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1.
J Biol Chem ; 291(24): 12641-12657, 2016 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-27036939

RESUMO

CXCR4 is a G protein-coupled receptor with excellent potential as a therapeutic target for a range of clinical conditions, including stem cell mobilization, cancer prognosis and treatment, fibrosis therapy, and HIV infection. We report here the development of a fully human single-domain antibody-like scaffold termed an "i-body," the engineering of which produces an i-body library possessing a long complementarity determining region binding loop, and the isolation and characterization of a panel of i-bodies with activity against human CXCR4. The CXCR4-specific i-bodies show antagonistic activity in a range of in vitro and in vivo assays, including inhibition of HIV infection, cell migration, and leukocyte recruitment but, importantly, not the mobilization of hematopoietic stem cells. Epitope mapping of the three CXCR4 i-bodies AM3-114, AM4-272, and AM3-523 revealed binding deep in the binding pocket of the receptor.


Assuntos
Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/imunologia , Anticorpos de Domínio Único/imunologia , Anticorpos de Domínio Único/farmacologia , Animais , Especificidade de Anticorpos/imunologia , Sítios de Ligação/imunologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Células Cultivadas , Cristalografia por Raios X , Mapeamento de Epitopos , Células HEK293 , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Células HL-60 , Humanos , Células Jurkat , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Modelos Moleculares , Ligação Proteica/imunologia , Domínios Proteicos , Receptores CXCR4/metabolismo , Anticorpos de Domínio Único/química , Ressonância de Plasmônio de Superfície
2.
Cancer Immunol Res ; 8(7): 895-911, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32312711

RESUMO

The immunoglobulin-like domain containing receptor 2 (ILDR2), a type I transmembrane protein belonging to the B7 family of immunomodulatory receptors, has been described to induce an immunosuppressive effect on T-cell responses. Besides its expression in several nonlymphoid tissue types, we found that ILDR2 was also expressed in fibroblastic reticular cells (FRC) in the stromal part of the lymph node. These immunoregulatory cells were located in the T-cell zone and were essential for the recruitment of naïve T cells and activated dendritic cells to the lymph nodes. Previously, it has been shown that an ILDR2-Fc fusion protein exhibits immunomodulatory effects in several models of autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and type I diabetes. Herein, we report the generation and characterization of a human/mouse/monkey cross-reactive anti-ILDR2 hIgG2 antibody, BAY 1905254, developed to block the immunosuppressive activity of ILDR2 for cancer immunotherapy. BAY 1905254 was shown to promote T-cell activation in vitro and enhance antigen-specific T-cell proliferation and cytotoxicity in vivo in mice. BAY 1905254 also showed potent efficacy in various syngeneic mouse cancer models, and the efficacy was found to correlate with increasing mutational load in the cancer models used. Additive or even synergistic antitumor effects were observed when BAY 1905254 was administered in combination with anti-PD-L1, an immunogenic cell death-inducing chemotherapeutic, or with tumor antigen immunization. Taken together, our data showed that BAY 1905254 is a potential drug candidate for cancer immunotherapy, supporting its further evaluation.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Imunoglobulina G/farmacologia , Ativação Linfocitária/imunologia , Proteínas de Membrana/imunologia , Neoplasias/tratamento farmacológico , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Tolerância Imunológica , Imunoglobulina G/imunologia , Imunoterapia/métodos , Leucócitos Mononucleares/imunologia , Proteínas de Membrana/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/imunologia , Neoplasias/metabolismo
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