Retifanlimab

Identification

Summary

Retifanlimab is a PD-1–blocking antibody indicated for the treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma.

Brand Names
Zynyz
Generic Name
Retifanlimab
DrugBank Accession Number
DB15766
Background

Retifanlimab is a humanized IgG4 kappa monoclonal antibody that binds to the programmed death receptor-1 (PD-1), blocking PD-1 interaction with its ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). By blocking the PD-1/PD-L1/2 pathway, retifanlimab potentiates T-cell activity and boosts the immune response against cancer cells.3 Other monoclonal antibodies that block PD-1 include pembrolizumab, nivolumab and cemiplimab.

On October 2021, Incyte Biosciences withdrew its application for a marketing authorization of retifanlimab for the treatment of squamous carcinoma of the anal canal.4,6 On March 2023, the FDA granted accelerated approval to retifanlimab for a different indication, the treatment of metastatic or recurrent locally advanced Merkel cell carcinoma (MCC).3,5 The use of retifanlimab in combination with other oncology drugs for the treatment of metastatic gastroesophageal adenocarcinoma has also been evaluated.1,2

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
C6456H9934N1702O2032S46
Protein Average Weight
148000.0 Da (approximate)
Sequences
>Retifanlimab_Heavy_chain
QVQLVQSGAEVKKPGASVKVSCKASGYSFTSYWMNWVRQAPGQGLEWIGVIHPSDSETWL
DQKFKDRVTITVDKSTSTAYMELSSLRSEDTAVYYCAREHYGTSPFAYWGQGTLVTVSSA
STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVF
LFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR
VVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKN
QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGN
VFSCSVMHEALHNHYTQKSLSLSLG
>Retifanlimab_Light_chain
EIVLTQSPATLSLSPGERATLSCRASESVDNYGMSFMNWFQQKPGQPPKLLIHAASNQGS
GVPSRFSGSGSGTDFTLTISSLEPEDFAVYFCQQSKEVPYTFGGGTKVEIKRTVAAPSVF
IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS
STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. WHO: International Nonproprietary Names for Pharmaceutical Substances (INN) - List 83 [Link]
Download FASTA Format
Synonyms
  • Anti-PD-1 monoclonal antibody MGA012
  • Retifanlimab
External IDs
  • AEX-1188
  • AEX1188
  • INCMGA-00012
  • INCMGA00012
  • MGA-012
  • MGA012
  • WHO 11095

Pharmacology

Indication

Retifanlimab is indicated for the treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma.3

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofMetastatic locally advanced merkel cell carcinoma••••••••••••••••••••••••••
Treatment ofRecurrent, locally advanced merkel cell carcinoma••••••••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

The exposure-response relationship and time course of pharmacodynamic response for safety and effectiveness of retifanlimab have not been fully characterized.3 Since retifanlimab targets the programmed death receptor-1 (PD-1) and blocks the PD-1/PD-ligand 1 (PD-L1) pathways, it has the potential to induce immune-mediated adverse reactions. The use of retifanlimab may lead to the development of immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, and other immune-mediated adverse reactions. The use of retifanlimab has also been associated to infusion-related reactions, serious complications during allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity.3

Mechanism of action

Retifanlimab is a programmed death receptor-1 (PD-1)–blocking antibody that potentiates T-cell activity and boosts the immune response against cancer cells. PD-1 is found on the surface of T-cells, and when it binds to its ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2), it inhibits T-cell proliferation and cytokine production. In normal conditions, cells produce PD-L1 and PD-L2 to maintain self-tolerance and ensure that the immune system does not attack health cells. However, in certain types of cancers, PD-L1 and PD-L2 are upregulated, contributing to a lower active T-cell immune surveillance of tumors. Retifanlimab binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2. By preventing the activation of this inhibitory pathway, retifanlimab promotes immune reactivity and enhances anti-tumor immune response.3

TargetActionsOrganism
AProgrammed cell death protein 1
antibody
blocker
Humans
Absorption

The pharmacokinetics of retifanlimab were assessed in patients with different types of solid tumors, including Merkel cell carcinoma (MCC). From 375 mg to 750 mg (0.75- to 1.5-fold of the approved recommended dose), the Cmax and AUC of retifanlimab increased in a dose-proportional manner. In patients given 500 mg of retifanlimab every 4 weeks, steady-state concentrations are reached at cycle 6 (approximately 6 months) with a 1.3-fold systemic accumulation.3 Factors such as age, sex, body weight, race, albumin level, renal function and mild hepatic impairment did not have a clinically significant effect on the pharmacogenetic profile of retifanlimab. The pharmacokinetics of retifanlimab have not been evaluated in patients with moderate or severe hepatic impairment.3

Volume of distribution

At steady-state, retifanlimab has a mean volume of distribution of 6.0 L.3

Protein binding

Not Available

Metabolism

As a monoclonal antibody, retifanlimab is expected to be metabolized by proteases throughout the body.

Route of elimination

No excretion studies were performed since, as an antibody, retifanlimab is degraded to small peptides and amino acids.4

Half-life

At steady-state, retifanlimab has an elimination half-life of 19 days.3

Clearance

Following the first dose of retifanlimab, clearance was 0.31 L/day, which decreased by approximately 23% over time. The steady-state clearance of retifanlimab was 0.24 L/day.3

Adverse Effects
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Toxicity

Toxicity information regarding retifanlimab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects, such as severe and fatal immune-mediated adverse reactions and severe infusion-related reactions.3 Symptomatic and supportive measures are recommended. The carcinogenicity and genotoxicity of retifanlimab have not been evaluated in non-clinical studies. In monkeys given 1-month and 3-month repeat doses, retifanlimab did not lead to no notable effects in the male and female reproductive organs; however, most animals were not sexually mature.3

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
AmbroxolThe risk or severity of methemoglobinemia can be increased when Retifanlimab is combined with Ambroxol.
ArticaineThe risk or severity of methemoglobinemia can be increased when Retifanlimab is combined with Articaine.
BenzocaineThe risk or severity of methemoglobinemia can be increased when Retifanlimab is combined with Benzocaine.
Benzyl alcoholThe risk or severity of methemoglobinemia can be increased when Retifanlimab is combined with Benzyl alcohol.
BupivacaineThe risk or severity of methemoglobinemia can be increased when Retifanlimab is combined with Bupivacaine.
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ZynyzInjection, solution, concentrate500 mgIntravenousIncyte Biosciences Distribution B.V.2024-07-10Not applicableEU flag
ZynyzInjection25 mg/1mLIntravenousIncyte Corporation2023-03-22Not applicableUS flag

Categories

ATC Codes
L01FF10 — Retifanlimab
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
2Y3T5IF01Z
CAS number
2079108-44-2

References

General References
  1. Rao S, Jones M, Bowman J, Tian C, Spano JP: POD1UM-303/InterAACT 2: A phase III, global, randomized, double-blind study of retifanlimab or placebo plus carboplatin-paclitaxel in patients with locally advanced or metastatic squamous cell anal carcinoma. Front Oncol. 2022 Aug 24;12:935383. doi: 10.3389/fonc.2022.935383. eCollection 2022. [Article]
  2. Catenacci DVT, Kang YK, Yoon HH, Shim BY, Kim ST, Oh DY, Spira AI, Ulahannan SV, Avery EJ, Boland PM, Chao J, Chung HC, Gardner F, Klempner SJ, Lee KW, Oh SC, Peguero J, Sonbol MB, Shen L, Moehler M, Sun J, Li D, Rosales MK, Park H: Margetuximab with retifanlimab as first-line therapy in HER2+/PD-L1+ unresectable or metastatic gastroesophageal adenocarcinoma: MAHOGANY cohort A. ESMO Open. 2022 Oct;7(5):100563. doi: 10.1016/j.esmoop.2022.100563. Epub 2022 Aug 24. [Article]
  3. FDA Approved Drug Products: ZYNYZ (retifanlimab-dlwr) injection, for intravenous use (March 2023) [Link]
  4. EMA Withdrawal Assessment Report: Zynyz (retifanlimab) [Link]
  5. US Food & Drug Administration: FDA grants accelerated approval to retifanlimab-dlwr for metastatic or recurrent locally advanced Merkel cell carcinoma [Link]
  6. EMA: Withdrawal of application for the marketing authorisation of Zynyz (retifanlimab) [Link]
RxNav
2632981
Wikipedia
Retifanlimab

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
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PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
3Active Not RecruitingTreatmentAnal Squamous Cell Carcinoma1somestatusstop reasonjust information to hide
3Active Not RecruitingTreatmentMetastatic Non-squamous Non Small Cell Lung Cancer / Metastatic squamous cell cancer Non-small cell lung cancer1somestatusstop reasonjust information to hide
3RecruitingTreatmentBreast Cancer / Breast Neoplasms / End Stage Cancer / Metastatic Breast Cancer1somestatusstop reasonjust information to hide
3WithdrawnTreatmentNon-Small Cell Lung Cancer (NSCLC)1somestatusstop reasonjust information to hide
2Active Not RecruitingTreatmentGlioma / High Grade Glioma: Glioblastoma (GBM)1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravenous25 mg/1mL
Injection, solution, concentrateIntravenous500 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antibody
Blocker
General Function
Inhibitory receptor on antigen activated T-cells that plays a critical role in induction and maintenance of immune tolerance to self (PubMed:21276005). Delivers inhibitory signals upon binding to ligands CD274/PDCD1L1 and CD273/PDCD1LG2 (PubMed:21276005). Following T-cell receptor (TCR) engagement, PDCD1 associates with CD3-TCR in the immunological synapse and directly inhibits T-cell activation (By similarity). Suppresses T-cell activation through the recruitment of PTPN11/SHP-2: following ligand-binding, PDCD1 is phosphorylated within the ITSM motif, leading to the recruitment of the protein tyrosine phosphatase PTPN11/SHP-2 that mediates dephosphorylation of key TCR proximal signaling molecules, such as ZAP70, PRKCQ/PKCtheta and CD247/CD3zeta (By similarity)
Specific Function
signaling receptor activity
Gene Name
PDCD1
Uniprot ID
Q15116
Uniprot Name
Programmed cell death protein 1
Molecular Weight
31646.635 Da
References
  1. Rao S, Jones M, Bowman J, Tian C, Spano JP: POD1UM-303/InterAACT 2: A phase III, global, randomized, double-blind study of retifanlimab or placebo plus carboplatin-paclitaxel in patients with locally advanced or metastatic squamous cell anal carcinoma. Front Oncol. 2022 Aug 24;12:935383. doi: 10.3389/fonc.2022.935383. eCollection 2022. [Article]
  2. Catenacci DVT, Kang YK, Yoon HH, Shim BY, Kim ST, Oh DY, Spira AI, Ulahannan SV, Avery EJ, Boland PM, Chao J, Chung HC, Gardner F, Klempner SJ, Lee KW, Oh SC, Peguero J, Sonbol MB, Shen L, Moehler M, Sun J, Li D, Rosales MK, Park H: Margetuximab with retifanlimab as first-line therapy in HER2+/PD-L1+ unresectable or metastatic gastroesophageal adenocarcinoma: MAHOGANY cohort A. ESMO Open. 2022 Oct;7(5):100563. doi: 10.1016/j.esmoop.2022.100563. Epub 2022 Aug 24. [Article]
  3. FDA Approved Drug Products: ZYNYZ (retifanlimab-dlwr) injection, for intravenous use (March 2023) [Link]
  4. EMA Withdrawal Assessment Report: Zynyz (retifanlimab) [Link]

Drug created at August 20, 2020 19:21 / Updated at March 25, 2023 04:38