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Fc-engineered anti-CD40 antibody enhances multiple effector functions and exhibits potent in vitro and in vivo antitumor activity against hematologic malignancies.

Authors: Horton, HM  Bernett, MJ  Peipp, M  Pong, E  Karki, S  Chu, SY  Richards, JO  Chen, H  Repp, R  Desjarlais, JR  Zhukovsky, EA 
Citation: Horton HM, etal., Blood. 2010 Oct 21;116(16):3004-12. Epub 2010 Jul 8.
Pubmed: (View Article at PubMed) PMID:20616215
DOI: Full-text: DOI:10.1182/blood-2010-01-265280

CD40 is highly expressed on various B-lineage malignancies and represents an attractive immunotherapy target for neoplastic disease. Previous work showed that engineering the Fc domain of an antibody for increased binding to Fcgamma receptors (FcgammaRs) significantly enhanced Fc-mediated immune effector function and antitumor activity in vitro and in vivo. We developed a humanized anti-CD40 antibody similarly Fc-engineered for increased FcgammaR binding (XmAbCD40) and compared its efficacy with that of an anti-CD40 native IgG1 analog and the anti-CD20 antibody rituximab. XmAbCD40 increased antibody-dependent cell-mediated cytotoxicity (ADCC) up to 150-fold relative to anti-CD40 IgG1 against B-lymphoma, leukemia, and multiple myeloma cell lines, and significantly enhanced ADCC against primary tumors. XmAbCD40 was also superior to rituximab in enhancing ADCC (both in cell lines and primary tumors) and in augmenting antibody-dependent cellular phagocytosis. XmAbCD40 significantly inhibited lymphoma growth in disseminated and established mouse xenografts and was more effective than the IgG1 analog or rituximab. An anti-CD40 antibody constructed to abrogate FcgammaR binding showed no reduction of tumor growth, indicating that the in vivo antitumor activity of XmAbCD40 is primarily mediated via FcgammaR-dependent mechanisms. These data demonstrate that XmAbCD40 displays potent antitumor efficacy and merits further evaluation for the treatment of CD40(+) malignancies.

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CRRD Object Information
CRRD ID: 5490532
Created: 2011-09-15
Species: All species
Last Modified: 2011-09-15
Status: ACTIVE



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