Amivantamab

Identification

Summary

Amivantamab is an EGF and MET receptor targeted antibody indicated in the treatment of non-small cell lung cancer with an EGFR 20 exon insertion mutation.

Brand Names
Rybrevant
Generic Name
Amivantamab
DrugBank Accession Number
DB16695
Background

Amivantamab, also known as JNJ-61186372, is an anti-EGFR-MET bispecific antibody, derived from Chinese hamster ovary cells, approved for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.1,9 Patients with NSCLC often develop resistance to drugs that target EGFR and MET individually, so amivantamab was developed to attack both targets, reducing the chance of resistance developing.1,2 Amivantamab was found to be more effective than the EGFR inhibitor erlotinib or the MET inhibitor crizotinib in vivo.1,3 Patients with NSCLC with exon 20 insertion mutations in EGFR do not respond to tyrosine kinase inhibitors, and were generally treated with platinum-based therapy.5

Amivantamab was granted FDA approval on 21 May 2021,9 followed by the approval by the EMA on 9 December 2021 12 and Health Canada on 30 March 2022.11

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
Not Available
Protein Average Weight
148000.0 Da (Approximate)
Sequences
Not Available
Synonyms
  • amivantamab-vmjw
External IDs
  • CNTO-4424
  • JNJ 61186372
  • JNJ-611
  • JNJ-61186372

Pharmacology

Indication

Amivantamab is indicated for the following conditions:

  • in combination with lazertinib, it is indicated for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.16
  • in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test.15,16
  • indicated as a single agent for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.9,11,13,14,15,16
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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofLocally advanced nsclc•••••••••••••••••••••••• ••••••••••• •• •• ••••• •••••••••••••• ••••••••••••• •••• •••• •• ••••••••• •••••••••••••••••
Used in combination to treatLocally advanced non-small cell lung cancerRegimen in combination with: Lazertinib (DB16216)••••••••••••
Used in combination to treatLocally advanced non-small cell lung cancerRegimen in combination with: Lazertinib (DB16216)••••••••••••
Used in combination to treatLocally advanced non-small cell lung cancerRegimen in combination with: Carboplatin (DB00958), Pemetrexed (DB00642)•••••••••••••••••••••••••• •••••
Used in combination to treatMetastatic non-small cell lung cancerRegimen in combination with: Lazertinib (DB16216)••••••••••••
Associated Therapies
Contraindications & Blackbox Warnings
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Pharmacodynamics

Amivantamab is an EGF and MET receptor targeted antibody indicated in the treatment of non-small cell lung cancer with an EGFR 20 exon insertion mutation.9 It has a long duration of action, as activity can be detected up to 8 weeks after treatment.1 Patients should be counselled regarding the risk of infusion-related reactions, interstitial lung disease and pneumonitis, skin reactions, ocular toxicity, and paronychia.9 Patients should not take amivantamab if they are pregnant or breastfeeding.9

Mechanism of action

Mesenchymal-epithelial transition factor (MET) is a receptor with tyrosine kinase activity expressed on epithelial cells that, upon signalling, dimerizes and activates downstream pathways that signal cell division.1,4 The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein with tyrosine kinase activity that can further activate downstream pathways that signal cell division, survival, and angiogenesis.1,4 Patients with NSCLC with exon 20 insertion mutations in EGFR do not respond to tyrosine kinase inhibitors, and are generally treated with platinum-based therapy.5 Exon 20 insertion mutations in EGFR also lead to conformational changes that activate EGFR.6

Amivantamab targets both EGFR and MET, preventing ligands from binding to the receptors, blocking signalling, marking the cancerous cells for antibody-dependant cellular cytotoxicity by natural killer cells, and allowing macrophages to perform trogocytosis.9

Amivantamab's binding to the EGFR H epitope shares some of the same amino acids that cetuximab binds to.1

Amivantamab's binding to the alpha chain of MET stabilizes the Sema domain loop 1 to 2 in a position 6 Angstroms away from the position it would be in under normal binding, preventing its interaction with the hepatocyte growth factor's (HGF) beta chain.1 Another smaller conformational change in the MET Sema domain loop 1 to 3 also contributes to preventing the interaction of the MET Sema domain with HGF's beta chain.1 HGF is no longer able to bind to MET, preventing downstream signalling.1

Amivantamab's Fc portion contains 90% less fucose than normal antibodies, allowing for increased binding to the FcγRIIIa region.4 Binding of the Fc portion of Amivantamab signals the complement system and innate immune system to target the bound cells for complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis.4 Binding of amivantamab to the Fc receptor also leads to and increase in levels of IFNγ.6

Amivantamab also significantly downregulates the expression of EGFR and MET on NSCLC cell surfaces, further reducing downstream signalling.6,7 EGFR and MET on the cell surface are internalized, and possibly degrading by fusing endosomes with lysosomes.6 Alternatively, EGFR and MET are the subjects of monocyte-dependent trogocytosis.7 Trogocytosis allows monocytes to internalize and break down EGFR and MET from the NSCLC cells without cytotoxicity, downmodulating EGFR and MET receptors.7

TargetActionsOrganism
AEpidermal growth factor receptor
antibody
downregulator
Humans
AHepatocyte growth factor receptor
antagonist
antibody
Humans
ALow affinity immunoglobulin gamma Fc region receptor III-A
inducer
Humans
Absorption

Not Available

Volume of distribution

The mean volume of distribution of amivantamab-vmjw is 5.13 ±1.78 L.9

Protein binding

Not Available

Metabolism

Antibodies are expected to be metabolized to oligopeptides and amino acids.8

Route of elimination

Not Available

Half-life

The terminal half life of amivantamab-vmjw is 11.3 ± 4.53 days.9

Clearance

The mean clearance of amivantamab-vmjw is 360 ± 144 mL/day.9

Adverse Effects
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Toxicity

Data regarding overdoses of amivantamab are not readily available.9 Patients experiencing an overdose should be treated with symptomatic and supportive measures.

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 Amivantamab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Amivantamab.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Amivantamab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Amivantamab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Amivantamab.
Food Interactions
No interactions found.

Products

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International/Other Brands
Rybrevant (Janssen Pharmaceutical Companies of Johnson & Johnson)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
RybrevantInjection350 mg/1IntravenousJanssen Biotech, Inc.2021-05-21Not applicableUS flag
RybrevantInjection, solution, concentrate350 mgIntravenousJanssen Cilag International Nv2022-05-04Not applicableEU flag
RybrevantSolution350 mg / 7 mLIntravenousJanssen Pharmaceuticals2022-04-26Not applicableCanada flag

Categories

ATC Codes
L01FX18 — Amivantamab
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
Not Available

Chemical Identifiers

UNII
0JSR7Z0NB6
CAS number
2171511-58-1

References

General References
  1. Neijssen J, Cardoso RMF, Chevalier KM, Wiegman L, Valerius T, Anderson GM, Moores SL, Schuurman J, Parren PWHI, Strohl WR, Chiu ML: Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET. J Biol Chem. 2021 Apr 8:100641. doi: 10.1016/j.jbc.2021.100641. [Article]
  2. Jarantow SW, Bushey BS, Pardinas JR, Boakye K, Lacy ER, Sanders R, Sepulveda MA, Moores SL, Chiu ML: Impact of Cell-surface Antigen Expression on Target Engagement and Function of an Epidermal Growth Factor Receptor x c-MET Bispecific Antibody. J Biol Chem. 2015 Oct 9;290(41):24689-704. doi: 10.1074/jbc.M115.651653. Epub 2015 Aug 10. [Article]
  3. Moores SL, Chiu ML, Bushey BS, Chevalier K, Luistro L, Dorn K, Brezski RJ, Haytko P, Kelly T, Wu SJ, Martin PL, Neijssen J, Parren PW, Schuurman J, Attar RM, Laquerre S, Lorenzi MV, Anderson GM: A Novel Bispecific Antibody Targeting EGFR and cMet Is Effective against EGFR Inhibitor-Resistant Lung Tumors. Cancer Res. 2016 Jul 1;76(13):3942-53. doi: 10.1158/0008-5472.CAN-15-2833. Epub 2016 May 23. [Article]
  4. Grugan KD, Dorn K, Jarantow SW, Bushey BS, Pardinas JR, Laquerre S, Moores SL, Chiu ML: Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells. MAbs. 2017 Jan;9(1):114-126. doi: 10.1080/19420862.2016.1249079. Epub 2016 Oct 27. [Article]
  5. Metro G, Baglivo S, Bellezza G, Mandarano M, Gili A, Marchetti G, Toraldo M, Molica C, Reda MS, Tofanetti FR, Siggillino A, Prosperi E, Giglietti A, Di Girolamo B, Garaffa M, Marasciulo F, Minotti V, Gunnellini M, Guida A, Sassi M, Sidoni A, Roila F, Ludovini V: Sensitivity to Immune Checkpoint Blockade in Advanced Non-Small Cell Lung Cancer Patients with EGFR Exon 20 Insertion Mutations. Genes (Basel). 2021 Apr 30;12(5). pii: genes12050679. doi: 10.3390/genes12050679. [Article]
  6. Yun J, Lee SH, Kim SY, Jeong SY, Kim JH, Pyo KH, Park CW, Heo SG, Yun MR, Lim S, Lim SM, Hong MH, Kim HR, Thayu M, Curtin JC, Knoblauch RE, Lorenzi MV, Roshak A, Cho BC: Antitumor Activity of Amivantamab (JNJ-61186372), an EGFR-MET Bispecific Antibody, in Diverse Models of EGFR Exon 20 Insertion-Driven NSCLC. Cancer Discov. 2020 Aug;10(8):1194-1209. doi: 10.1158/2159-8290.CD-20-0116. Epub 2020 May 15. [Article]
  7. Vijayaraghavan S, Lipfert L, Chevalier K, Bushey BS, Henley B, Lenhart R, Sendecki J, Beqiri M, Millar HJ, Packman K, Lorenzi MV, Laquerre S, Moores SL: Amivantamab (JNJ-61186372), an Fc Enhanced EGFR/cMet Bispecific Antibody, Induces Receptor Downmodulation and Antitumor Activity by Monocyte/Macrophage Trogocytosis. Mol Cancer Ther. 2020 Oct;19(10):2044-2056. doi: 10.1158/1535-7163.MCT-20-0071. Epub 2020 Aug 3. [Article]
  8. Ryman JT, Meibohm B: Pharmacokinetics of Monoclonal Antibodies. CPT Pharmacometrics Syst Pharmacol. 2017 Sep;6(9):576-588. doi: 10.1002/psp4.12224. Epub 2017 Jul 29. [Article]
  9. FDA Approved Drug Products: Rybrevant (Amivantamab-vmjw) Intravenous Injection [Link]
  10. US Patent: US9593164B2 [Link]
  11. Health Canada Approved Drug Products: Rybrevant (amivantamab) injection, for intravenous infusion (March 2022) [Link]
  12. European Medicines Agency Medicines: Rybrevant (amivantamab) [Link]
  13. EMA Approved Drug Products: Rybrevant (amivantamab) intravenous injection [Link]
  14. FDA Approved Drug Products: RYBREVANT (amivantamab-vmjw) injection, for intravenous use (November 2022) [Link]
  15. Health Canada Approved Drug Products: RYBREVANT (amivantamab) Intravenous Injection (June 2024) [Link]
  16. FDA Approved Drug Products: RYBREVANT (amivantamab-vmjw) injection, for intravenous use (August 2024) [Link]
RxNav
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Wikipedia
Amivantamab

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Not AvailableApproved for MarketingNot AvailableMetastatic Non-Small Cell Lung Cancer1somestatusstop reasonjust information to hide
3Active Not RecruitingTreatmentMetastatic or Advanced Non-Small Cell Lung Cancer (NSCLC)1somestatusstop reasonjust information to hide
3Active Not RecruitingTreatmentNon-Small Cell Lung Carcinoma3somestatusstop reasonjust information to hide
2Active Not RecruitingTreatmentMetastatic Non-Small Cell Lung Cancer / Recurrent Non-small Cell Lung Cancer1somestatusstop reasonjust information to hide
2Active Not RecruitingTreatmentNon-Small Cell Lung Carcinoma1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravenous350 mg/1
Injection, solution, concentrateIntravenous350 mg
SolutionIntravenous350 mg / 7 mL
SolutionIntravenous350.00 mg
Injection, solution, concentrateIntravenous350 mg/7mL
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antibody
Downregulator
General Function
Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses (PubMed:10805725, PubMed:27153536, PubMed:2790960, PubMed:35538033). Known ligands include EGF, TGFA/TGF-alpha, AREG, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF (PubMed:12297049, PubMed:15611079, PubMed:17909029, PubMed:20837704, PubMed:27153536, PubMed:2790960, PubMed:7679104, PubMed:8144591, PubMed:9419975). Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules (PubMed:27153536). May also activate the NF-kappa-B signaling cascade (PubMed:11116146). Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling (PubMed:11602604). Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin (PubMed:11483589). Positively regulates cell migration via interaction with CCDC88A/GIV which retains EGFR at the cell membrane following ligand stimulation, promoting EGFR signaling which triggers cell migration (PubMed:20462955). Plays a role in enhancing learning and memory performance (By similarity). Plays a role in mammalian pain signaling (long-lasting hypersensitivity) (By similarity)
Specific Function
actin filament binding
Gene Name
EGFR
Uniprot ID
P00533
Uniprot Name
Epidermal growth factor receptor
Molecular Weight
134276.185 Da
References
  1. Neijssen J, Cardoso RMF, Chevalier KM, Wiegman L, Valerius T, Anderson GM, Moores SL, Schuurman J, Parren PWHI, Strohl WR, Chiu ML: Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET. J Biol Chem. 2021 Apr 8:100641. doi: 10.1016/j.jbc.2021.100641. [Article]
  2. Vijayaraghavan S, Lipfert L, Chevalier K, Bushey BS, Henley B, Lenhart R, Sendecki J, Beqiri M, Millar HJ, Packman K, Lorenzi MV, Laquerre S, Moores SL: Amivantamab (JNJ-61186372), an Fc Enhanced EGFR/cMet Bispecific Antibody, Induces Receptor Downmodulation and Antitumor Activity by Monocyte/Macrophage Trogocytosis. Mol Cancer Ther. 2020 Oct;19(10):2044-2056. doi: 10.1158/1535-7163.MCT-20-0071. Epub 2020 Aug 3. [Article]
  3. Cavaliere A, Sun S, Lee S, Bodner J, Li Z, Huang Y, Moores SL, Marquez-Nostra B: Development of [(89)Zr]ZrDFO-amivantamab bispecific to EGFR and c-MET for PET imaging of triple-negative breast cancer. Eur J Nucl Med Mol Imaging. 2021 Feb;48(2):383-394. doi: 10.1007/s00259-020-04978-6. Epub 2020 Aug 8. [Article]
  4. FDA Approved Drug Products: Rybrevant (Amivantamab-vmjw) Intravenous Injection [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
Antibody
General Function
Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including proliferation, scattering, morphogenesis and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with the morphogenetic effects while PI3K/AKT coordinates prosurvival effects. During embryonic development, MET signaling plays a role in gastrulation, development and migration of neuronal precursors, angiogenesis and kidney formation. During skeletal muscle development, it is crucial for the migration of muscle progenitor cells and for the proliferation of secondary myoblasts (By similarity). In adults, participates in wound healing as well as organ regeneration and tissue remodeling. Promotes also differentiation and proliferation of hematopoietic cells. May regulate cortical bone osteogenesis (By similarity)
Specific Function
ATP binding
Gene Name
MET
Uniprot ID
P08581
Uniprot Name
Hepatocyte growth factor receptor
Molecular Weight
155540.035 Da
References
  1. Neijssen J, Cardoso RMF, Chevalier KM, Wiegman L, Valerius T, Anderson GM, Moores SL, Schuurman J, Parren PWHI, Strohl WR, Chiu ML: Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET. J Biol Chem. 2021 Apr 8:100641. doi: 10.1016/j.jbc.2021.100641. [Article]
  2. Cavaliere A, Sun S, Lee S, Bodner J, Li Z, Huang Y, Moores SL, Marquez-Nostra B: Development of [(89)Zr]ZrDFO-amivantamab bispecific to EGFR and c-MET for PET imaging of triple-negative breast cancer. Eur J Nucl Med Mol Imaging. 2021 Feb;48(2):383-394. doi: 10.1007/s00259-020-04978-6. Epub 2020 Aug 8. [Article]
  3. FDA Approved Drug Products: Rybrevant (Amivantamab-vmjw) Intravenous Injection [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inducer
General Function
Receptor for the invariable Fc fragment of immunoglobulin gamma (IgG). Optimally activated upon binding of clustered antigen-IgG complexes displayed on cell surfaces, triggers lysis of antibody-coated cells, a process known as antibody-dependent cellular cytotoxicity (ADCC). Does not bind free monomeric IgG, thus avoiding inappropriate effector cell activation in the absence of antigenic trigger (PubMed:11711607, PubMed:21768335, PubMed:22023369, PubMed:24412922, PubMed:25786175, PubMed:25816339, PubMed:28652325, PubMed:8609432, PubMed:9242542). Mediates IgG effector functions on natural killer (NK) cells. Binds antigen-IgG complexes generated upon infection and triggers NK cell-dependent cytokine production and degranulation to limit viral load and propagation. Involved in the generation of memory-like adaptive NK cells capable to produce high amounts of IFNG and to efficiently eliminate virus-infected cells via ADCC (PubMed:24412922, PubMed:25786175). Regulates NK cell survival and proliferation, in particular by preventing NK cell progenitor apoptosis (PubMed:29967280, PubMed:9916693). Fc-binding subunit that associates with CD247 and/or FCER1G adapters to form functional signaling complexes. Following the engagement of antigen-IgG complexes, triggers phosphorylation of immunoreceptor tyrosine-based activation motif (ITAM)-containing adapters with subsequent activation of phosphatidylinositol 3-kinase signaling and sustained elevation of intracellular calcium that ultimately drive NK cell activation. The ITAM-dependent signaling coupled to receptor phosphorylation by PKC mediates robust intracellular calcium flux that leads to production of pro-inflammatory cytokines, whereas in the absence of receptor phosphorylation it mainly activates phosphatidylinositol 3-kinase signaling leading to cell degranulation (PubMed:1825220, PubMed:23024279, PubMed:2532305). Costimulates NK cells and trigger lysis of target cells independently of IgG binding (PubMed:10318937, PubMed:23006327). Mediates the antitumor activities of therapeutic antibodies. Upon ligation on monocytes triggers TNFA-dependent ADCC of IgG-coated tumor cells (PubMed:27670158). Mediates enhanced ADCC in response to afucosylated IgGs (PubMed:34485821)
Specific Function
IgG binding
Gene Name
FCGR3A
Uniprot ID
P08637
Uniprot Name
Low affinity immunoglobulin gamma Fc region receptor III-A
Molecular Weight
29088.895 Da
References
  1. Grugan KD, Dorn K, Jarantow SW, Bushey BS, Pardinas JR, Laquerre S, Moores SL, Chiu ML: Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells. MAbs. 2017 Jan;9(1):114-126. doi: 10.1080/19420862.2016.1249079. Epub 2016 Oct 27. [Article]

Drug created at May 22, 2021 03:10 / Updated at August 28, 2024 20:13