Session: 604. Molecular Pharmacology and Drug Resistance: Myeloid Neoplasms: Poster II
Hematology Disease Topics & Pathways:
Biological therapies, Bispecific Antibody Therapy, drug development, Immunotherapy, Therapies
Materials and Methods: IGM-2537 was constructed using the pentameric human IgM framework. Recombinant IgM heavy chains and light chains with high affinity variable domains derived from an anti-CD123 IgG were co-expressed with a J-chain fused to anti-CD3 scFv. Surface plasma resonance (SPR), cell membrane protein array, and alanine scanning were utilized to characterize human CD123 binding affinity, specificity, and epitope mapping, respectively. Bispecific enzyme-linked immunosorbent assay (ELISA), T-cell NFAT reporter assay and T-cell dependent cellular cytotoxicity (TDCC) assays were employed to evaluate the potency of IGM-2537 to co-engage both CD123 and CD3 antigens, to induce T cell activation and target cytotoxicity, respectively. Ex vivo AML colony formation assay was applied to assess its activity to eliminate AML blasts. Human MV4-11 xenograft tumor model in humanized NSGdKO mice were utilized to determine anti-tumor efficacy of IGM-2537. Lastly, to confirm that CD123 directed IgM-based TCE molecule can potentially provide better safety profile, a benchmark IgM TCE comparator was assessed in cynomolgus monkeys for tolerability and PK/PD responses.
Results and Conclusions: IGM-2537 bound to human CD123 with high affinity, avidity, and specificity. Furthermore, IGM-2537 bound a unique epitope of human CD123 in domain 2 which does not overlap with IL-3. IGM-2537 co-engaged with both CD123 and CD3 antigens, leading to T cell-redirected killing of AML cell lines with concomitant T cell activation. Moreover, IGM-2537 eliminated AML blast cells at physiologically relevant effector/target (E/T) ratios in an ex vivo assay. Most importantly, IGM-2537 demonstrated comparable maximal killing activity to a benchmark IgG TCE molecule but shows significant reduction of cytokine release exemplified by IFN-γ, TNF-α and IL-6, which provide initial evidence of better preclinical safety profile for a CD123 directed IgM-based T-cell engager. As expected, the efficient in vitro TDCC activity of IGM-2537 translated into in vivo anti-tumor efficacy with tumor growth inhibition observed at dose ranges from 1 to 10 mg/kg. To further support that the IgM TCE format can provide a better safety window, a benchmark IgM TCE comparator was evaluated for tolerability (including cytokine production), PK and PD responses in cynomolgus monkeys. All animals tolerated the benchmark comparator well at dose levels up to 10 mg/kg (the maximal dose level evaluated); however, the tolerability observed with IgM TCE was 100x greater compared to IgG TCE. Complete depletion of CD123-positive basophils and substantial reduction of plasmacytoid dendritic cells (pDC) were seen in blood and bone marrow with minimal to no cytokine induction. In summary, our IGM-2537 demonstrates potent in vitro and in vivo activity with minimal cytokine induction. IgM as the framework of a TCE molecule can potentially provide better safety profile and an improved therapeutic window.
Disclosures: Liu: IGM Biosciences: Current Employment, Current equity holder in publicly-traded company. Li: IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Wang: IGM Biosciences: Current Employment, Current equity holder in publicly-traded company. Yakkundi: IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Hinton: IGM Biosciences: Current Employment, Current equity holder in publicly-traded company. Pandya: IGM Biosciences: Current Employment, Current equity holder in publicly-traded company. Amoury: IGM Biosciences: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Sekar: IGM Biosciences: Current Employment, Current equity holder in publicly-traded company. Liu: IGM Biosciences: Current Employment, Current equity holder in publicly-traded company. Rosete: IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Hanna: IGM Biosciences: Current Employment, Current equity holder in publicly-traded company. Kotturi: IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: WO2022109023A1. Bogaert: IGM Biosciences: Current Employment, Current equity holder in publicly-traded company. Hong: IGM Biosciences: Current Employment, Current equity holder in publicly-traded company. Tsai: IGM Biosciences: Current Employment, Current equity holder in publicly-traded company. Keyt: IGM Biosciences: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Sinclair: IGM Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties.
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