Biologics targeted at TNF: design, production and challenges

B. Gatto
2011 Reumatismo  
diseases. Tumor necrosis factor alpha (TNFα) emerged from these studies as a pivotal regulator of expression of other pro-inflammatory cytokines such as Interleukin-1 (IL-1) and Interleukin-6 (IL-6) (2), thus becoming a key target for therapeutic intervention in a redundant cytokine environment. The term TNF indicates two glycoproteins with high homology (≈30% amino-acid identity) belonging to the TNF superfamily. Human lymphotoxin (LT) was the first cytokine to be purified from a
more » ... rom a B-lymphoblastoid cell line (3) followed soon by the isolation of a second cytotoxic factor, named TNF or cachectin, from a human myeloidcell line (4). The binding of TNF to its receptor and its displacement by LT further confirmed the functional homologies between the two proteins (5), and TNF and LT, upon isolation of their c-DNAs (6, 7) were renamed TNFα and TNFβ, respectively. Reumatismo, 2006; 58(2):94-103 RIASSUNTO Negli ultimi anni sono stati approvati per l'utilizzo clinico tre antagonisti del TNF sviluppati tramite biotecnologie innovative: questi farmaci hanno profondamente cambiato l'approccio terapeutico alle malattie autoimmuni su base infiammatoria, portando all'attenzione del mercato farmaceutico il potenziale di crescita dei biologici diretti alle citochine. Lo sviluppo di proteine ricombinanti come farmaci mirati al TNF fu la logica conseguenza della dimostrazione che anticorpi anti-TNF erano in grado di modulare la risposta infiammatoria in modelli animali di artrite reumatoide. I primi prodotti biotecnologici ad essere sviluppati per uso terapeutico furono gli anticorpi monoclonali, ed esistono oggi in terapia due monoclonali specifici per il TNF, uno chimerico e uno completamente umano. In parallelo allo sviluppo dei primi anticorpi terapeutici anti-TNF furono progettati recettori solubili del TNF capaci di legare e neutralizzare l'eccesso di citochina circolante. Il grande successo clinico dei recettori solubili fu realizzato grazie alla progettazione di una nuova proteina ricombinante dimerica, ottenuta tramite fusione della parte extracellulare del recettore umano del TNF con la porzione costante di un'immunoglobulina umana. Tutti gli antagonisti del TNF approvati in terapia sono stati ottenuti grazie a tecniche di biologia molecolare applicata, e costituiscono un paradigma importante nel campo delle biotecnologie farmaceutiche. Finalità di questa rassegna è di analizzare la progettazione e lo sviluppo dei biologici anti-TNF, descriverne i metodi di produzione biotecnologica e le sfide aperte per il miglioramento di questi prodotti innovativi. Biologics targeted at TNF: design, production and challenges 101 SUMMARY Several biotech-derived drugs aimed at Tumor Necrosis Factor (TNF) have been licensed in the last years, profoundly changing the therapy of several autoimmune diseases based on inflammation, affecting the life of patients and bringing to the market attention the growth potentials of biologics directed at cytokines. The proof of principles that led to the design of these compounds dates back from the nineties, when the involvement of TNF in rheumatoid arthritis was proved by the ability of specific anti-TNF proteins to modulate the inflammatory response in animal models. Monoclonal antibodies aimed at neutralizing the excess TNF were developed with therapeutic purposes, and a chimeric and a full human antibody are now approved for several clinical indications. The design of soluble receptors able to bind and neutralize human TNF paralleled the development of antibodies as therapeutics, and the clinical success of these drugs was achieved by the clever design of a novel recombinant dimeric protein, consisting of the extracellular portion of human TNF receptor linked to the constant portion of a human immunoglobulin. All approved biologics designed to bind and neutralize TNF were obtained through the power of biotechnological methods: the development of these important biopharmaceutical products, their means of production and the challenges they face will be analyzed here in details.
doi:10.4081/reumatismo.2006.94 fatcat:2zkgd6yv7jd4ldkxnkl4ifzcgm