Fc-engineered antibody therapeutics with improved anti-SARS-CoV-2 efficacy

Abstract

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ADNKA overcomes SARS-CoV2-mediated NK cell inhibition through non-spike antibodies

“…The genetic loss of NKG2C (a hallmark of adaptive NK cells, capable of enhanced ADCC) is also a risk factor for severe disease 4 , implying a protective role in COVID19 infection. In support of this, in animal models, Fc-mediated functions correlate with protection in vaccination 5 , and monoclonal antibody-mediated control of SARS-CoV2 infection is enhanced by Fc-dependent mechanisms 6–11 , which enable control of disease even in the absence of neutralising activity 12 . Furthermore, although neutralising monoclonal antibodies are effective when administered prophylactically, Fc-activity is required for efficacy when administered to animals therapeutically 11 .…”

“…In animal models of vaccination 5 and monoclonal antibody administration 6–9,11 against SARS-CoV2, antibody-mediated activation of cellular immunity is a critical component of the protective immune response. However, inflammation dominates severe COVID-19 disease 62,63 .…”

Anti-SARS-CoV-1 and −2 nanobody engineering towards avidity-inspired therapeutics

“…Since the ADE effect is generally overlooked, we suggest that a careful selection, engineering and optimization of immunoglobulin Fc domains that offer improved potency and safer routes be considered. For instance, Yamin et al [181] and Pinto et al [182] have exceptionally demonstrated approaches to circumvent detrimental immunopathology, which may prove helpful for avidity-inspired therapeutics.…”

Update on and Future Directions for Use of Anti–SARS-CoV-2 Antibodies: National Institutes of Health Summit on Treatment and Prevention of COVID-19

“…The role of the interaction between the Fc portion of antibodies and the Fc receptors can also be evaluated in the transgenic mouse models ( 58 ). Interactions between Fc and FcγR are required for in vivo protective activity of neutralizing anti–SARS-CoV-2 mAbs by comparing the efficacy of the antibody treatment in animals expressing the human FcγR versus genetically defined FcγR-null mice.…”

“…Interactions between Fc and FcγR are required for in vivo protective activity of neutralizing anti–SARS-CoV-2 mAbs by comparing the efficacy of the antibody treatment in animals expressing the human FcγR versus genetically defined FcγR-null mice. Furthermore, Fc domain variants engineered for selectively enhanced binding to activating FcγRs exhibit improved efficacy using the SARS-CoV-2 mouse-adapted model ( 58 ). The Collaborative Cross mice, a recombinant inbred mouse strain ( 59 , 60 ), have been valuable in addressing the natural genetic variation linked to SARS-CoV-2 pathogenesis.…”