A potent tetravalent T-cell-engaging bispecific antibody against CD33 in acute myeloid leukemia

Blood Adv. 2018 Jun 12;2(11):1250-1258. doi: 10.1182/bloodadvances.2017014373.

Abstract

Acute myeloid leukemia (AML), the most common acute leukemia in adults and the second most common cancer in children, is still a lethal disease in the majority of patients, but immunologic approaches have improved outcome. Bispecific antibodies (BsAbs) are novel immunotherapeutics that can redirect immune cells against AML. We now report a tetravalent (2+2) humanized BsAb in the immunoglobulin G light chain single chain fragment variable [IgG(L)-scFv] format to engage polyclonal T cells to kill CD33+ AML targets. In vitro, this BsAb demonstrated strong antigen-specific T-cell-dependent cell-mediated cytotoxicity (TDCC) with an 50% effective concentration (EC50) in the femtomolar range that translated into treatment of established human AML IV xenografts in vivo. Importantly, it could redirect intraperitoneally injected T cells to ablate established and rapidly growing extramedullary subcutaneous AML xenografts in vivo. Furthermore, internalization of CD33 upon BsAb binding was identical to that of a bivalent (1+1) heterodimer, both being substantially less than anti-CD33 IgG. In contrast to the heterodimer, the tetravalent IgG-scFv BsAb was >10-fold more efficient in TDCC of AML cells in vitro and in vivo. This BsAb did not react with and did not kill CD38-CD34+ hematopoietic stem cells from cord blood. We conclude that the novel anti-CD33 IgG(L)-scFv BsAb construct reported here is a potential candidate for clinical development.

Publication types

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

MeSH terms

  • AC133 Antigen* / antagonists & inhibitors
  • AC133 Antigen* / immunology
  • Animals
  • Antibodies, Bispecific / pharmacology*
  • Antibody-Dependent Cell Cytotoxicity*
  • Antineoplastic Agents, Immunological / pharmacology*
  • Cell Line, Tumor
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Leukemia, Myeloid, Acute* / immunology
  • Mice
  • Mice, Knockout
  • Mice, SCID
  • T-Lymphocytes / immunology*
  • Xenograft Model Antitumor Assays

Substances

  • AC133 Antigen
  • Antibodies, Bispecific
  • Antineoplastic Agents, Immunological
  • PROM1 protein, human