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Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Background Currently, cytokine therapy for cancer has demonstrated efficacy in certain diseases but is generally accompanied by severe toxicity. The field of antibody-cytokine fusion proteins (immunocytokines) arose to target these effector molecules to the tumor microenvironment to expand the therapeutic window of cytokine therapy. Therefore, we have developed a novel immunocytokine that binds specifically to programmed death 1 (PD1) and fuses IL15/IL15Rα complex (referred to as IAP0971) for cancer immunotherapy. Methods We report here the making of IAP0971, a novel immunocytokine that binds specifically to PD1 and fuses IL15/IL15Rα complex, and preclinical characterization including pharmacology, pharmacodynamics, pharmacokinetics and toxicology, and discuss its potential as a novel agent for treating patients with advanced malignant tumors. Results IAP0971 bound to human IL2/15Rβ proteins specifically and blocked PD1/PDL1 signaling transduction pathway. IAP0971 promoted the proliferation of CD8 + T cells and natural killer T (NKT) cells, and further activated NK cells to kill tumor cells validated by in vitro assays. In an hPD1 knock-in mouse model, IAP0971 showed potent anti-tumor activity. Preclinical studies in non-human primates following single or repeated dosing of IAP0971 showed favorable pharmacokinetics and well-tolerated toxicology profile. Conclusion IAP0971 has demonstrated a favorable safety profile and potent anti-tumor activities in vivo. A Phase I/IIa clinical trial to evaluate the safety, tolerability and preliminary efficacy of IAP0971 in patients with advanced malignant tumors is on-going (NCT05396391).