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

Authors: Hoseini, S. S.; Guo, H.; Wu, Z.; Nakajima Hatano, M.; Cheung, N. K. V.
Article Title: A potent tetravalent T-cell-engaging bispecific antibody against CD33 in acute myeloid leukemia
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.
Keywords: therapy; gemtuzumab ozogamicin; expression; stem-cells; target; aml; gd2
Journal Title: Blood Advances
Volume: 2
Issue: 11
ISSN: 2473-9529
Publisher: American Society of Hematology  
Date Published: 2018-06-12
Start Page: 1250
End Page: 1258
Language: English
ACCESSION: WOS:000434963600010
DOI: 10.1182/bloodadvances.2017014373
PMCID: PMC5998923
PUBMED: 29858209
Notes: Article -- Source: Wos
Citation Impact
MSK Authors
  1. Nai-Kong Cheung
    531 Cheung
  2. Hong-Fen Guo
    39 Guo
  3. Zhihao Wu
    6 Wu