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dc.contributor.authorChang, De-Kuanen_US
dc.contributor.authorMoniz, Raymond J.en_US
dc.contributor.authorXu, Zhongyaoen_US
dc.contributor.authorSun, Jiusongen_US
dc.contributor.authorSignoretti, Sabinaen_US
dc.contributor.authorZhu, Quanen_US
dc.contributor.authorMarasco, Wayne A.en_US
dc.date.accessioned2015-07-13T18:46:41Z
dc.date.issued2015en_US
dc.identifier.citationChang, De-Kuan, Raymond J. Moniz, Zhongyao Xu, Jiusong Sun, Sabina Signoretti, Quan Zhu, and Wayne A. Marasco. 2015. “Human anti-CAIX antibodies mediate immune cell inhibition of renal cell carcinoma in vitro and in a humanized mouse model in vivo.” Molecular Cancer 14 (1): 119. doi:10.1186/s12943-015-0384-3. http://dx.doi.org/10.1186/s12943-015-0384-3.en
dc.identifier.issn1476-4598en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:17295608
dc.description.abstractBackground: Carbonic anhydrase (CA) IX is a surface-expressed protein that is upregulated by the hypoxia inducible factor (HIF) and represents a prototypic tumor-associated antigen that is overexpressed on renal cell carcinoma (RCC). Therapeutic approaches targeting CAIX have focused on the development of CAIX inhibitors and specific immunotherapies including monoclonal antibodies (mAbs). However, current in vivo mouse models used to characterize the anti-tumor properties of fully human anti-CAIX mAbs have significant limitations since the role of human effector cells in tumor cell killing in vivo is not directly evaluated. Methods: The role of human anti-CAIX mAbs on CAIX+ RCC tumor cell killing by immunocytes or complement was tested in vitro by antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP) as well as on CAIX+ RCC cellular motility, wound healing, migration and proliferation. The in vivo therapeutic activity mediated by anti-CAIX mAbs was determined by using a novel orthotopic RCC xenograft humanized animal model and analyzed by histology and FACS staining. Results: Our studies demonstrate the capacity of human anti-CAIX mAbs that inhibit CA enzymatic activity to result in immune-mediated killing of RCC, including nature killer (NK) cell-mediated ADCC, CDC, and macrophage-mediated ADCP. The killing activity correlated positively with the level of CAIX expression on RCC tumor cell lines. In addition, Fc engineering of anti-CAIX mAbs was shown to enhance the ADCC activity against RCC. We also demonstrate that these anti-CAIX mAbs inhibit migration of RCC cells in vitro. Finally, through the implementation of a novel orthotopic RCC model utilizing allogeneic human peripheral blood mononuclear cells in NOD/SCID/IL2Rγ−/− mice, we show that anti-CAIX mAbs are capable of mediating human immune response in vivo including tumor infiltration of NK cells and activation of T cells, resulting in inhibition of CAIX+ tumor growth. Conclusions: Our findings demonstrate that these novel human anti-CAIX mAbs have therapeutic potential in the unmet medical need of targeted killing of HIF-driven CAIX+RCC. The orthotopic tumor xenografted humanized mouse provides an improved model to evaluate the in vivo anti-tumor capabilities of fully human mAbs for RCC therapy. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0384-3) contains supplementary material, which is available to authorized users.en
dc.language.isoen_USen
dc.publisherBioMed Centralen
dc.relation.isversionofdoi:10.1186/s12943-015-0384-3en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464115/pdf/en
dash.licenseLAAen_US
dc.subjectOrthotopic tumoren
dc.subjectNSG mouseen
dc.subjectAntibody engineeringen
dc.subjectCarbonic anhydrase IXen
dc.subjectImmunotherapyen
dc.subjectXenograften
dc.titleHuman anti-CAIX antibodies mediate immune cell inhibition of renal cell carcinoma in vitro and in a humanized mouse model in vivoen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalMolecular Canceren
dash.depositing.authorChang, De-Kuanen_US
dc.date.available2015-07-13T18:46:41Z
dc.identifier.doi10.1186/s12943-015-0384-3*
dash.contributor.affiliatedChang, De-Kuan
dash.contributor.affiliatedMarasco, Wayne
dash.contributor.affiliatedZhu, Quan
dash.contributor.affiliatedSun, Jiusong
dash.contributor.affiliatedSignoretti, Sabina


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