Resistance represents a major challenge for antibody-based therapy for COVID-19^1,2,3,4. Here we engineered an immunoglobulin M (IgM) neutralizing antibody (IgM-14) to overcome the resistance encountered by immunoglobulin G (IgG)-based therapeutics. IgM-14 is over 230-fold more potent than its parental IgG-14 in neutralizing SARS-CoV-2. IgM-14 potently neutralizes the resistant virus raised by its corresponding IgG-14, three variants of concern—B.1.1.7 (Alpha, which first emerged in the UK), P.1 (Gamma, which first emerged in Brazil) and B.1.351 (Beta, which first emerged in South Africa)—and 21 other receptor-binding domain mutants, many of which are resistant to the IgG antibodies that have been authorized for emergency use. Although engineering IgG into IgM enhances antibody potency in general, selection of an optimal epitope is critical for identifying the most effective IgM that can overcome resistance. In mice, a single intranasal dose of IgM-14 at 0.044 mg per kg body weight confers prophylactic efficacy and a single dose at 0.4 mg per kg confers therapeutic efficacy against SARS-CoV-2. IgM-14, but not IgG-14, also confers potent therapeutic protection against the P.1 and B.1.351 variants. IgM-14 exhibits desirable pharmacokinetics and safety profiles when administered intranasally in rodents. Our results show that intranasal administration of an engineered IgM can improve efficacy, reduce resistance and simplify the prophylactic and therapeutic treatment of COVID-19.

耐药性是 COVID-19 抗体疗法的主要挑战^1,2,3,4. 在这里，我们设计了一种免疫球蛋白 M (IgM) 中和抗体 (IgM-14)，以克服基于免疫球蛋白 G (IgG) 的疗法遇到的耐药性。IgM-14 在中和 SARS-CoV-2 方面比其亲本 IgG-14 强 230 倍以上。IgM-14 可有效中和由其相应的 IgG-14 产生的耐药病毒，这三种变体令人担忧——B.1.1.7（Alpha，首次出现在英国）、P.1（Gamma，首次出现在巴西）和B.1.351（Beta，首先出现在南非）和其他 21 个受体结合域突变体，其中许多对已获准紧急使用的 IgG 抗体具有抗性。虽然将 IgG 工程化为 IgM 通常会增强抗体效力，但选择最佳表位对于确定可以克服耐药性的最有效 IgM 至关重要。在小鼠中，0.044 mg/kg 体重的单次鼻内剂量 IgM-14 具有预防功效，0.4 mg/kg 的单次鼻内剂量具有抗 SARS-CoV-2 的治疗功效。IgM-14，但不是 IgG-14，也赋予针对 P.1 和 B.1.351 变体的有效治疗保护。IgM-14 在啮齿动物鼻内给药时表现出理想的药代动力学和安全性。我们的结果表明，鼻内施用工程化 IgM 可以提高疗效、降低耐药性并简化 COVID-19 的预防和治疗。IgM-14 在啮齿动物鼻内给药时表现出理想的药代动力学和安全性。我们的结果表明，鼻内施用工程化 IgM 可以提高疗效、降低耐药性并简化 COVID-19 的预防和治疗。IgM-14 在啮齿动物鼻内给药时表现出理想的药代动力学和安全性。我们的结果表明，鼻内施用工程化 IgM 可以提高疗效、降低耐药性并简化 COVID-19 的预防和治疗。