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CA215 and GnRH receptor as targets for cancer therapy

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Abstract

Two monoclonal antibodies (Mabs), RP215 and GHR106, were selected for the preclinical evaluations of anti-cancer drugs targeting various human cancers including those of the ovary, cervix, lung, and liver. Both Mabs were shown to react with pan cancer markers, which are over-expressed on the surface of almost all human cancers. RP215 Mab was shown to react with the carbohydrate-associated epitope(s) of cancer cell–expressed glycoproteins, mainly consisting of immunoglobulin superfamily (IgSF) proteins and mucins, generally known as CA215. GHR106 Mab was generated against the extracellular domain of human GnRH receptor, which is also highly expressed on the cancer cell surface. Preclinical studies were performed to evaluate the efficacy of these two Mabs as anti-cancer drugs for treating human cancers. High tumor specificity of RP215 Mab was demonstrated with immunohistochemical staining studies of various cancer cell lines, as well as normal and cancerous tissue sections. These two Mabs were shown to induce apoptosis as well as complement-dependent cytotoxicity upon treatment to many cultured cancer cells. Significant dose-dependent growth inhibition of tumor cells from several different tissue origins were demonstrated by nude mouse experiments. It was further demonstrated that GHR106 Mab can function as long-acting GnRH analogs in its biological actions. Efforts were made to generate human/mouse chimeric forms of the GHR106 Mab. Based on the results of these preclinical studies, we believe that these two Mabs, in chimeric or humanized forms, can be developed into suitable therapeutic agents for treatment of human cancers as anti-cancer drugs.

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Abbreviations

AH:

Antibody high dose

AL:

Antibody low dose

CDC:

Complement-dependent cytotoxicity

CDR:

Complementarity determining region of immunoglobulin

ChRP215:

Mouse/human chimeric form of RP215

ChGHR106:

Mouse/human chimeric form of GHR106

EGF:

Epidermal growth factor

ELISA:

Enzyme-linked immunosorbent assay

Fab:

Fragment, antigen-binding region of immunoglobulin

Fc:

Fragment, crystallizable region of immunoglobulin

FR:

Framework region of immunoglobulin

GnRH:

Gonadotropin-releasing hormone

IgG:

Immunoglobulin G

IHC:

Immunohistochemical staining

Mab:

Monoclonal antibody

MALDI-TOF MS:

Matrix-assisted laser desorption ionization time-of-flight mass spectrometry

NFKB-1:

Nuclear factor of kappa light polypeptide gene enhancer in B-cells

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling (for apoptosis assay)

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Acknowledgments

This project was supported in parts by Vancouver Biotech Ltd, the NSERC and IRAP (#743918) research support. The authors would also like to thank NSERC-supported student from UBC, Alice Gao, for her assistance with this project.

Conflicts of interest

Gregory Lee is a co-founder of Vancouver Biotech Ltd. For the remaining authors, none are declared.

Author information

Authors and Affiliations

  1. Andrology Laboratory, University of British Columbia Center for Reproductive Health, 4500 Oak Street, Vancouver, BC, V6H 3N1, Canada

    Gregory Lee, Anthony P. Cheung, Bixia Ge, Mingang Zhu, Brett Giolma, Bo Li & Eric Wong

  2. Department of Cell Engineering, Fourth Military Medical University, Xi’an, China

    Yu Li, Yu Wang & Zinan Chen

  3. Molecular Pathology Laboratory, Shantou University Medical College, Shantou, China

    Jiang Gu

Authors
  1. Gregory Lee
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  2. Anthony P. Cheung
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  11. Jiang Gu
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Correspondence to Gregory Lee.

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Lee, G., Cheung, A.P., Ge, B. et al. CA215 and GnRH receptor as targets for cancer therapy. Cancer Immunol Immunother 61, 1805–1817 (2012). https://doi.org/10.1007/s00262-012-1230-8

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