Effect of immune complex formation on the distribution of a novel antibody to the ovarian tumor antigen CA125.
3A5 is a novel antibody that binds repeated epitopes within CA125, an ovarian tumor antigen that is shed into the circulation. Binding to shed antigen may limit the effectiveness of therapeutic antibodies because of unproductive immune complex (IC) formation and/or altered antibody distribution. To evaluate this possibility, we characterized the impact of shed CA125 on the in vivo distribution of 3A5. In vitro, 3A5 and CA125 were found to form ICs in a concentration-dependent manner. This phenomenon was then evaluated in vivo using quantitative whole-body autoradiography to assess the tissue distribution of (125)I-3A5 in an orthotopic OVCAR-3 tumor mouse model at different stages of tumor burden. Low doses of 3A5 (75 μg/kg) and pathophysiological levels of shed CA125 led to the formation of ICs in vivo that were rapidly distributed to the liver. Under these conditions, increased clearance of 3A5 from normal tissues was observed in mice bearing CA125-expressing tumors. Of importance, despite IC formation, 3A5 uptake by tumors was sustained over time. At a therapeutically relevant dose of 3A5 (3.5 mg/kg), IC formation was undetectable and distribution to normal tissues followed that of blood. In contrast, increased levels of radioactivity were observed in the tumors. These data demonstrate that CA125 and 3A5 do form ICs in vivo and that the liver is involved in their uptake. However, at therapeutic doses of 3A5 and clinically relevant CA125 levels, IC formation consumes only a minor fraction of 3A5, and tumor targeting seems to be unaffected.
Pastuskovas
Cinthia V
CV
Pharmacokinetic and Pharmacodynamic Sciences, Genentech, Inc., South San Francisco, CA, USA.
Mallet
William
W
Clark
Suzanna
S
Kenrick
Margaret
M
Majidy
Mohammed
M
Schweiger
Michelle
M
Van Hoy
Marjie
M
Tsai
Siao Ping
SP
Bennett
Gregory
G
Shen
Ben-Quan
BQ
Ross
Sarajane
S
Fielder
Paul
P
Khawli
Leslie
L
Tibbitts
Jay
J
D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D000936:Antigen-Antibody Complex / Q000378:metabolism*; D018394:CA-125 Antigen / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D010051:Ovarian Neoplasms / Q000276:immunology*; D014018:Tissue Distribution
D000906:Antibodies; D000936:Antigen-Antibody Complex; D018394:CA-125 Antigen