Yang Huabing, Chen Yuxin, Jiang Dongcheng, Feng Xiaoli, Xu Ying, Wei Jiayu, Zou Qingcui, Yang Qiaojiang, Chen Jihong, Jiang Xiaoling, Qin Chunling, Huang Zhenzhen, Wu Chongbing, Zhou Ying, Li Minghua, Yin Liusong
SunHo (China) BioPharmaceutical Co., Ltd., No.5 Xingjian Road, Economic and Technological Development Zone, Nanjing 210046, Jiangsu, China.
Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, Jiangsu, China.
Antib Ther. 2023 Mar 6;6(2):97-107. doi: 10.1093/abt/tbad003. eCollection 2023 Apr.
Ending the global COVID-19 pandemic requires efficacious therapies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nevertheless, the emerging Omicron sublineages largely escaped the neutralization of current authorized monoclonal antibody therapies. Here we report a tetravalent bispecific antibody ISH0339, as a potential candidate for long-term and broad protection against COVID-19.
We report here the making of ISH0339, a novel tetravalent bispecific antibody composed of a pair of non-competing neutralizing antibodies that binds specifically to two different neutralizing epitopes of SARS-CoV-2 receptor-binding domain (RBD) and contains an engineered Fc region for prolonged antibody half-life. We describe the preclinical characterization of ISH0339 and discuss its potential as a novel agent for both prophylactic and therapeutic purposes against SARS-CoV-2 infection.
ISH0339 bound to SARS-CoV-2 RBD specifically with high affinity and potently blocked the binding of RBD to the host receptor hACE2. ISH0339 demonstrated greater binding, blocking and neutralizing efficiency than its parental monoclonal antibodies, and retained neutralizing ability to all tested SARS-CoV-2 variants of concern. Single dosing of ISH0339 showed potent neutralizing activity for treatment via intravenous injection and for prophylaxis via nasal spray. Preclinical studies following single dosing of ISH0339 showed favorable pharmacokinetics and well-tolerated toxicology profile.
ISH0339 has demonstrated a favorable safety profile and potent anti-SARS-CoV-2 activities against all current variants of concern. Furthermore, prophylactic and therapeutic application of ISH0339 significantly reduced the viral titer in lungs. Investigational New Drug studies to evaluate the safety, tolerability and preliminary efficacy of ISH0339 for both prophylactic and therapeutic purposes against SARS-CoV-2 infection have been filed.
终结全球新冠疫情需要有效的抗严重急性呼吸综合征冠状病毒2（SARS-CoV-2）疗法。然而，新出现的奥密克戎亚谱系在很大程度上逃脱了当前获批的单克隆抗体疗法的中和作用。在此，我们报告一种四价双特异性抗体ISH0339，它是一种有望提供针对新冠病毒长期广泛保护的候选药物。
我们在此报告ISH0339的制备，这是一种新型四价双特异性抗体，由一对非竞争性中和抗体组成，可特异性结合SARS-CoV-2受体结合域（RBD）的两个不同中和表位，并含有一个经过工程改造的Fc区域以延长抗体半衰期。我们描述了ISH0339的临床前特性，并讨论了其作为预防和治疗SARS-CoV-2感染的新型药物的潜力。
ISH0339以高亲和力特异性结合SARS-CoV-2 RBD，并有效阻断RBD与宿主受体人血管紧张素转换酶2（hACE2）的结合。ISH0339表现出比其亲本单克隆抗体更高的结合、阻断和中和效率，并且对所有测试过的值得关注的SARS-CoV-2变异株均保留中和能力。单次给药ISH0339通过静脉注射显示出有效的治疗中和活性，通过鼻喷雾显示出有效的预防中和活性。单次给药ISH0339后的临床前研究显示出良好的药代动力学和耐受性良好的毒理学特征。
ISH0339已证明具有良好的安全性，并且对所有当前值得关注的变异株均具有强大的抗SARS-CoV-2活性。此外，ISH0339的预防和治疗应用显著降低了肺部病毒滴度。已提交研究性新药申请，以评估ISH0339预防和治疗SARS-CoV-2感染的安全性、耐受性和初步疗效。
