Identification

Summary

Cilgavimab is an extended half-life recombinant monoclonal IgG1κ antibody directed against the SARS-CoV-2 S protein for COVID-19 prophylaxis in individuals unable to undergo COVID-19 immunization.

Generic Name
Cilgavimab
DrugBank Accession Number
DB16393
Background

SARS-CoV-2, the causative agent of COVID-19, enters cells via the interaction between the trimeric spike (S) glycoprotein and host cell angiotensin-converting enzyme 2 (ACE2). Blocking the interaction between the receptor-binding domain (RBD) of the S1 subunit and ACE2 inhibits viral host cell entry; animal studies indicate that antibodies capable of blocking this interaction reduce viral load and improve clinical symptoms of infection.2,3 Cilgavimab (formerly AZD1061) is a recombinant monoclonal antibody produced in Chinese hamster ovary (CHO) cells derived from a neutralizing antibody isolated from a patient with a natural history of SARS-CoV-2 infection and modified through targeted amino acid substitutions to exhibit an extended (~85-day) half-life.1,2,4 As the RBD binding site of cilgavimab does not overlap with that of tixagevimab, the two can be administered to synergistically impair SARS-CoV-2 infection in individuals who may be exposed to the virus.1,3,4

Cilgavimab is not approved for any indication by the FDA. Cilgavimab, in combination with tixagevimab, was issued an FDA emergency use authorization (EUA) on December 9, 2021, for the pre-exposure prophylaxis of COVID-19 in individuals at increased risk for whom vaccination is not recommended. The combination is co-packaged and available under the name EVUSHELD (formerly AZD7442).4 EVUSHELD was granted marketing authorization by the EMA on March 28, 2022.5 EVUSHELD was approved in Canada soon after, on April 14, 2022.7

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
C6626H10218N1750O2078S44
Protein Average Weight
152000.0 Da (approximate)
Sequences
Not Available
Synonyms
  • Cilgavimab
External IDs
  • AZD-1061
  • AZD1061

Pharmacology

Indication

Cilgavimab has been issued an emergency use authorization (EUA) by the FDA, in combination with tixagevimab, for the pre-exposure prophylaxis of COVID-19 in adult and pediatric patients aged 12 years and older weighing at least 40 kg. Furthermore, patients must not be currently infected with SARS-CoV-2 or have had known exposure to an individual infected with SARS-CoV-2 and must either be immunocompromised due to a medical condition, medication, or treatment or be otherwise ineligible for vaccination with any eligible COVID-19 vaccine due to a history of severe adverse reactions.4

In the US, the combination of cilgavimab and tixagevimab is not authorized for the treatment or post-exposure prophylaxis of COVID-19 and is not a substitute for COVID-19 vaccination. Individuals receiving therapy following COVID-19 vaccination should wait at least two weeks.4

In Europe and Canada, cilgavimab in combination with tixagevimab is an approved pre-exposure prophylaxis therapy for COVID-19 in adults and adolescents aged 12 years and older weighing at least 40 kg.6,7

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Associated Conditions
Associated Therapies
Contraindications & Blackbox Warnings
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Pharmacodynamics

Cilgavimab is an extended half-life recombinant human IgG1κ monoclonal antibody directed against the SARS-CoV-2 spike (S) protein. Administered concurrently with tixagevimab, the combination carries a risk of hypersensitivity reactions and requires caution when administering to patients with thrombocytopenia or a coagulation disorder. Based on limited clinical experience, caution should also be exercised in patients with cardiac risk factors or a history of cardiovascular disease. As there is limited experience with this combination, unexpected serious adverse events may occur.4

Mechanism of action

SARS-CoV-2, the causative agent of COVID-19, enters cells via the interaction between the trimeric spike (S) glycoprotein and host cell angiotensin-converting enzyme 2 (ACE2). Of the two subunits comprising the trimeric S glycoprotein, the S1 subunit binds ACE2 via its receptor-binding domain (RBD) while the central S2 subunit mediates fusion following S1 shedding.1,2 Large-scale screens suggest that the most potently neutralizing antibodies recovered from the B cells of those convalescing following natural infection with SARS-CoV-2 bind to the RBD of S1 and are capable of disrupting the interaction between the RBD and human ACE2.2

Cilgavimab (AZD1061) is a recombinant human IgG1κ monoclonal antibody based on a neutralizing antibody (COV2-2130) isolated from patients with a natural history of SARS-CoV-2 infection and modified through specific amino acid substitutions to extend its half-life and reduce antibody effector functions.4 Cilgavimab binds to a non-overlapping region of the S1 RBD as tixagevimab and is capable of binding the S protein in both "up" and "down" conformations with a KD of 13.0 pM.2,3,4 Cell culture studies suggest little to no antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), or antibody-dependent natural killer cell activation (ADNKA), suggesting the protective effect is due solely to inhibition of the RBD-ACE2 interaction. Cilgavmiab inhibits RBD-ACE2 binding with an IC50 of 0.53 nM (80 ng/mL) and neutralizes SARS-CoV-2 (strain USA-WA1/2020) in a cellular assay with an EC50 value of 211.5 pM (32 ng/mL).4

As with other antiviral treatments, there is a risk of resistant variants emerging during treatment. Experiments to identify escape variants during culture of recombinant vesicular stomatitis virus expressing the S protein (VSV-SARS-CoV-2) or authentic SARS-CoV-2 (strain USA-WA1/2020) identified K444E, K444R, and R346I as potential single-nucleotide escape variants for cilgavimab (conferring a >200-fold reduction in susceptibility). However, no escape variants were identified to tixagevimab or the combination of cilgavimab and tixagevimab.3,4

TargetActionsOrganism
ASpike glycoprotein
binder
SARS-CoV-2
Absorption

A single 150 mg intramuscular dose of cilgavimab, given concurrently with 150 mg of tixagevimab, resulted in a Cmax geometric mean (%CV) of 15.3 (38.5) μg/mL in a median Tmax of 14.0 (range 3.1-60) days. The observed geometric mean (%CV) one, 150, or 210 days following dosing was 3.9 (94.4), 5.5 (35.2), and 3.9 (37.1) μg/mL. This single dose resulted in an AUC0-∞ of 2133 (31.7) μg*day/mL.4

Volume of distribution

Cilgavimab has an apparent volume of distribution of 8.7 ± 2.73 L.4

Protein binding

Not Available

Metabolism

As a monoclonal antibody, cilgavimab is expected to undergo proteolytic degradation.4

Route of elimination

Cilgavimab is unlikely to undergo renal excretion.4

Half-life

Cilgavimab has a half-life of 82.9 ± 12.3 days.4

Clearance

Cilgavimab has an apparent clearance of 0.074 ± 0.028 L/day.4

Adverse Effects
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Toxicity

Toxicity information regarding cilgavimab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects. Symptomatic and supportive measures are recommended.4

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Cilgavimab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Cilgavimab.
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Cilgavimab.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Cilgavimab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Cilgavimab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Cilgavimab.
AmivantamabThe risk or severity of adverse effects can be increased when Cilgavimab is combined with Amivantamab.
AnifrolumabThe risk or severity of adverse effects can be increased when Anifrolumab is combined with Cilgavimab.
AnsuvimabThe risk or severity of adverse effects can be increased when Ansuvimab is combined with Cilgavimab.
Anthrax immune globulin humanThe risk or severity of adverse effects can be increased when Anthrax immune globulin human is combined with Cilgavimab.
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Food Interactions
No interactions found.

Products

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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
EvusheldCilgavimab (150 mg / 1.5 mL) + Tixagevimab (150 mg / 1.5 mL)SolutionIntramuscularAstra Zeneca2022-04-19Not applicableCanada flag
EvusheldCilgavimab (100 mg/ml) + Tixagevimab (100 mg/ml)Injection, solutionIntramuscularAstra Zeneca Ab2022-05-04Not applicableEU flag

Categories

ATC Codes
J06BD03 — Tixagevimab and cilgavimab
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
1KUR4BN70F
CAS number
2420563-99-9

References

General References
  1. Zost SJ, Gilchuk P, Chen RE, Case JB, Reidy JX, Trivette A, Nargi RS, Sutton RE, Suryadevara N, Chen EC, Binshtein E, Shrihari S, Ostrowski M, Chu HY, Didier JE, MacRenaris KW, Jones T, Day S, Myers L, Eun-Hyung Lee F, Nguyen DC, Sanz I, Martinez DR, Rothlauf PW, Bloyet LM, Whelan SPJ, Baric RS, Thackray LB, Diamond MS, Carnahan RH, Crowe JE Jr: Rapid isolation and profiling of a diverse panel of human monoclonal antibodies targeting the SARS-CoV-2 spike protein. Nat Med. 2020 Sep;26(9):1422-1427. doi: 10.1038/s41591-020-0998-x. Epub 2020 Jul 10. [Article]
  2. Zost SJ, Gilchuk P, Case JB, Binshtein E, Chen RE, Nkolola JP, Schafer A, Reidy JX, Trivette A, Nargi RS, Sutton RE, Suryadevara N, Martinez DR, Williamson LE, Chen EC, Jones T, Day S, Myers L, Hassan AO, Kafai NM, Winkler ES, Fox JM, Shrihari S, Mueller BK, Meiler J, Chandrashekar A, Mercado NB, Steinhardt JJ, Ren K, Loo YM, Kallewaard NL, McCune BT, Keeler SP, Holtzman MJ, Barouch DH, Gralinski LE, Baric RS, Thackray LB, Diamond MS, Carnahan RH, Crowe JE Jr: Potently neutralizing and protective human antibodies against SARS-CoV-2. Nature. 2020 Aug;584(7821):443-449. doi: 10.1038/s41586-020-2548-6. Epub 2020 Jul 15. [Article]
  3. Dong J, Zost SJ, Greaney AJ, Starr TN, Dingens AS, Chen EC, Chen RE, Case JB, Sutton RE, Gilchuk P, Rodriguez J, Armstrong E, Gainza C, Nargi RS, Binshtein E, Xie X, Zhang X, Shi PY, Logue J, Weston S, McGrath ME, Frieman MB, Brady T, Tuffy KM, Bright H, Loo YM, McTamney PM, Esser MT, Carnahan RH, Diamond MS, Bloom JD, Crowe JE Jr: Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail. Nat Microbiol. 2021 Oct;6(10):1233-1244. doi: 10.1038/s41564-021-00972-2. Epub 2021 Sep 21. [Article]
  4. FDA EUA Fact Sheet: EVUSHELD (tixagevimab and cilgavimab) injection [Link]
  5. Astrazeneca Press Release: Evusheld long-acting antibody combination approved in the EU for pre-exposure prophylaxis (prevention) of COVID-19 in a broad population [Link]
  6. EMA Approved Drug Products: Evusheld (tixagevimab, cilgavimab) Intramuscular Injection [Link]
  7. Health Canada Approved Drug Products: EVUSHELD (tixagevimab and cilgavimab) intramuscular injection [Link]
RxNav
2587306
Wikipedia
Tixagevimab/cilgavimab

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingPreventionCoronavirus Disease 2019 (COVID‑19)2
3Active Not RecruitingTreatmentCoronavirus Disease 2019 (COVID‑19)2
3RecruitingPreventionCoronavirus Disease 2019 (COVID‑19)1
3RecruitingTreatmentCoronavirus Disease 2019 (COVID‑19)1
2Not Yet RecruitingTreatmentChronic Lymphocytic Leukemia (CLL) / Coronavirus Disease 2019 (COVID‑19)1
2RecruitingPreventionCoronavirus Disease 2019 (COVID‑19)1
2, 3Active Not RecruitingTreatmentCoronavirus Disease 2019 (COVID‑19) / Infections, Coronavirus1
1Active Not RecruitingOtherCoronavirus Disease 2019 (COVID‑19) / Healthy Subjects (HS)1
1Active Not RecruitingTreatmentCoronavirus Disease1
1RecruitingTreatmentCoronavirus Disease 2019 (COVID‑19)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntramuscular
Injection, solution; kitIntramuscular; Intravenous
SolutionIntramuscular
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

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Kind
Protein
Organism
SARS-CoV-2
Pharmacological action
Yes
Actions
Binder
Curator comments
Cilgavimab binds to the RBD of the S1 subunit and inhibits interaction of the S protein with human ACE2.
General Function
Spike protein S1 attaches the virion to the cell membrane by interacting with host receptor, initiating the infection. Binding to human ACE2 receptor and internalization of the virus into the endosomes of the host cell induces conformational changes in the Spike glycoprotein (PubMed:32142651, PubMed:32075877, PubMed:32155444). Uses also human TMPRSS2 for priming in human lung cells which is an essential step for viral entry (PubMed:32142651). Can be alternatively processed by host furin (PubMed:32362314). Proteolysis by cathepsin CTSL may unmask the fusion peptide of S2 and activate membranes fusion within endosomes.
Specific Function
Host cell surface receptor binding
Gene Name
S
Uniprot ID
P0DTC2
Uniprot Name
Spike glycoprotein
Molecular Weight
141177.29 Da
References
  1. Zost SJ, Gilchuk P, Chen RE, Case JB, Reidy JX, Trivette A, Nargi RS, Sutton RE, Suryadevara N, Chen EC, Binshtein E, Shrihari S, Ostrowski M, Chu HY, Didier JE, MacRenaris KW, Jones T, Day S, Myers L, Eun-Hyung Lee F, Nguyen DC, Sanz I, Martinez DR, Rothlauf PW, Bloyet LM, Whelan SPJ, Baric RS, Thackray LB, Diamond MS, Carnahan RH, Crowe JE Jr: Rapid isolation and profiling of a diverse panel of human monoclonal antibodies targeting the SARS-CoV-2 spike protein. Nat Med. 2020 Sep;26(9):1422-1427. doi: 10.1038/s41591-020-0998-x. Epub 2020 Jul 10. [Article]
  2. Zost SJ, Gilchuk P, Case JB, Binshtein E, Chen RE, Nkolola JP, Schafer A, Reidy JX, Trivette A, Nargi RS, Sutton RE, Suryadevara N, Martinez DR, Williamson LE, Chen EC, Jones T, Day S, Myers L, Hassan AO, Kafai NM, Winkler ES, Fox JM, Shrihari S, Mueller BK, Meiler J, Chandrashekar A, Mercado NB, Steinhardt JJ, Ren K, Loo YM, Kallewaard NL, McCune BT, Keeler SP, Holtzman MJ, Barouch DH, Gralinski LE, Baric RS, Thackray LB, Diamond MS, Carnahan RH, Crowe JE Jr: Potently neutralizing and protective human antibodies against SARS-CoV-2. Nature. 2020 Aug;584(7821):443-449. doi: 10.1038/s41586-020-2548-6. Epub 2020 Jul 15. [Article]
  3. Dong J, Zost SJ, Greaney AJ, Starr TN, Dingens AS, Chen EC, Chen RE, Case JB, Sutton RE, Gilchuk P, Rodriguez J, Armstrong E, Gainza C, Nargi RS, Binshtein E, Xie X, Zhang X, Shi PY, Logue J, Weston S, McGrath ME, Frieman MB, Brady T, Tuffy KM, Bright H, Loo YM, McTamney PM, Esser MT, Carnahan RH, Diamond MS, Bloom JD, Crowe JE Jr: Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail. Nat Microbiol. 2021 Oct;6(10):1233-1244. doi: 10.1038/s41564-021-00972-2. Epub 2021 Sep 21. [Article]
  4. FDA EUA Fact Sheet: EVUSHELD (tixagevimab and cilgavimab) injection [Link]

Drug created at December 23, 2020 15:59 / Updated at May 04, 2022 06:58