DAC-002：一种用于MM治疗的新型IKZF1/3 MGD-CD38降解剂-抗体偶联物

Introduction: Immunomodulatory drugs (IMiDs), which degrade Ikaros family zinc finger proteins 1 and 3 (IKZF1/3), have shown promising efficacy in the treatment of multiple myeloma (MM). Notably, since IKZF1/3 are essential transcription factors (TFs) for the differentiation of B and T lymphocytes, single-agent IMiD therapy is hampered by a limited therapeutic window: as next-generation IMiDs (e.g., iberdomide, mezigdomide, cemsidomide) exhibit enhanced IKZF1/3 degradation activity, the incidence of grade ≥ 3 hematologic treatment-emergent adverse events (TEAEs) is correspondingly elevated. Therefore, combination therapy regimens represent the mainstay of clinical practice for achieving improved efficacy, with key combinations including anti-CD38 monoclonal antibodies (anti-CD38 mAbs). On the other hand, it has also been demonstrated that IMiD-induced degradation of IKZF1/3 results in upregulated CD38 surface expression on MM cells (Fedele PL, et al. Blood. 2018; 132: 2166-2178), which enhances the anti-myeloma efficacy of anti-CD38 mAbs and overcomes acquired resistance associated with decreased CD38 expression. Combining the precision targeting feature of ADCs and catalytic degradation of protein degraders, Degrader-Antibody Conjugates (DACs) have emerged as a next-generation therapeutic modality. Here we presented DAC-002, an highly potent IKZF1/3 degrader as payload conjugated with anti-CD38 mAb. The synergistic effect of IMiD and anti-CD38 mAb resulted in improved in vivo efficacy with reduced usage of either agent comparing to combo therapy. Results: CY001-80 was developed as an highly potent and selective IKZF1/3 MGD with sub-nanomolar IKZF1/3 DC50. Treatment of CY001-80 induced the degradation of IKZF1/3 and upregulated the expression of CD38 on MM cell. In a previously described co-incubation assay, CY001-80 demonstrated superior neutrophil safety compared to mezigdomide and cemsidomide, while equivalent inhibition of MM cell viability. Degrader-Antibody conjugates (DACs) was generated by conjugation of CY001-80 (payload) to daratumumab monoclonal antibody (anti-CD38) using an optimized cleavable linker. In the MM-H929 tumor xenograft model, administration of DAC-002 (2 mpk) with a single intravenous injection promoted tumor regression (73% tumor growth inhibition by 15 days), outperforming daratumumab (6 mpk, IV, once)+ CY001-80 (0.01 mpk, PO, QD*14) combo in terms of efficacy. High level DAC-002 (18 mpk, IV, once) enabled complete tumor regression. PK studies on the H929-tumor-bearing mice demonstrated sustainable high exposure of IKZF1/3 MGD in the tumor and low release of free payload in plasma. Conclusions: In summary, DAC-002 is an highly potent IKZF1/3 MGD-CD38 DAC. In MM-H929 xenograft tumor model, DAC-002 treatment lead to robust tumor growth inhibition. No obvious safety concerns were observed in the preliminary NHP toxicology study. These findings support further development.