A first-in-class IKZF1/3 degrader antibody conjugate (DAC) as a potential myeloma treatment
Presenter: Shuai Wu Session: Antibodies, Antibody-Drug Conjugates, and Nucleic Acids Time: 4/20/2026 9:00:00 AM → 4/20/2026 12:00:00 PM
Authors
Shuai Wu 1 , Jinyu Yang 2 , Mo Dan 2 , Xiwu Hui 3 , Bing Yao 3 , Miaomiao Wei 2 , Bin Bao 1 , Qiwen Zhu 1 , Linlin Xiao 2 , Penghui Wen 2 , Xiaodan Zhang 1 , Wei Fang 1 , Xiao Li 2 1 CSPC Megalith Biopharmaceutical Technology, Shanghai, China, 2 CSPC Pharmaceutical Group Ltd., Shijiazhuang, China, 3 CSPC Megalith Biopharmaceutical Technology, Shijiazhuang, China
Abstract
Antibody-drug conjugates (ADCs) deliver potent cytotoxins to tumors but are limited by off-target toxicity and resistance. This drives the development of Degrader Antibody Conjugates (DACs) platform, which combine the catalytic activity of targeted protein degradation (TPD) with the tissue specificity of antibodies. We applied this innovative approach to multiple myeloma, where most patients relapse after frontline regimens (e.g., RVd, PVd), creating a critical need for novel therapies that overcome IMiD resistance. Emerging novel IKZF1/3 degraders, which allosterically reprogram CRBN, offer a potent solution by overcoming IMiD resistance in the clinic. We hypothesized that conjugating these catalytic degraders to CD38 antibody would create a synergistic therapeutic, migrating this potent mechanism from late-line to frontline treatment. Here we describe the rational design and pre-clinical profile of ADC-2419, the first-in-class CD38-directed DAC that delivers the potent IKZF1/3 degrader P5 to tumors. From a panel of candidate payloads, we identified P5 that binds CRBN with an 80-fold higher affinity (Kd max ) in tumor cells. Quantitative proteomics of >8,000 proteins confirmed exquisite selectivity; no endogenous CRBN neosubstrates were significantly reduced. Consequently, P5 shows potent cytotoxicity against MM cells (IC₅₀ in vitro and in vivo and was well tolerated in cynomolgus monkey toxicity study, supporting its development as a next-generation payload. Therefore, conjugation of P5 to the human CD38 antibody via a cathepsin-cleavable linker generated ADC-2419. ADC-2419 demonstrates potent cytotoxicity against CD38-expressing cells in vitro. In NCI-H929 xenograft model, a single 1 mpk dose achieved complete tumor regression, outperforming parental CD38 antibody at the same dose. In the PBMC-humanized mouse model, ADC-2419 demonstrated enhanced efficacy and maintained significant superiority over the CD38 antibody. Furthermore, pronounced tumor accumulation was observed in tumor-bearing mice, aligning with the in vivo efficacy and validating the targeted-delivery capability of our DAC platform. Collectively, the robust preclinical evidence for ADC-2419, which synergizes antibody targeting with catalytic protein degradation, supports its translational promise in overcoming key limitations in myeloma treatment.
Disclosure
S. Wu, None.. J. Yang, None.. M. Dan, None.. X. Hui, None.. B. Yao, None.. M. Wei, None.. B. Bao, None.. Q. Zhu, None.. L. Xiao, None.. P. Wen, None.. X. Zhang, None.. W. Fang, None.. X. Li, None.
Cited in
Control: 510 · Presentation Id: 6482 · Meeting 21436