An overview of the preclinical discovery and development of bamlanivimab for the treatment of novel coronavirus infection (COVID-19): reasons for limited clinical use and lessons for the future

Abstract

Introduction : In the COVID-19 pandemic emergency, research has been oriented toward the development of therapies that could cure critically ill patients and treatments that can reduce the number of hospitalized patients, in order to ease the pressure on health-care systems. Bamlanivimab, developed from human convalescent plasma, was the first monoclonal antibody to become available for emergency use in several countries. Expectations related to its use in COVID-19 patients as a single agent have been largely disregarded, especially against E484K-carrying SARS-CoV-2 variants. Areas covered : In this drug discovery case history, the development of the drug is described starting from the identification and selection of the antibody, from the pre-clinical and clinical trials up to the post-authorization phase. Expert opinion : Bamlanivimab has shown some efficacy in patients with mild to moderate COVID-19. Initially approved as a monotherapy, due to poor efficacy it is currently only usable in combination with etesevimab. Pharmacokinetic limitations and mainly the onset of SARS-CoV-2 variants are the main reasons for this limited clinical use. The use in preventing hospitalization also has ethical limits related to the sustainability of care, especially if, considering similar effectiveness, bamlanivimab is compared with convalescent plasma.

Monoclonal antibody therapies against SARS-CoV-2

“…We previously reviewed the limitations of the bamlanivimab plus etesevimab, 121 and the casirivimab plus imdevimab 122 cocktails, and especially their loss of neutralising activity against the omicron variant of concern, which is currently the dominant variant worldwide.…”

Smaller, Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein

“…The first therapeutics approved for clinical use were monoclonal antibodies that recognize the spike protein, through which the virus contacts its receptor ACE2 expressed on lung epithelial cells [ 3 , 4 ]. Thus, binding of the antibodies to the spike protein prevents attachment of the virus to its host cell [ 5 , 6 ]. In addition, two orally available small molecules have recently been introduced as anti-SARS-CoV-2 drugs.…”

Evolution of Anti-SARS-CoV-2 Therapeutic Antibodies

“…The antibodies of the Lilly’s cocktail were obtained from two sources [ 64 , 65 , 66 ]. Bamlanivimab was obtained via high-throughput microfluidic screening of antigen-specific B cells from a hospitalized convalescent patient with COVID-19.…”