title: Anti-tumor activity of human IgG1 anti-gp75 TA99 mAb against B16F10 melanoma in human FcgammaRI transgenic mice.
abstract: Patients suffering from advanced melanoma have a very poor prognosis. Despite recent advances in the understanding of oncogenic mechanisms and therapeutic interventions, the median survival of patients with metastatic disease is less than 12 months. Immunotherapy of melanoma has been intensely investigated and holds great promises. Tyrosinase-related protein-1 or gp75 (TYRP-1/gp75) antigen is a melanosomal polypeptide. It is the most abundant glycoprotein synthesized by pigmented melanocytes and melanomas. It is specific for melanocytes and both primary and metastatic melanomas. In mice, administration of the mouse mAb anti-gp75 TA99 prevents outgrowth of B16F10 melanoma metastases. The activity of TA99 is dependent on the presence and activity of the IgG specific, Fc receptors. TA99 cross-reacts with human gp75, and is currently being used for diagnosis of patients. Here, we sequenced mIgG2a TA99 and found that the locus harboring the endogenous light chain of the fusion partner in the TA99 hybridoma cells is not inactivated, resulting in the production of a mixed pool of mAbs that mitigates binding to gp75. Since human IgG1 (hIgG1) is the most frequently used mAb format in clinical studies, we produced a recombinant hIgG1 TA99 molecule. Whereas it is known that hIgG1 can functionally interact with mouse Fc receptors, we found that hIgG1 TA99 did not exhibit in vivo activity against B16F10 melanoma in wild type C57BL/6 mice. However, results obtained in this study demonstrated anti-tumor activity of hIgG1 TA99 in FcγRIIB knockout mice and in human FcγRI transgenic mice. These results emphasize the need for testing hIgG mAb in mice with functional human FcγRs.
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center Utrecht, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Boross
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center Utrecht, The Netherlands.
authors.forename: J H Marco
authors.initials: JH
authors.lastname: Jansen
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center Utrecht, The Netherlands.
authors.forename: Geert
authors.initials: G
authors.lastname: van Tetering
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center Utrecht, The Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: Nederend
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center Utrecht, The Netherlands.
authors.forename: Arianne
authors.initials: A
authors.lastname: Brandsma
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center Utrecht, The Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: Meyer
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center Utrecht, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Torfs
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center Utrecht, The Netherlands.
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: van den Ham
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center Utrecht, The Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: Meulenbroek
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center Utrecht, The Netherlands.
authors.forename: Simone
authors.initials: S
authors.lastname: de Haij
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center Utrecht, The Netherlands. Electronic address: jleusen@umcutrecht.nl.
authors.forename: Jeanette H W
authors.initials: JH
authors.lastname: Leusen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D003429:Cross Reactions; D006801:Humans; D006825:Hybridomas / Q000737:chemistry / Q000276:immunology; D007074:Immunoglobulin G / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D019076:Transgenes
chemical_list: D000911:Antibodies, Monoclonal; C489017:FCGR1A protein, human; C080571:Fc gamma receptor IIB; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D010088:Oxidoreductases; C489799:TYRP1 protein, human
keywords: Antibody therapy; Fc receptor; Melanoma; TA99; gp75