Open AccessTargeting the membrane-proximal C2-set domain of CD33 for improved CD33-directed immunotherapy
Author(s) -
Colin D. Godwin,
George S. Laszlo,
Salvatore Fiorenza,
Eliotte E. Garling,
Tinh-Doan Phi,
Olivia M. Bates,
Colin Correnti,
Benjamin G. Hoffstrom,
Margaret C. Lunn,
Olivier Humbert,
Hans–Peter Kiem,
Cameron J. Turtle,
Roland B. Walter
Publication year - 2021
Publication title -
leukemia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.539
H-Index - 192
eISSN - 1476-5551
pISSN - 0887-6924
DOI - 10.1038/s41375-021-01160-1
Subject(s) - cd33 , antibody , gemtuzumab ozogamicin , epitope , immunotherapy , cancer research , biology , immunology , chemistry , microbiology and biotechnology , immune system , cd34 , stem cell
There is increasing interest in targeting CD33 in malignant and non-malignant disorders. In acute myeloid leukemia, longer survival with the CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO) validates this strategy. Still, GO benefits only some patients, prompting efforts to develop more potent CD33-directed therapeutics. As one limitation, CD33 antibodies typically recognize the membrane-distal V-set domain. Using various artificial CD33 proteins, in which this domain was differentially positioned within the extracellular portion of the molecule, we tested whether targeting membrane-proximal epitopes enhances the effector functions of CD33 antibody-based therapeutics. Consistent with this idea, a CD33 V-set /CD3 bispecific antibody (BsAb) and CD33 V-set -directed chimeric antigen receptor (CAR)-modified T cells elicited substantially greater cytotoxicity against cells expressing a CD33 variant lacking the entire C2-set domain than cells expressing full-length CD33, whereas cytotoxic effects induced by GO were independent of the position of the V-set domain. We therefore raised murine and human antibodies against the C2-set domain of human CD33 and identified antibodies that bound CD33 regardless of the presence/absence of the V-set domain ("CD33 PAN antibodies"). These antibodies internalized when bound to CD33 and, as CD33 PAN /CD3 BsAb, had potent cytolytic effects against CD33 + cells. Together, our data provide the rationale for further development of CD33 PAN antibody-based therapeutics.