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Imunogenicidade dos medicamentos biológicos em oncologia : qual o impacto para os biossimilares?
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São medicamentos biológicos aqueles cujos princípios ativos são proteínas obtidas através de biotecnologia. Incluem hormonas recombinantes, fatores de crescimento e anticorpos monoclonais, entre outros, e embora seja vasto o seu campo de intervenção, as principais aplicações são na área da oncologia e das doenças auto-imunes.
Por serem moléculas biologicamente ativas, os medicamentos biológicos apresentam a capacidade de desencadear uma resposta imunológica. Esta imunogenicidade envolve muitas vezes a produção de anticorpos dirigidos contra o medicamento (ADAs). Tais anticorpos podem ser ligantes ou neutralizantes, sendo a interação destes últimos feita com a porção do medicamento essencial para a ligação ao recetor, o que o inativa medicamento.
A imunogenicidade é um parâmetro relevante aquando da formulação e introdução no mercado de medicamentos biológicos e dos seus biossimilares (versão genérica de medicamentos biológicos).
Os medicamentos biológicos podem ser utilizados, em oncologia, diretamente no tratamento do cancro (anticorpos monoclonais) ou como terapêutica de suporte. Foram identificados anticorpos neutralizantes contra o cetuximab, trastuzumab, panitumumab e nivolumab, embora sem relevância clínica; os dados relativos ao nivolumab aplicam-se somente em monoterapia. Embora ainda não esteja completamente esclarecido, os ADAs dirigidos contra o rituximab podem diminuir a eficácia deste. O bevacizumab não originou ADAs, embora as elevadas concentrações do medicamento nos métodos de deteção possam ter influência. Também o pertuzumab e o ipilimumab foram capazes de induzir ADAs, não tendo sido identificados anticorpos neutralizantes contra o ipilimumab. Relativamente à terapêutica de suporte, os estudos indicam que os fatores de crescimento apresentam um fraco potencial imunogénico, porém, os anticorpos neutralizantes dirigidos contra a eritropoietina, após uma alteração na formulação desta, foram responsáveis por centenas de casos de Aplasia das Células Vermelhas. Este é, talvez, e até agora, o acontecimento mais marcante resultante da imunogenicidade dos medicamentos biológicos.
Biological medicinal products are those whose active ingredients are proteins obtained through biotechnology, such as recombinant hormones, growth factors and monoclonal antibodies, amongst others. Although its broad field of intervention, the main applications of biopharmaceuticals are in the field of oncology and autoimmune diseases. Being biologically active molecules, biopharmaceuticals have the ability to elicit an immune response. This immunogenicity often involves the production of anti-drug antibodies (ADAs), which can be binding antibodies or neutralizing antibodies. Neutralizing antibodies bind to or near the target-binding domain of the biopharmaceutical, which inhibits the drug’s ability to bind to the target, thus reducing or neutralizing the pharmacological activity. Immunogenicity is an important parameter in the formulation and market introduction of both biopharmaceuticals and biosimilars (generic versions of biological medicinal products). Biopharmaceuticals may be used in oncology, directly in cancer treatment (monoclonal antibodies) or as supportive therapy. Neutralizing antibodies were identified against cetuximab, trastuzumab, panitumumab and nivolumab, although no clinical relevance was found; data relating to nivolumab is only applied in monotherapy. Although not yet fully understood, ADAs directed against rituximab may reduce its effectiveness. Bevacizumab has not originated ADAs, although higher drug concentrations in detection methods may influence the results. Pertuzumab and ipilimumab were also able to induce ADAs; neutralizing antibodies against ipilimumab had not been identified. For support therapy, studies indicate that growth factors have a low immunogenic potential; however, neutralizing antibodies against erythropoietin due to a change in the formulation, were responsible for hundreds of cases of pure red cell aplasia. This is, perhaps, and even now, the most important event resulting from the immunogenicity of biopharmaceuticals.
Biological medicinal products are those whose active ingredients are proteins obtained through biotechnology, such as recombinant hormones, growth factors and monoclonal antibodies, amongst others. Although its broad field of intervention, the main applications of biopharmaceuticals are in the field of oncology and autoimmune diseases. Being biologically active molecules, biopharmaceuticals have the ability to elicit an immune response. This immunogenicity often involves the production of anti-drug antibodies (ADAs), which can be binding antibodies or neutralizing antibodies. Neutralizing antibodies bind to or near the target-binding domain of the biopharmaceutical, which inhibits the drug’s ability to bind to the target, thus reducing or neutralizing the pharmacological activity. Immunogenicity is an important parameter in the formulation and market introduction of both biopharmaceuticals and biosimilars (generic versions of biological medicinal products). Biopharmaceuticals may be used in oncology, directly in cancer treatment (monoclonal antibodies) or as supportive therapy. Neutralizing antibodies were identified against cetuximab, trastuzumab, panitumumab and nivolumab, although no clinical relevance was found; data relating to nivolumab is only applied in monotherapy. Although not yet fully understood, ADAs directed against rituximab may reduce its effectiveness. Bevacizumab has not originated ADAs, although higher drug concentrations in detection methods may influence the results. Pertuzumab and ipilimumab were also able to induce ADAs; neutralizing antibodies against ipilimumab had not been identified. For support therapy, studies indicate that growth factors have a low immunogenic potential; however, neutralizing antibodies against erythropoietin due to a change in the formulation, were responsible for hundreds of cases of pure red cell aplasia. This is, perhaps, and even now, the most important event resulting from the immunogenicity of biopharmaceuticals.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2016
Palavras-chave
Medicamentos biológicos Imunogenicidade Cancro Anticorpos monoclonais Anti-drug antibodies Mestrado Integrado - 2016