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

Overview

abstract

  • 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.

publication date

  • May 1, 2021

Research

keywords

  • Antibodies, Bispecific
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents, Immunological
  • Leukemia, Myeloid, Acute
  • Lymphocyte Activation
  • Sialic Acid Binding Ig-like Lectin 3
  • T-Lymphocytes

Identity

PubMed Central ID

  • PMC8154967

Scopus Document Identifier

  • 85106919369

Digital Object Identifier (DOI)

  • 10.1182/blood-2019-129042

PubMed ID

  • 34035113

Additional Document Info

volume

  • 9

issue

  • 5