A first-in-class IKZF1/3 degrader antibody conjugate (DAC) as a potential myeloma treatment

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 <10 nM) than lenalidomide. This ultra-high affinity enables robust ternary-complex formation even at low intracellular CRBN levels, thereby bypassing the resistance mechanisms that cripple IMiD efficacy. P5 exhibits low-picomolar degradation potency (IKZF1 EC₅₀ < 0.1 nM; IKZF3 EC₅₀ < 0.1 nM) and drives deep target degradation (≥ 90% D 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 < 1 nM) while exhibiting limited cytotoxicity toward PBMCs up to 1 µM. P5 exhibited favorable PK 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.