Synthetic gene in antibody drug discovery, undergoing clinical approval

Antibody Drug Discovery (ADD) is an arduous process that often starts with the extensive screening of antibody libraries to identify optimal candidates, namely those having high-affinity antigen binding and other desirable functional properties. For example, during the COVID-19 pandemic, discovering potent neutralizing anti-SARS-CoV-2 antibodies has been prioritized. From the early stages of the pandemic, neutralizing antibodies were proposed to correlate with protection from infection (Addetia et al. 2020). Over time, more evidence upheld this view; thus, efforts to identify and characterize anti-SARS-CoV-2 neutralizing antibodies of potential clinical value continue to this date (Quiros-Roldan et al. 2021). While the now available SARS-CoV-2 vaccines represent the first line of defense for most people, monoclonal antibodies can serve as prophylactic or therapeutic bio drugs for a fraction of the population that remain unprotected due to comorbidities or inability to respond to vaccines.

The first FDA-approved monoclonal antibody drug for infectious diseases was granted back in 1998 to palivizumab to prevent lower respiratory tract complications following respiratory syncytial virus (RSV) infections in high-risk infants. Most recently, and during earlier stages of the COVID-19 pandemic, in 2020, the monoclonal antibody mixture Inmazeb (i.e., atoltivimab, maftivimab, and odesivimab-ebgn) received FDA approval for use in adult and pediatric patients to neutralize Ebola viral attachment and cell entry. Following up on the heels of these successful precedents, scientists have taken advantage of the rich diversity of patient-derived monoclonal antibodies to identify potential candidates for COVID-19 prevention or treatment.

af068705743deffb8339a066f7c8af0aBased on this year’s “Antibodies to Watch in 2022” report, an unprecedented number of antibody therapies (~115 candidates) are currently in the late stages of clinical evaluation. Of these, a large proportion of candidates are being evaluated for cancer and immune-related indications (Kaplon et al. 2022). Additionally, in tune with the ongoing pandemic, a substantial number of therapeutic antibodies for COVID-19 continue to progress through late-stage clinical studies. These include antibodies that directly target SARS-CoV-2 antigens (e.g., Adintrevimab and Upanovimab), interact with cellular receptors blocking viral entry (e.g., Meplazumab-humanized anti-CD147 monoclonal antibody), and alleviate COVID-19 associated complications, such as the cytokine release syndrome or cytokine storm (e.g., Lenzilumab).

Early therapeutic antibody approvals
By the end of 2021, about 17 antibody drugs were undergoing regulatory reviews in the USA, and just at the start of 2022, three new therapeutic antibodies secured FDA approval. First, in January, the bispecific antibody, Tebentafusp, was approved in the USA for metastatic melanoma. Tebentafusp targets gp100 melanoma-associated antigen and engages T cells for tumor cell killing by binding to their CD3 receptor. Soon after, still in January, the FDA’s approval of Faricimab, a bispecific antibody for a non-cancer indication, represents the first of its kind. Faricimab was developed by Roche to recognize VEGF-A and angiopoietin-2, which together contribute to vision loss by promoting leaky vessels, vascular destabilization, and inflammation. The FDA has approved Faricimab for macular degeneration and diabetic-associated macular oedema. Lastly, in February, Sutimlimab was approved for hemolysis associated with cold agglutinin disease (CAD). Sutimlimab is a humanized monoclonal antibody that targets the complement serine protease C1s and inhibits activation of the classical complement cascade, therefore preventing normal red blood cell lysis.

Other antibody drug candidates expected to receive approval early in 2022 include Relatlimab and Ublituximab, indicated for melanoma and multiple sclerosis, respectively (Kaplon et al. 2022). In addition, approval for the use of Sintilimab, an immune checkpoint inhibitor (i.e., anti-Programmed cell death protein 1 or PD-1), in combination with pemetrexed and platinum chemotherapy as a first-line treatment of patients with nonsquamous non–small cell lung cancer (NSCLC) was expected early in 2022. Nevertheless, the FDA recently rejected its approval pending findings from additional USA-based clinical studies.

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