Monoclonal Antibody Cocktail therapy for COVID-19: A Pharmacological innovation

The novel SARS-CoV-2 infection has ripped through international health systems and protocols causing unprecedented mortality, morbidity and global trade deficits amounting to billions. Various monoclonal antibodies have been proposed for use in the treatment of COVID-19 infections. One such drug is LY-CoV555 which in an ongoing phase two trial study conducted by Chen P et al, showed to have an elimination of 99.97% of the viral RNA. The monoclonal antibody 47D11 discovered by Wang et al, binds to SARS-CoV-2. The 47D11 has been reconfigured into a human IgG1 isotope. It has shown that the 47D11 mAb effectively neutralizes the SARS-COV-2 virus. The stance and development however for the treatment of COVID-19 with monoclonal antibodies has shifted from a monotherapy to a so-called monoclonal antibody “cocktail” therapy. REGN-COV2 is such a cocktail developed with the use of two monoclonal antibodies REGN10987 and REGN10933 which have subsequently been named Imdevimab and Casirivimab. REGN-COV2 is currently under study in four phase 2 and 3 trial studies. These studies are multicentric in nature and are being conducted to evaluate the drug’s efficacy, dosing and clinical use as compared to the placebo. The mechanism of action of such monoclonal antibodies is related chiefly to the inhibition of the virus’s ability to perform its invasion and multiplication within the human body. The severity coupled with the sheer novelty of the SARSCoV-2 virus demands the use of newer therapies to both decrease the mortality and morbidity in patients suffering from the infection. The use of a combination of monoclonal antibodies is thereby well established and evident to both decrease the viral infection load, but is also useful in disrupting the virus’s life cycle and thus decreases the replication and viral shedding. It is therefore poignant that a combination of monoclonal antibodies, a “cocktail” therapy is employed so as to attack the virus at its various stages and thus this multifaceted approach may enhance the patient’s prognosis.

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Characterization of a Broadly Reactive Monoclonal Antibody against Norovirus Genogroups I and II: Recognition of a Novel Conformational Epitope

Journal of Virology ◽

10.1128/jvi.00891-07 ◽

2007 ◽

Vol 81 (22) ◽

pp. 12298-12306 ◽

Cited By ~ 44

Author(s):

Tomoyuki Shiota ◽

Michio Okame ◽

Sayaka Takanashi ◽

Pattara Khamrin ◽

Makiko Takagi ◽

...

Keyword(s):

Monoclonal Antibody ◽

Monoclonal Antibodies ◽

Conformational Epitope ◽

The Novel ◽

Antigen Specificity ◽

Virus Like Particle ◽

The Family ◽

Immunological Diagnosis ◽

Further Development

ABSTRACT Norovirus, which belongs to the family Caliciviridae, is one of the major causes of nonbacterial acute gastroenteritis in the world. The main human noroviruses are of genogroup I (GI) and genogroup II (GII), which were subdivided further into at least 15 and 18 genotypes (GI/1 to GI/15 and GII/1 to GII/18), respectively. The development of immunological diagnosis for norovirus had been hindered by the antigen specificity of the polyclonal antibody. Therefore, several laboratories have produced broadly reactive monoclonal antibodies, which recognize the linear GI and GII cross-reactive epitopes or the conformational GI-specific epitope. In this study, we characterized the novel monoclonal antibody 14-1 (MAb14-1) for further development of the rapid immunochromatography test. Our results demonstrated that MAb14-1 could recognize 15 recombinant virus-like particles (GI/1, 4, 8, and 11 and GII/1 to 7 and 12 to 15) and showed weak affinity to the virus-like particle of GI/3. This recognition range is the broadest of the existing monoclonal antibodies. The epitope for MAb14-1 was identified by fragment, sequence, structural, and mutational analyses. Both terminal antigenic regions (amino acid positions 418 to 426 and 526 to 534) on the C-terminal P1 domain formed the conformational epitope and were in the proximity of the insertion region (positions 427 to 525). These regions contained six amino acids responsible for antigenicity that were conserved among genogroup(s), genus, and Caliciviridae. This epitope mapping explained the broad reactivity and different titers among GI and GII. To our knowledge, we are the first group to identify the GI and GII cross-reactive monoclonal antibody, which recognizes the novel conformational epitope. From these data, MAb14-1 could be used further to develop immunochromatography.

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Establishment of a pig influenza challenge model for evaluation of monoclonal antibody delivery platforms

10.1101/2020.03.12.988808 ◽

2020 ◽

Author(s):

Adam McNee ◽

Trevor Smith ◽

Barbara Holzer ◽

Becky Clark ◽

Emily Bessell ◽

...

Keyword(s):

Monoclonal Antibody ◽

Monoclonal Antibodies ◽

Viral Load ◽

Influenza Virus Infection ◽

Small Animal ◽

H1n1 Influenza ◽

Lung Pathology ◽

Host Animal ◽

Viral Shedding ◽

Robust Model

AbstractMonoclonal antibodies are a possible adjunct to vaccination and drugs in treatment of influenza virus infection. However questions remain whether small animal models accurately predict efficacy in humans. We have established the pig, a large natural host animal for influenza, with many physiological similarities to humans, as a robust model for testing monoclonal antibodies. We show that a strongly neutralizing monoclonal antibody (2-12C) against the hemagglutinin head administered prophylactically at 15 mg/kg reduced viral load and lung pathology after pandemic H1N1 influenza challenge. A lower dose of 1 mg/kg of 2-12C or a DNA plasmid encoded version of 2-12C, reduced pathology and viral load in the lungs, but not viral shedding in nasal swabs. We propose that the pig influenza model will be useful for testing candidate monoclonal antibodies and emerging delivery platforms prior to human trials.

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Post-exposure protection of SARS-CoV-2 lethal infected K18-hACE2 transgenic mice by neutralizing human monoclonal antibody

10.1101/2020.10.26.354811 ◽

2020 ◽

Author(s):

Ronit Rosenfeld ◽

Tal Noy-Porat ◽

Adva Mechaly ◽

Efi Makdasi ◽

Yinon Levy ◽

...

Keyword(s):

Monoclonal Antibody ◽

Monoclonal Antibodies ◽

Transgenic Mice ◽

Neutralizing Antibodies ◽

Global Economy ◽

Human Monoclonal Antibody ◽

Human Monoclonal Antibodies ◽

Mortality And Morbidity ◽

Life Saving ◽

Therapeutic Value

AbstractCoronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits high levels of mortality and morbidity and has dramatic consequences on human live, sociality and global economy. Neutralizing antibodies constitute a highly promising approach for treating and preventing infection by this novel pathogen. In the present study, we characterized and further evaluated the recently identified human monoclonal MD65 antibody for its ability to provide protection against a lethal SARS-CoV-2 infection of K18-hACE2 transgenic mice. 75% of the untreated mice succumbed 6-9 days post-infection while administration of the MD65 antibody as late as 3 days after exposure, rescued all infected animals. The data unprecedentedly demonstrate, the therapeutic value of human monoclonal antibodies as a life-saving treatment of severe COVID-19 infection.

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The future of anti-CD20 monoclonal antibodies: are we making progress?

Blood ◽

10.1182/blood-2010-07-298356 ◽

2011 ◽

Vol 117 (11) ◽

pp. 2993-3001 ◽

Cited By ~ 93

Author(s):

Waleed Alduaij ◽

Tim M. Illidge

Keyword(s):

Monoclonal Antibody ◽

Clinical Trials ◽

Monoclonal Antibodies ◽

Personalized Medicine ◽

Clinical Development ◽

The Novel ◽

Next Generation ◽

B Cell Malignancies ◽

Clinical Community ◽

Anti Cd20

AbstractThe anti-CD20 monoclonal antibody (mAb) rituximab has revolutionized the treatment of B-cell malignancies. This unprecedented success has not only substantially changed the mindset of the clinical community about the ability of mAb to improve outcomes but has catalyzed the interest in the pharmaceutical industry to develop the next generation of anti-CD20 mAbs. Since the introduction of rituximab 15 years ago, we have learned much about the potential mechanisms underlying the therapeutic efficacy of anti-CD20 mAbs. In parallel, many novel anti-CD20 mAbs have entered the clinic, each designed with modifications to structure aimed at further improving efficacy. On review of the newer generation of anti-CD20 mAbs entering clinical trials, it appears that the link between the novel mechanistic insights and the development of these next-generation anti-CD20 mAbs is unclear. As we move into an era of personalized medicine, it will become increasingly important for us to develop closer links between the emerging mechanistic insights and the clinical development, to further enhance the potency of anti-CD20 mAbs beyond that achieved with rituximab.

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Monoclonal antibodies in acute lymphoblastic leukemia

Blood ◽

10.1182/blood-2014-08-596403 ◽

2015 ◽

Vol 125 (26) ◽

pp. 4010-4016 ◽

Cited By ~ 93

Author(s):

Elias Jabbour ◽

Susan O’Brien ◽

Farhad Ravandi ◽

Hagop Kantarjian

Keyword(s):

Monoclonal Antibody ◽

Monoclonal Antibodies ◽

Acute Lymphoblastic Leukemia ◽

Median Survival ◽

Lymphoblastic Leukemia ◽

Complete Response ◽

Surface Antigens ◽

Leukemic Cells ◽

The Novel ◽

Cure Rates

Abstract With modern intensive combination polychemotherapy, the complete response (CR) rate in adults with acute lymphoblastic leukemia (ALL) is 80% to 90%, and the cure rate is 40% to 50%. Hence, there is a need to develop effective salvage therapies and combine novel agents with standard effective chemotherapy. ALL leukemic cells express several surface antigens amenable to target therapies, including CD20, CD22, and CD19. Monoclonal antibodies target these leukemic surface antigens selectively and minimize off-target toxicity. When added to frontline chemotherapy, rituximab, an antibody directed against CD20, increases cure rates of adults with Burkitt leukemia from 40% to 80% and those with pre-B ALL from 35% to 50%. Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, has resulted in marrow CR rates of 55% and a median survival of 6 to 7 months when given to patients with refractory-relapsed ALL. Blinatumomab, a biallelic T cell engaging the CD3-CD19 monoclonal antibody, also resulted in overall response rates of 40% to 50% and a median survival of 6.5 months in a similar refractory-relapsed population. Other promising monoclonal antibodies targeting CD20 (ofatumumab and obinutuzumab) or CD19 or CD20 and bound to different cytotoxins or immunotoxins are under development. Combined modalities of chemotherapy and the novel monoclonal antibodies are under investigation.

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The Spike Proteins of SARS-CoV-2 B.1.617 and B.1.618 Variants Identified in India Provide Partial Resistance to Vaccine-elicited and Therapeutic Monoclonal Antibodies.

10.1101/2021.05.14.444076 ◽

2021 ◽

Author(s):

Takuya Tada ◽

Hao Zhou ◽

Belinda M Dcosta ◽

Marie I Samanovic ◽

Mark J Mulligan ◽

...

Keyword(s):

Monoclonal Antibody ◽

Monoclonal Antibodies ◽

Partial Resistance ◽

Spike Protein ◽

Therapeutic Monoclonal Antibodies ◽

Antibody Cocktail ◽

Spike Proteins

Highly transmissible SARS-CoV-2 variants recently identified in India designated B.1.617 and B.1.618 have mutations within the spike protein that may contribute to their increased transmissibility and that could potentially result in re-infection or resistance to vaccine-elicited antibody. B.1.617 encodes a spike protein with mutations L452R, E484Q, D614G and P681R while the B.1.618 spike has mutations Δ145-146, E484K and D614G. We generated lentiviruses pseudotyped by the variant proteins and determined their resistance to neutralization by convalescent sera, vaccine-elicited antibodies and therapeutic monoclonal antibodies. Viruses with B.1.617 and B.1.618 spike were neutralized with a 2-5-fold decrease in titer by convalescent sera and vaccine-elicited antibodies. The E484Q and E484K versions were neutralized with a 2-4-fold decrease in titer. Virus with the B.1.617 spike protein was neutralized with a 4.7-fold decrease in titer by the Regeneron monoclonal antibody cocktail as a result of the L452R mutation. The modest neutralization resistance of the variant spike proteins to vaccine elicited antibody suggests that current vaccines will remain protective against the B.1.617 and B.1.618 variants.

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Evaluation of MEDI8852, an Anti-Influenza A Monoclonal Antibody, in Treating Acute Uncomplicated Influenza

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00694-18 ◽

2018 ◽

Vol 62 (11) ◽

Cited By ~ 17

Author(s):

S. Omar Ali ◽

Therese Takas ◽

Andrew Nyborg ◽

Kathryn Shoemaker ◽

Nicole L. Kallewaard ◽

...

Keyword(s):

Monoclonal Antibody ◽

Influenza A ◽

Virus Genome ◽

Binding Region ◽

Viral Shedding ◽

Igg1 Monoclonal Antibody ◽

Before And After ◽

Human Igg1 ◽

Single Intravenous Infusion ◽

Human Igg1 Monoclonal Antibody

ABSTRACT We evaluated MEDI8852, a human IgG1 monoclonal antibody that binds a highly conserved influenza A hemagglutinin stalk epitope, in outpatients with uncomplicated influenza A infection. A total of 126 subjects aged 18 to 65 years were enrolled during the 2015 to 2016 Northern and 2016 Southern Hemisphere seasons. Subjects with symptom onset ≤5 days before dosing were randomized to four cohorts: 750 mg (cohort 1) or 3,000 mg (cohort 2) MEDI8852 (single intravenous infusion) plus 75 mg oseltamivir, placebo plus 75 mg oseltamivir (cohort 3), and 3,000 mg MEDI8852 alone (cohort 4). Subjects were monitored through day 10 for solicited influenza symptoms, day 28 for adverse events (AEs), and day 101 for serious AEs and AEs of special interest. Nasopharyngeal samples were collected through day 7 for confirmation of influenza A infection, viral shedding, and oseltamivir and MEDI8852 susceptibility. Slightly more AEs were reported in subjects receiving MEDI8852 (cohorts 1, 2, and 4 combined: 39/93, 41.9%) than oseltamivir only (cohort 3: 10/32, 31.3%). Most AEs were mild or moderate. The most common AE was bronchitis (11/93, 11.8%; 1/32, 3.1%). The median (range) decrease in viral shedding (log10 virus genome copies/ml) was similar between the two groups (−3.58 [−6.2. 0.5]; −3.43 [−5.9, 0.9]). Genotypic analyses found a limited number of hemagglutinin and neuraminidase amino acid changes between viruses isolated before and after therapy; however, none appeared within a known oseltamivir-resistant site or MEDI8852-binding region. The safety profile of MEDI8852 supports its continued development for treatment of patients hospitalized with influenza A infection. (This study has been registered at ClinicalTrials.gov under identifier NCT02603952.)

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Casirivimab and imdevimab as investigational monoclonal antibodies for COVID-19 patients – review of the literature

Current Issues in Pharmacy and Medical Sciences ◽

10.2478/cipms-2021-0030 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Gabriela Reka ◽

Angelika Pawlak ◽

Piotr Machowiec ◽

Marcela Maksymowicz ◽

Halina Piecewicz-Szczesna

Keyword(s):

Monoclonal Antibodies ◽

Viral Load ◽

Animal Studies ◽

Serum Antibody ◽

High Viral Load ◽

Supplemental Oxygen ◽

Low Grade ◽

Treatment Resistant ◽

Human Igg1 ◽

Antibody Cocktail

Abstract Casirivimab and imdevimab (REGN-COV-2) are investigational monoclonal antibodies approved in November 2020 by the Food and Drug Administration for emergency use in mild and moderate COVID-19. These two noncompeting human IgG1 monoclonal antibodies can target the receptor-binding domain of the spike protein of SARSCoV-2, prevent its entry into human cells, and reduce viral load. The antibodies can be administered intravenously for mild-to-moderate COVID-19 patients who do not require hospitalization and supplemental oxygen. The purpose of the study is to review the latest available data on COVID-19 treatment using casirivimab and imdevimab. According to recent preclinical studies, the antibody cocktail presents optimal antiviral strength and has the potential to minimize the chances of the virus escaping. It was shown in animal studies that the cocktail reduces the pathological consequences caused by viruses, decreases the number of viruses in the respiratory system, and reduces lung titers and pneumonia symptoms. Casirivimab and imdevimab as a cocktail also prevents the rapid appearance of treatment-resistant mutants. In the clinical trial, REGN-COV-2 decreased viral load, particularly in patients with a non-initiated immune response (serum antibody-negative) and with high viral load at baseline. The adverse effects were comparable in the combined REGN-COV2 dose groups (2.4 g and 8.0 g), as well as in the placebo group. The cocktail caused few and mainly low-grade toxic effects. Casirivimab and imdevimab seem to be effective and safe antiviral therapy for nonhospitalized patients with COVID-19. Further observations and research are extremely necessary to assess the efficacy, security and indications in a wider group of patients.

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Rapid quantification and in situ detection of nitrifying bacteria in biofilms by monoclonal antibody method

Water Science & Technology ◽

10.2166/wst.2000.0459 ◽

2000 ◽

Vol 41 (4-5) ◽

pp. 301-308 ◽

Cited By ~ 1

Author(s):

N. Noda ◽

H. Ikuta ◽

Y. Ebie ◽

A. Hirata ◽

S. Tsuneda ◽

...

Keyword(s):

Monoclonal Antibody ◽

Monoclonal Antibodies ◽

Fluorescent Antibody ◽

Nitrifying Bacteria ◽

Fluorescent Antibody Technique ◽

Antibody Technique ◽

Antibody Method ◽

In Situ Detection ◽

Rapid Quantification

Fluorescent antibody technique by the monoclonal antibody method is very useful and helpful for the rapid quantification and in situ detection of the specific bacteria like nitrifiers in a mixed baxterial habitat such as a biofilm. In this study, twelve monoclonal antibodies against Nitrosomonas europaea (IFO14298) and sixteen against Nitrobacter winogradskyi (IFO14297) were raised from splenocytes of mice (BALB/c). It was found that these antibodies exhibited little cross reactivity against various kinds of heterotrophic bacteria. The direct cell count method using monoclonal antibodies could exactly detect and rapidly quantify N. europaea and N. winogradskyi. Moreover, the distribution of N. europaea and N. winogradskyi in a biofilm could be examined by in situ fluorescent antibody technique. It was shown that most of N. winogradskyi existed near the surface part and most of N. europaea existed at the inner part of the polyethylene glycol (PEG) gel pellet, which had entrapped activated sludge and used in a landfill leachate treatment reactor. It was suggested that this monoclonal antibody method was utilized for estimating and controlling the population of nitrifying bacteria as a quick and favorable tool.

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Therapeutic Monoclonal Antibodies in Clinical Practice against Cancer

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200703191653 ◽

2020 ◽

Vol 20 (16) ◽

pp. 1895-1907

Author(s):

Navgeet Kaur ◽

Anju Goyal ◽

Rakesh K. Sindhu

Keyword(s):

Monoclonal Antibody ◽

Monoclonal Antibodies ◽

Clinical Practice ◽

Therapeutic Agent ◽

Hematologic Malignancies ◽

Immune Checkpoints ◽

Malignant Cells ◽

Main Target ◽

Therapeutic Monoclonal Antibodies ◽

Cancerous Cells

The importance of monoclonal antibodies in oncology has increased drastically following the discovery of Milstein and Kohler. Since the first approval of the monoclonal antibody, i.e. Rituximab in 1997 by the FDA, there was a decline in further applications but this number has significantly increased over the last three decades for various therapeutic applications due to the lesser side effects in comparison to the traditional chemotherapy methods. Presently, numerous monoclonal antibodies have been approved and many are in queue for approval as a strong therapeutic agent for treating hematologic malignancies and solid tumors. The main target checkpoints for the monoclonal antibodies against cancer cells include EGFR, VEGF, CD and tyrosine kinase which are overexpressed in malignant cells. Other immune checkpoints like CTLA-4, PD-1 and PD-1 receptors targeted by the recently developed antibodies increase the capability of the immune system in destroying the cancerous cells. Here, in this review, the mechanism of action, uses and target points of the approved mAbs against cancer have been summarized.

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