RBD-SPECIFIC POLYCLONAL F(ab)2 FRAGMENTS of EQUINE ANTIBODIES in PATIENTS with MODERATE to SEVERE COVID-19 DISEASE

ABSTRACT

SARS-CoV-2, the causative agent of COVID-19, is currently generating a global pandemic. So far, dexamethasone and remdesivir have shown efficacy in adequately powered clinical trials. In addition, passive immunotherapy appears as a promising therapeutic approach, particularly for early stages of the disease in which patients have not yet established their specific immune response. Different anti-receptor binding domain (RBD) human monoclonal antibodies (mAbs) have been evaluated in the treatment of COVID-19. It has been previously shown that the RBD from the viral spike glycoprotein elicits high titers of NAbs against SARS-CoV-2 when used as immunogen in horses. In this regard, equine polyclonal antibodies (EpAbs) can represent a practical and efficient source of NAbs. EpAbs are composed of F(ab)'2 fragments generated by pepsin digestion. These fragments retain the bivalent binding capacity of IgG immunoglobulins but lack the constant region (Fc), responsible for serum sickness reactions and Fc-triggered side effects. EpAbs recognize a vast array of epitopes (limiting the risk of viral escape mutations) and tend to develop greater avidity than mAbs for their cognate antigens. In addition, EpAbs are relatively easy to manufacture allowing a fast development and scaling up for a treatment. We have previously described the development and in vitro characterization of a therapeutic based on purified equine anti-RBD F(ab)2 fragments, called INM005. INM005 shows a very high serum neutralization titer against SARS-CoV-2. We conducted a phase 2/3 clinical to test the therapeutic effect of INM005 on COVID-19 patients. Albeit not having reached the primary endpoint, we found clinical improvement of hospitalized patients with SARS-CoV-2 pneumonia, particularly those with severe disease. Rate of improvement in at least two categories was statistically significantly higher for INM005 at days 14 and 21 of follow-up. Time to improvement in two ordinal categories or hospital discharge was 14·2 (± 0·7) days in the INM005 group and 16·3 (± 0·7) days in the placebo group. Subgroup analyses showed a beneficial effect of INM005 over severe patients and in those with negative baseline antibodies. Overall mortality was 6·9% the INM005 group and 11·4% in the placebo group. Adverse events of special interest were mild or moderate;no anaphylaxis was reported. Based on these results, ANMAT granted the emergency use approval of INM005 to treat hospitalized COVID-19 severe patients. Following approval, more than 20,000 patients have been treated with INM005. We will be presenting the results of the "real world use of this immunotherapy during the second wave of the pandemics in Argentina.