The autophilic anti-CD20 antibody DXL625 displays enhanced potency due to lipid raft-dependent induction of apoptosis.
Despite widespread use of anti-CD20 antibodies as therapeutic agents for oncologic and autoimmune indications, precise descriptions of killing mechanisms remain incomplete. Complement-dependent cytolysis and antibody-dependent cell-mediated cytotoxicity are indicated as modes of target cell depletion; however, the importance of apoptosis induction is controversial. Studies showing that the therapeutic anti-CD20 antibody rituximab (Rituxan) mediates apoptosis of tumor cell targets in vitro after cross-linking by anti-Fc reagents suggest that enhancement strategies applied to Fc-independent activities for anti-CD20 antibodies could improve therapeutic efficacy. An anti-CD20 antibody designated DXL625, with autophilic properties such as increased binding avidity, is shown here to independently induce caspase-mediated apoptosis of an established B-cell lymphoma line in vitro. Depletion of membrane cholesterol or chelation of extracellular calcium abrogated the pro-apoptotic activity of DXL625, indicating that intact lipid rafts and calcium are required for this activity. The Fc-mediated complement-dependent and antibody-dependent cellular killing mechanisms are maintained by DXL625 despite conjugation of the parental Rituxan antibody to the autophilic DXL peptide sequence. This study shows a strategy for improving anti-CD20 immunotherapy by endowing therapeutic antibodies with self-interacting properties.
Bingaman
Marc G
MG
InNexus Biotechnology Inc, Scottsdale, Arizona, USA.
Basu
Gargi D
GD
Golding
Tiana C
TC
Chong
Samuel K
SK
Lassen
Andrew J
AJ
Kindt
Thomas J
TJ
Lipinski
Christopher A
CA
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D021962:Membrane Microdomains / Q000187:drug effects*; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D000069283:Rituximab; D002118:Calcium