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Antiangiogenic chimeric anti-endoglin (CD105) antibody: pharmacokinetics and immunogenicity in nonhuman primates and effects of doxorubicin

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Abstract

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.

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Notes

  1. Haba A, Norderhaug L, and Seon BK. Generation of IgG1 and IgG3 human/mouse chimeric anti-endoglin monoclonal antibodies and comparative studies with the IgG1, IgG3 and parental monoclonal antibodies. Manuscript in preparation

  2. Harada N, Shiozaki KA, Martin L, Buitrago S, and Seon BK. Toxicity Tests of an Antiangiogenic and Chimeric Anti-Endoglin (CD105) Monoclonal Antibody in Nonhuman Primates after Repeated Systemic Injections. Manuscript in preparation

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Acknowledgements

We wish to thank Drs. Lisa Martin and Sandra Buitrago for help in the primate study, and Dr. Youcef Rustum for useful discussions and help. We thank Tom Spence for help in the preparation of the manuscript. This work was supported by Translational Research Grant DAMD17-97-1-7197 and Clinical Translational Research Grant DAMD17-03-1-0463 from the Breast Cancer Research Program of US Department of Defense, a grant from the New York Center for Advanced Technology, and Roswell Park Cancer Center Support Grant P30 CA16056 from the National Cancer Institute.

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Authors and Affiliations

  1. Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Ken Shiozaki, Naoko Harada, Akinao Haba, Shima Uneda, Hilda Tsai & Ben K. Seon

  2. Department of Biostatistics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    William R. Greco

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  1. Ken Shiozaki
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Correspondence to Ben K. Seon.

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Ken shiozaki and Naoko Harada have contributed equally to the present work.

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Shiozaki, K., Harada, N., Greco, W.R. et al. Antiangiogenic chimeric anti-endoglin (CD105) antibody: pharmacokinetics and immunogenicity in nonhuman primates and effects of doxorubicin. Cancer Immunol Immunother 55, 140–150 (2006). https://doi.org/10.1007/s00262-005-0691-4

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