenografts. Myddosome signaling was tracked using mRNA and phosphoprotein markers, while cell viability and cycle were assessed via flow cytometry. Tumor xenograft studies involved transplanting ABC DLBCL cell lines into immunodeficient mice and monitoring tumor growth.

KYM-001 demonstrated potent degradation of IRAK4 dependent on E3 ligase. It was more effective in inhibiting TLR-activated Myddosome signaling in human PBMCs compared to IRAK4 kinase inhibitors. The degradation was highly selective for IRAK4, with no significant impact on over 10,000 other detected proteins in the MYD88 L265P mutant ABC DLBCL line OCI-LY10. KYM-001 induced cell cycle arrest and apoptosis in ABC DLBCL within 48-72 hours, showing a preference for MYD88-mutant over MYD88-wild type cell lines. Oral administration of KYM-001 showed dose-dependent antitumor activity in several mouse xenograft models of human MYD88-mutant ABC DLBCL at well-tolerated doses and schedules. In the OCI-LY10 model, tumor regression was linked to over 80% degradation of IRAK4, indicating the necessary pharmacodynamic effect for optimal efficacy.

Considering that BCR signaling alterations and MYD88 mutations often occur together in B-cell malignancies, the study also explored the combined effect of IRAK4 degradation and BTK inhibition. In the OCI-LY10 xenograft model, which has activating mutations in both CD79B and MYD88, BTK inhibition with ibrutinib enhanced the antitumor activity of KYM-001.

The findings suggest that KYM-001 is a promising new IRAK4 degrader that can induce tumor regression in ABC-DLBCL models, both as a monotherapy and in combination with BTK inhibitors. The degradation of IRAK4 eliminates both its kinase and scaffolding functions, potentially offering a superior therapeutic approach to kinase inhibition alone. This research supports the potential of IRAK4 degraders as a novel treatment option for MYD88-driven lymphoma.