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

J Immunother Cancer. 2021 May;9(5):e002509. doi: 10.1136/jitc-2021-002509.

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.

Keywords: antibodies; antigens; immunotherapy; neoplasm.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Bispecific / immunology
  • Antibodies, Bispecific / pharmacology*
  • Antibodies, Monoclonal, Humanized / immunology
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antineoplastic Agents, Immunological / immunology
  • Antineoplastic Agents, Immunological / pharmacology*
  • Cell Proliferation / drug effects
  • Coculture Techniques
  • Cytokines / metabolism
  • Humans
  • Immunoglobulin Domains
  • Immunoglobulin Variable Region
  • K562 Cells
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / immunology
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Lymphocyte Activation / drug effects*
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, SCID
  • Sialic Acid Binding Ig-like Lectin 3 / antagonists & inhibitors*
  • Sialic Acid Binding Ig-like Lectin 3 / immunology
  • Sialic Acid Binding Ig-like Lectin 3 / metabolism
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • THP-1 Cells
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Bispecific
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents, Immunological
  • CD33 protein, human
  • Cytokines
  • Immunoglobulin Variable Region
  • Sialic Acid Binding Ig-like Lectin 3