①Science. 2020 Jun 15 : eabd0827. Published online 2020 Jun 15. doi: 10.1126/science.abd0827 PMCID: PMC7299284 PMID: 32540901 Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail
② Science. 2020 Jun 15 : eabd0831. Published online 2020 Jun 15. doi: 10.1126/science.abd0831 PMCID: PMC7299283 PMID: 32540904 Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies
②の論文に以下のように記載されている。 The subsequent success of combination therapy for HIV demonstrated that requiring the virus to simultaneously mutate at multiple genetic positions may be the most effective way to avoid drug resistance.
The prospective goal of generating this very large collection was to select pairs of highly potent individual antibodies that could simultaneously bind the RBD spike, and thus might be ideal partners for a therapeutic antibody cocktail that could not only be an effective treatment, but might also protect against antibody resistance due to virus escape mutants that could arise in response to selective pressure from single antibody treatments.
As RNA viruses are well known to accumulate mutations over time, a significant concern for any antiviral therapeutic is the potential for selection of treatment-induced escape mutants. A common strategy to safeguard against escape to antibody therapeutics involves selection of antibodies binding to conserved epitopes, however this strategy may not suffice. While some informed analysis can be made regarding epitope conservation based on sequence and structural analysis (6), the possibility of escape still exists under strong selection pressure. Indeed, escape studies performed with anti-influenza HA stem binding antibodies have shown that escape mutants can arise despite high conservation of the stem epitope between diverse influenza subtypes, with some escape mutations arising outside of the antibody epitope region (7, 8). Antibodies that demonstrate broad neutralization across multiple species of coronaviruses, and thus may be targeting more conserved residues, have not been shown to be immune to escape upon selective pressure. In addition, their neutralization potency is orders of magnitude lower than that of the most potent neutralizing antibodies specific for SARS-CoV-2 (6, 9–11). Neutralization is thought to be the key mechanism of action of anti-coronavirus spike antibodies and has previously been shown to correlate with efficacy in animal models (12), and may therefore prove to be the most important driver of initial clinical efficacy. However, as demonstrated with our single antibody escape studies, even highly potent neutralization does not protect against the rapid generation of viral escape mutants, and escape remains a major concern with individual antibody approaches.
しかし、著者らは、論文の終盤に、以下のように述べていて、カクテル療法の治療としての有用性を強調している。 組み合わせる抗体は、distinct and non-overlapping regions of the viral target であるべきで、別の場所に同時にウイルス抗原変異をきたしてしまうような抗体ペアを選んではだめですよ！とのことである。
The data described herein strongly support the notion that cocktail therapy may provide a powerful way to minimize mutational escape by SARS-CoV-2; in particular, our studies point to the potential value of antibody cocktails in which two antibodies were chosen so as to bind to distinct and non-overlapping regions of the viral target (in this case, the RBD of the spike protein), and thus require the unlikely occurrence of simultaneous mutations at two distinct genetic sites for viral escape.
Next, we evaluated escape following treatment with our previously described antibody cocktail (REGN10987+REGN10933), rationally designed to avoid escape through inclusion of two antibodies that bind distinct and non-overlapping regions of the RBD, and which can thus simultaneously bind and block RBD function.
前記事で紹介した②の論文のTable 2, Fig. 1, B and C, and Fig. 2にそうした実験結果が書かれているし、ペアを組んでダメなのは、10989/34 であり、望ましい抗体ペアは、10987/33 であるそうだ。