RESUMO
Unlike conventional chemical drugs where immunogenicity typically does not occur, the development of anti-drug antibodies following treatment with biologics has led to concerns about their impact on clinical safety and efficacy. Hence the elucidation of the immunogenicity of biologics is required for drug approval by health regulatory authorities worldwide. Published ADA 'incidence' rates can vary greatly between same-class products and different patient populations. Such differences are due to disparate bioanalytical methods and interpretation approaches, as well as a plethora of product-specific and patient-specific factors that are not fully understood. Therefore, the incidence of ADA and their association with clinical consequences cannot be generalized across products. In this context, the intent of this review article is to discuss the complex nature of ADA and key nuances of the methodologies used for immunogenicity assessments, and to dispel some fallacies and myths.
Assuntos
Anticorpos Neutralizantes/imunologia , Formação de Anticorpos/imunologia , Produtos Biológicos/antagonistas & inibidores , Produtos Biológicos/imunologia , Anticorpos Neutralizantes/sangue , Produtos Biológicos/uso terapêutico , Humanos , Imunoensaio/métodosAssuntos
Toxinas Bacterianas , Citotoxinas/imunologia , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/imunologia , Listeria monocytogenes/imunologia , Linfócitos T/imunologia , Proteínas de Choque Térmico/metabolismo , Proteínas Hemolisinas , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Listeria monocytogenes/genética , Listeria monocytogenes/metabolismo , Neoplasias/imunologia , Neoplasias/terapia , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/imunologia , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/imunologia , Vaccinia virus/genética , Vaccinia virus/metabolismoRESUMO
Two recombinant Listeria monocytogenes (rLm) strains were produced that secrete the human papilloma virus-16 (HPV-16) E7 protein expressed in HPV-16-associated cervical cancer cells. One, Lm-E7, expresses and secretes E7 protein, whereas a second, Lm-LLO-E7, secretes E7 as a fusion protein joined to a nonhemolytic listeriolysin O (LLO). Lm-LLO-E7, but not Lm-E7, induces the regression of the E7-expressing tumor, TC-1, established in syngeneic C57BL/6 mice. Both recombinant E7-expressing rLm vaccines induce measurable anti-E7 CTL responses that stain positively for H-2D(b) E7 tetramers. Depletion of the CD8+ T cell subset before treatment abrogates the ability of Lm-LLO-E7 to impact on tumor growth. In addition, the rLm strains induce markedly different CD4+ T cell subsets. Depletion of the CD4+ T cell subset considerably reduces the ability of Lm-LLO-E7 to eliminate established TC-1 tumors. Surprisingly, the reverse is the case for Lm-E7, which becomes an effective anti-tumor immunotherapeutic in mice lacking this T cell subset. Ab-mediated depletion of TGF-beta and CD25+ cells improves the effectiveness of Lm-E7 treatment, suggesting that TGF-beta and CD25+ cells are in part responsible for this suppressive response. CD4+ T cells from mice immunized with Lm-E7 are capable of suppressing the ability of Lm-LLO-E7 to induce the regression of TC-1 when transferred to tumor-bearing mice. These studies demonstrate the complexity of L. monocytogenes-mediated tumor immunotherapy targeting the human tumor Ag, HPV-16 E7.