Disrupting LILRB4/APOE Interaction by an Efficacious Humanized Antibody Reverses T-cell Suppression and Blocks AML Development

Cancer Immunol Res. 2019 Aug;7(8):1244-1257. doi: 10.1158/2326-6066.CIR-19-0036. Epub 2019 Jun 18.

Abstract

Therapeutic strategies are urgently needed for patients with acute myeloid leukemia (AML). Leukocyte immunoglobulin-like receptor B4 (LILRB4), which suppresses T-cell activation and supports tissue infiltration of AML cells, represents an attractive drug target for anti-AML therapeutics. Here, we report the identification and development of an LILRB4-specific humanized mAb that blocks LILRB4 activation. This mAb, h128-3, showed potent activity in blocking the development of monocytic AML in various models including patient-derived xenograft mice and syngeneic immunocompetent AML mice. MAb h128-3 enhanced the anti-AML efficacy of chemotherapy treatment by stimulating mobilization of leukemia cells. Mechanistic studies revealed four concordant modes of action for the anti-AML activity of h128-3: (i) reversal of T-cell suppression, (ii) inhibition of monocytic AML cell tissue infiltration, (iii) antibody-dependent cellular cytotoxicity, and (iv) antibody-dependent cellular phagocytosis. Therefore, targeting LILRB4 with antibody represents an effective therapeutic strategy for treating monocytic AML.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Blocking
  • Antibodies, Monoclonal
  • Antibody-Dependent Cell Cytotoxicity
  • Antineoplastic Agents, Immunological / pharmacology*
  • Antineoplastic Agents, Immunological / therapeutic use
  • Apolipoproteins E / chemistry
  • Apolipoproteins E / metabolism*
  • Apoptosis
  • Cell Line
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / immunology*
  • Cell Transformation, Neoplastic / metabolism*
  • Coculture Techniques
  • Disease Models, Animal
  • Humans
  • Leukemia, Myeloid, Acute / etiology*
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Models, Molecular
  • Protein Binding / drug effects
  • Rabbits
  • Receptors, Immunologic / antagonists & inhibitors
  • Receptors, Immunologic / chemistry
  • Receptors, Immunologic / metabolism*
  • Structure-Activity Relationship
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Blocking
  • Antibodies, Monoclonal
  • Antineoplastic Agents, Immunological
  • ApoE protein, human
  • Apolipoproteins E
  • LILRB4 protein, human
  • Membrane Glycoproteins
  • Receptors, Immunologic