T cell engaging bispecific antibodies targeting CD33 IgV and IgC domains for the treatment of acute myeloid leukemia.

Background: Acute myeloid leukemia (AML) remains one of the most challenging hematological malignancies. Despite progress in therapeutics, majority of patients succumb to this neoplasm. CD33 is a proven therapeutic target, given its expression on most AML cells. Almost all anti-CD33 antibodies target the membrane distal immunoglobulin V (IgV) domain of the CD33 extracellular domain.
Methods: In this manuscript, we present data on three bispecific antibodies (BsAbs) against the CD33 IgV and membrane proximal immunoglobulin C (IgC) domains. We use in vitro binding and cytotoxicity assays to show the effect of these BsAbs on AML cell lines. We also use immunodeficient mice-bearing leukemias from cell lines and patient-derived xenografts to show the effect of these BsAbs in vivo.
Results: In vitro, the IgV-targeting BsAb had higher binding to AML cell lines using flow cytometry and delivered more potent cytotoxicity in T-cell-dependent cytotoxicity assays; importantly, the IgC domain-targeting outperformed the IgV domain-targeting BsAb in medullary and extramedullary leukemia animal models.
Conclusions: These data support further clinical development of this BsAb for first-in-human phase I clinical trial.
Competing Interests: Competing interests: SSH and N-KVC were named as co-inventors in patents on CD33 bispecific antibodies filed by Memorial Sloan Kettering Cancer Center (MSKCC). BC133 and BC275 were licensed to Y-mAbs Therapeutics by MSKCC. Both MSKCC and N-KVC have financial interest in Y-mAbs. SSH and MV are employees of Y-mAbs Therapeutics. The remaining authors declare no competing financial interests.
(© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)