Antiangiogenic chimeric anti-endoglin (CD105) antibody: pharmacokinetics and immunogenicity in nonhuman primates and effects of doxorubicin.
We generated a human/mouse chimeric antibody c-SN6j of human IgG1 isotype from a murine anti-human endoglin (EDG) monoclonal antibody (mAb) SN6j that suppressed angiogenesis, tumor growth and metastasis in mice. We determined pharmacokinetics (PKs) and immunogenicity of c-SN6j in monkeys after multiple i.v. injections. A dose-escalation study was performed by administration of c-SN6j into six monkeys at the dose of 1 mg, 3 mg and 10 mg per kg body weight. In addition, both c-SN6j (3 mg/kg) and doxorubicin (0.275 mg/kg) were injected into two monkeys. c-SN6j and doxorubicin were injected twice a week for 3 weeks. We developed a unique and sensitive ELISA by sequentially targeting the common and idiotypic epitopes of c-SN6j-Fv to quantify plasma c-SN6j. Application of the ELISA showed that increasing the c-SN6j dose resulted in a proportional increase in the circulating c-SN6j after the first injection. In addition, the estimated area under the curve (AUC) for the first injection of c-SN6j is proportional to dose. We carried out detailed analyses of PKs of c-SN6j during and after the repeated injections. Our model of PKs fitted the empirical data well. Addition of doxorubicin modulated the PK parameters. We developed two ELISAs to separately determine the immune responses to the murine part and the human part of c-SN6j in monkeys. Interestingly, the murine part induced a weaker immune response than the human part. Doxorubicin potentiated the immune responses. Increasing the dose of c-SN6j increased plasma levels of c-SN6j but did not increase the immune responses to c-SN6j.
Shiozaki
Ken
K
Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Harada
Naoko
N
Greco
William R
WR
Haba
Akinao
A
Uneda
Shima
S
Tsai
Hilda
H
Seon
Ben K
BK
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000276:immunology* / Q000493:pharmacokinetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology* / Q000493:pharmacokinetics*; D015703:Antigens, CD; D004306:Dose-Response Relationship, Immunologic; D004317:Doxorubicin / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D000071063:Endoglin; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D023421:Models, Animal; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology*
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D019010:Vascular Cell Adhesion Molecule-1; D004317:Doxorubicin