TY - JOUR
T1 - Development and preclinical characterization of a humanized antibody targeting CXCL12
AU - Zhong, Cuiling
AU - Wang, Jianyong
AU - Li, Bing
AU - Xiang, Hong
AU - Ultsch, Mark
AU - Coons, Mary
AU - Wong, Terence
AU - Chiang, Nancy Y.
AU - Clark, Suzy
AU - Clark, Robyn
AU - Quintana, Leah
AU - Gribling, Peter
AU - Suto, Eric
AU - Barck, Kai
AU - Corpuz, Racquel
AU - Yao, Jenny
AU - Takkar, Rashi
AU - Lee, Wyne P.
AU - Damico-Beyer, Lisa A.
AU - Carano, Richard D.
AU - Adams, Camellia
AU - Kelley, Robert F.
AU - Wang, Weiru
AU - Ferrara, Napoleone
PY - 2013/8
Y1 - 2013/8
N2 - Purpose: Our goal was to develop a potent humanized antibody against mouse/human CXCL12. This report summarized its in vitro and in vivo activities. Experimental Design: Cell surface binding and cell migration assays were used to select neutralizing hamster antibodies, followed by testing in several animal models. Monoclonal antibody (mAb) 30D8 was selected for humanization based on its in vitro and in vivo activities. Results: 30D8, a hamster antibody against mouse and human CXCL12α, CXCL12β, and CXCL12γ, was shown to dose-dependently block CXCL12α binding to CXCR4 and CXCR7, and CXCL12α-induced Jurkat cell migration in vitro. Inhibition of primary tumor growth and/or metastasis was observed in several models. 30D8 alone significantly ameliorated arthritis in a mouse collagen-induced arthritis model (CIA). Combination with a TNF-a antagonist was additive. In addition, 30D8 inhibited 50% of laser-induced choroidal neovascularization (CNV) in mice. Humanized 30D8 (hu30D8) showed similar in vitro and in vivo activities as the parental hamster antibody. A crystal structure of the hu30D8 Fab/CXCL12α complex in combination with mutational analysis revealed a "hot spot" around residues Asn44/Asn45 of CXCL12α and part of the RFFESH region required for CXCL12α binding to CXCR4 and CXCR7. Finally, hu30D8 exhibited fast clearance in cynomolgus monkeys but not in rats. Conclusion: CXCL12 is an attractive target for treatment of cancer and inflammation-related diseases; hu30D8 is suitable for testing this hypothesis in humans.
AB - Purpose: Our goal was to develop a potent humanized antibody against mouse/human CXCL12. This report summarized its in vitro and in vivo activities. Experimental Design: Cell surface binding and cell migration assays were used to select neutralizing hamster antibodies, followed by testing in several animal models. Monoclonal antibody (mAb) 30D8 was selected for humanization based on its in vitro and in vivo activities. Results: 30D8, a hamster antibody against mouse and human CXCL12α, CXCL12β, and CXCL12γ, was shown to dose-dependently block CXCL12α binding to CXCR4 and CXCR7, and CXCL12α-induced Jurkat cell migration in vitro. Inhibition of primary tumor growth and/or metastasis was observed in several models. 30D8 alone significantly ameliorated arthritis in a mouse collagen-induced arthritis model (CIA). Combination with a TNF-a antagonist was additive. In addition, 30D8 inhibited 50% of laser-induced choroidal neovascularization (CNV) in mice. Humanized 30D8 (hu30D8) showed similar in vitro and in vivo activities as the parental hamster antibody. A crystal structure of the hu30D8 Fab/CXCL12α complex in combination with mutational analysis revealed a "hot spot" around residues Asn44/Asn45 of CXCL12α and part of the RFFESH region required for CXCL12α binding to CXCR4 and CXCR7. Finally, hu30D8 exhibited fast clearance in cynomolgus monkeys but not in rats. Conclusion: CXCL12 is an attractive target for treatment of cancer and inflammation-related diseases; hu30D8 is suitable for testing this hypothesis in humans.
UR - http://www.scopus.com/inward/record.url?scp=84882990634&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-13-0943
DO - 10.1158/1078-0432.CCR-13-0943
M3 - Article
SN - 1078-0432
VL - 19
SP - 4433
EP - 4445
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -
