Cytotoxic Mechanisms of Tumor Specific Antibodies
Abstract
Although many mechanisms have been proposed to account for the anti-tumor activities of therapeutic antibodies, including extended half-life, blockade of signaling pathways, activation of apoptosis and effector-cell-mediated cytotoxicity, we have demonstrated (Clynes RA, Towers TL, Presta LG, Ravetch JV, Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nature Medicine 6:443-446 (2000)) that engagement of Fcgamma receptors on effector cells is a dominant component of the in vivo activity of antibodies against tumors. Engagement of activating Fc receptors (FcRI and/or III) was required for the in vivo activity of mouse monoclonal antibodies and vaccines in syngenic melanoma models, as well as of humanized, clinically effective therapeutic mAbs Herceptin and Rituxan in breast cancer and lymphoma xenograft system) . Mice deficient in the inhibitory receptor FcgammaRIIB showed much more antibody-dependent cell-mediated cytotoxicity; while in contrast, mice deficient in activating Fc receptors as well as antibodies engineered to disrupt Fc binding to those receptors were unable to arrest tumor growth in vivo.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2001
- Accession Number
- ADA405219
Entities
People
- Raphael Clynes
Organizations
- Columbia University