Monoclonal antibodies as a weapon to fight against Covid-19 — Implications & opportunities
Neutralizing monoclonal antibodieshas been used as an emergency therapeutic intervention to reduce viral load of patients with mild to moderate COVID19.
Passive immunization — a means to combat novel infectious diseases
Passive immunization as a means of immunological intervention against infectious diseases dated back 100 years ago(1). Convalescent plasma therapy (CPT) is where blood plasma from the recovered patients was used to treat infected patients. The high titre of antibodies can reduce the pathogen burden by two mechanisms. One is by antibody effector activity by presenting the pathogen to the immune cells and the other is by neutralizing the pathogens before they infect the cells(2). However, a counterproductive mechanism would be augmenting the pathogenicity by providing immune cells as a vehicle to replicate and further infect. This is known as the antibody dependent enhancement (3). One another issue that limits the use of CPT is the risk of blood borne diseases during transfusion. This can be mitigated using different biological tricks however it faces many logistical difficulties. Alternatively, using monoclonal antibodies (mAbs) to neutralize the pathogens mitigate these issues besides solving the issues of scalability and specificity. A minor concern is the high infusion of mAbs can impact active immunity however the presence of intact T-cell memory mitigates the risk. The major concern is of the appearance of the variants (mutations in the gene) that can render the inactivity of the antibody that target specific epitope and hence combinatorial mAbs are advised to stop the evade of the variant. In the past, mAbs have been successfully used against HIV, RSV infection, Ebola etc though there is a consensus that these treatments are highly effective when treated in the very early stage of infections.
Passive immunization approach to treat COVID19
Treatment of COVID19 with CPT did not exhibit a significant difference in the mortality of the patients or worsening, however there is a consensus that the CPT reduces the viral load(4). The spike protein (S), which is present on the viral surface binds to the angiotensin converting enzyme (ACE2) found on the specialized epithelial cells of the host. Once the viral particle gets endocytosed, they start replicating inside the host cells. mAbs are raised to bind to the receptor binding domain (RBD) of the S protein thereby preventing its binding to the ACE2 receptor(5).
Three mAbs, REGN — COV2 (Casirivimab and imdevimab), Bamlanivimab mono therapy and Bamlanivimab and etesevimab (Figure2) have been granted emergency use authorisation by the FDA for the treatment of non-hospitalised patients with mild to moderate symptoms.
All the studies showed a significant decrease in the viral load, both reduced hospitalisations and progression to severe infections compared to the placebo and concomitantly a better clinical outcome(6,7).
Both the interim and post-hoc analysis clearly showed a significant improvement when treated with mAbs and this effect was also true for high-risk patients. No adverse reaction was observed in disease related treatment. In severe covid patients that are in-hospitalized did not demonstrate a clinically significant improvement highlighting other health factors that are associated with the severe infections. Tens of monoclonal antibodies are currently in different clinical phases and a complete list can be found at Covid-19 biologics trackers.
Do new variants reduce the neutralizing abilities of the monoclonal antibodies?
As of 26th Jan 2021, the number of deaths to covid-19 mounted to 5.62 million and the emergence of new variants was observed with high caution. Series of deleterious mutations that can cause reduced activity of vaccines has always been a great concern to the world(8). Lab testing experiments showed the emergence of variants when selective pressure was applied with the mAbs treatments however the clinical importance of these variants is unknown. Among the globally dominant variants, both the bamlanivimab and imdevimab showed neutralizing effect against the dominant variant in the UK, B.1.1.7 suggesting that these mAbs would still exert its action against any upcoming new ones in the UK. However, the mAbs might not be effective against the South African variants, B.1.351 or the Brazilian variant, P1 or the US ones however this has not been tested systematically(9).
Timing matters
The significant effect of all the approved mAbs treatment relied on the timing of the treatment.
The major conclusions of all the studies are that the mAbs treatment is highly effective if given early in the course of the infection that could be within a time interval of hours or a day following a symptom onset or when individuals were seronegative at diagnosis (9)
Interestingly 78% of patients admitted to the hospital have at least one comorbidity however there have been patients who become severely ill without any comorbidity. Moreover 10% of patients with mild infections slipped to severe. This triggers the question; can we stratify patients using predictive algorithms to identify unidentified risk factors? The information gleaned from the randomized clinical trials hints at different ways of stratification(9).
· Individuals those were seronegative at diagnosis
· The amount of viral load
· Patients who have a history of reduced antiviral responses
Covid19 pandemic has pushed our limits to try different interventions to combat virus infection. Using monoclonal antibodies against the pathogen still proved to be one of the major arsenals in our fight against the infectious diseases. The randomized clinical trial data proved that using neutralizing mAbs is an effective way to treat individuals when they are symptomatic or in the very early days of infection. A risk mitigating factor would be using the combinatorial approach of using multiple mAbs.The data also highlights further important tweaking such as the optimal timing, dosing, and identifying predictive risk factors to make the treatment effective and personalized. Learning lessons from this information would enable us to make the next generation of antibodies more potent and to prepare better in the future for any novel infections.
References
1. Kaufmann SHE. Immunology’s foundation: the 100-year anniversary of the Nobel Prize to Paul Ehrlich and Elie Metchnikoff. Nature immunology. 2008;9(7):705–12.
2. Mair-Jenkins J, Saavedra-Campos M, Baillie JK, Cleary P, Khaw F-M, Lim WS, et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. The Journal of infectious diseases. 2015;211(1):80–90.
3. Iwasaki A, Yang Y. The potential danger of suboptimal antibody responses in COVID-19. Nature Reviews Immunology. 2020;20(6):339–41.
4. Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial. Jama. 2020 ;324(5) :460–70.
5. Chen X, Li R, Pan Z, Qian C, Yang Y, You R, et al. Human monoclonal antibodies block the binding of SARS-CoV-2 spike protein to angiotensin converting enzyme 2 receptor. Cellular & molecular immunology. 2020;17(6):647–9.
6. Gottlieb RL, Nirula A, Chen P, Boscia J, Heller B, Morris J, et al. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: a randomized clinical trial. Jama. 2021;325(7):632–44.
7. Lilly E. Company. New Data Show Treatment with Lilly’s Neutralizing Antibodies Bamlanivimab (LY-CoV555) and Etesevimab (LY-CoV016) Together Reduced Risk of COVID-19 Hospitalizations and Death by 70 Percent. 2021. Eli Lilly and Company. 2021;
8. Janik E, Niemcewicz M, Podogrocki M, Majsterek I, Bijak M. The Emerging Concern and Interest SARS-CoV-2 Variants. Pathogens. 2021;10(6):633.
9. Taylor PC, Adams AC, Hufford MM, de la Torre I, Winthrop K, Gottlieb RL. Neutralizing monoclonal antibodies for treatment of COVID-19. Nature Reviews Immunology. 2021;1–12.
