Relatlimab

Identification

Summary

Relatlimab is a monoclonal antibody targeted against LAG-3 which is used in combination with nivolumab for the treatment of unresectable or metastatic melanoma.

Brand Names

Opdualag

Generic Name

Relatlimab

DrugBank Accession Number

DB14851

Background

Relatlimab is a human IgG4 monoclonal antibody and novel immune checkpoint inhibitor that targets lymphocyte activation gene-3 (LAG-3).^3,4 It was the first commercially developed anti-LAG-3 antibody, entering clinical trials in 2013,¹ and has garnered interest in the treatment of a variety of cancers, including leukemia² and melanoma.⁶ As immune checkpoint inhibitors have limited efficacy when used alone, drugs like relatlimab have been trialed in combination with other checkpoint inhibitors - for example, PD-1 inhibitors like nivolumab or CTLA-4 inhibitors like ipilimumab - to enhance their efficacy.¹

Relatlimab received FDA approval in March 2022, alongside the PD-1 inhibitor nivolumab in the combination product Opdualag (Bristol-Myers Squibb), for the treatment of unresectable or metastatic melanoma.^4,5 It was the first anti-LAG-3 antibody to demonstrate benefit in a Phase 3 study, as well as the first to receive FDA approval.⁵ Opdualag was subsequently approved in the European Union in July 2022⁷ and in Canada in September 2023.⁸

Type

Biotech

Groups

Approved, Investigational

Biologic Classification

Protein Based Therapies
Monoclonal antibody (mAb)

Protein Chemical Formula

C₆₄₇₂H₉₉₄₀O₂₀₂₆N₁₇₀₄S₃₈

Protein Average Weight

148000.0 Da

Sequences

>SUBUNIT_1
QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHRGSTNSN
PSLKSRVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTLVTVSS
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV
FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG
NVFSCSVMHEALHNHYTQKSLSLSLG

>SUBUNIT_2
QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHRGSTNSN
PSLKSRVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTLVTVSS
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV
FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG
NVFSCSVMHEALHNHYTQKSLSLSLG

>SUBUNIT_3
EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIYDASNRATGIPA
RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGQGTNLEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

>SUBUNIT_4
EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIYDASNRATGIPA
RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGQGTNLEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

References:

NIH Inxight: Relatlimab [Link]

Download FASTA Format

Synonyms

Relatlimab

External IDs

BMS-986016

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Pharmacology

Indication

Relatlimab is indicated in combination with nivolumab, in the combination product Opdualag, for the treatment of adult and pediatric patients ≥12 years old with unresectable or metastatic melanoma.⁴ In Canada and the EU, it is specifically indicated as a first-line treatment,^8,9 and the EU adds an additional requirement that tumor cell PD-L1 expression be < 1%.⁹

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Used in combination to treat	Metastatic melanoma	Combination Product in combination with: Nivolumab (DB09035)	••••••••••••	•••••• •••••••••	••••• •••••••••• • ••	•••••••••
Used in combination to treat	Metastatic melanoma	Combination Product in combination with: Nivolumab (DB09035)	••••••••••••	•••••• •••••••••		•••••••••
Used in combination to treat	Metastatic melanoma	Combination Product in combination with: Nivolumab (DB09035)	••••••••••••	•••••• •••••••••		•••••••••
Used in combination to treat	Unresectable melanoma	Combination Product in combination with: Nivolumab (DB09035)	••••••••••••	•••••• •••••••••	••••• •••••••••• • ••	•••••••••
Used in combination to treat	Unresectable melanoma	Combination Product in combination with: Nivolumab (DB09035)	••••••••••••	•••••• •••••••••		•••••••••

Contraindications & Blackbox Warnings

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Pharmacodynamics

Relatlimab is administered with nivolumab at 4-week intervals via a 30-minute infusion.⁴ Infusion-related reactions are uncommon but can be severe - infusion may be interrupted or slowed in patients with mild-to-moderate reactions, but should be discontinued in patients experiencing severe reactions.⁴ The combination of relatlimab and nivolumab can cause severe and fatal immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, myocarditis, and hypophysitis.⁴ The early identification and management of immune-mediated adverse reactions is essential for the safe use of this therapy. Additionally, the combination of relatlimab and nivolumab is likely to cause fetal harm when administered to pregnant patients.⁴ Females of reproductive potential should be advised to use effective contraception throughout treatment and for at least 5 months following the last dose.⁴

Mechanism of action

Lymphocyte-activation gene 3 (LAG-3) - also known as CD223 - is a type I transmembrane protein belonging to the immunoglobulin superfamily.¹ Its expression on activated T-cells is induced following antigen stimulation,³ and they serve a number of functions including the inhibition of Th1 cell proliferation and the reduction of cytokine production - such as IL-2, IFNγ, and TNF - in these activated T-cells.¹ Ligands of LAG-3 include antigen-presenting cells such as MHC class II molecules and liver sinusoidal endothelial cell lectin (LSECtin), the latter of which has been shown to promote tumor progression when expressed on melanoma cells by inhibiting anti-tumor T-cell responses.¹

As LAG-3 expression is tied to antigen presentation, continuous antigen exposure owing to chronic infection or tumor-associated antigens can lead to high and sustained expression of LAG-3 on T-cells, which eventually lose their effector functions by becoming functionally "exhausted".³ This loss of T-cell function leads to lessened immunosurveillance and promotes tumor escape.²

Relatlimab is a human IgG4 monoclonal antibody that binds LAG-3 and inhibits its signaling pathway, the antagonism of which promotes T-cell proliferation, cytokine secretion, and, subsequently, restored tumor immunosurveillance.⁴ Used in combination with nivolumab, a PD-1 receptor blocker, relatlimab has been shown to potentiate the anti-tumor effects of PD-1 blockade.⁴

Target	Actions	Organism
ALymphocyte activation gene 3 protein	antibody	Humans

Absorption

Following once-monthly administration alongside nivolumab, steady-state concentrations of relatlimab were reached after 16 weeks.⁴ At the recommended dosage, the C_max and C_avg of relatlimab at steady-state were 62.2 µg/mL and 28.8 µg/mL, respectively.⁴

Volume of distribution

The geometric mean volume of distribution of relatlimab at steady-state is 6.6 liters.⁴

Protein binding

Not Available

Metabolism

As with other therapeutic proteins, the metabolism of relatlimab likely occurs via non-specific catabolism to smaller peptides and amino acids.

Route of elimination

Not Available

Half-life

The geometric mean effective half-life of relatlimab, when administered alongside nivolumab, is 26.2 days.⁴

Clearance

At steady-state, the geometric mean clearance of relatlimab is 5.5 mL/h.⁴ Clearance at steady-state appears to be approximately 10% lower than after the first dose.⁴

Adverse Effects

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Toxicity

No data is available regarding overdosage with relatlimab.

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.

Drug	Interaction
Integrate drug-drug interactions in your software
Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Relatlimab.
Adalimumab	The risk or severity of adverse effects can be increased when Adalimumab is combined with Relatlimab.
Aducanumab	The risk or severity of adverse effects can be increased when Aducanumab is combined with Relatlimab.
Alemtuzumab	The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Relatlimab.
Alirocumab	The risk or severity of adverse effects can be increased when Alirocumab is combined with Relatlimab.

Food Interactions

No interactions found.

Products

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Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End
Opdualag	Relatlimab (80 mg / 20 mL) + Nivolumab (240 mg / 20 mL)	Solution	Intravenous	Bristol Myers Squibb	Not applicable	Not applicable
Opdualag	Relatlimab (4 mg/1mL) + Nivolumab (12 mg/1mL)	Injection	Intravenous	E.R. Squibb & Sons, L.L.C.	2022-03-18	Not applicable
Opdualag	Relatlimab (4 mg/ml) + Nivolumab (12 mg/ml)	Injection, solution, concentrate	Intravenous	Bristol Myers Squibb Pharma Eeig	2022-12-02	Not applicable

Chemical Identifiers

UNII: AF75XOF6W3
CAS number: 1673516-98-7

References

General References

Yu X, Huang X, Chen X, Liu J, Wu C, Pu Q, Wang Y, Kang X, Zhou L: Characterization of a novel anti-human lymphocyte activation gene 3 (LAG-3) antibody for cancer immunotherapy. MAbs. 2019 Aug/Sep;11(6):1139-1148. doi: 10.1080/19420862.2019.1629239. Epub 2019 Jun 26. [Article]
Sordo-Bahamonde C, Lorenzo-Herrero S, Gonzalez-Rodriguez AP, Payer AR, Gonzalez-Garcia E, Lopez-Soto A, Gonzalez S: LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic Leukemia. Cancers (Basel). 2021 Apr 27;13(9). pii: cancers13092112. doi: 10.3390/cancers13092112. [Article]
Maruhashi T, Sugiura D, Okazaki IM, Okazaki T: LAG-3: from molecular functions to clinical applications. J Immunother Cancer. 2020 Sep;8(2). pii: jitc-2020-001014. doi: 10.1136/jitc-2020-001014. [Article]
FDA Approved Drug Products: Opdualag (nivolumab and relatlimab-rmbw) injection for intravenous use [Link]
BioSpace: U.S. Food and Drug Administration Approves First LAG-3-Blocking Antibody Combination, Opdualag™ (nivolumab and relatlimab-rmbw), as Treatment for Patients with Unresectable or Metastatic Melanoma [Link]
NIH National Cancer Institute: Nivolumab and Relatlimab Combination Shows Promise in Advanced Melanoma [Link]
EMA EPAR: Opdualag (relatlimab/nivolumab) [Link]
Health Canada Product Monograph: Opdualag (nivolumab and relatlimab) solution for intravenous injection [Link]
EMA Summary of Product Characteristics: Opdualag (nivolumab/relatlimab) solution for intravenous injection [Link]

External Links

RxNav: 2596773
Wikipedia: Relatlimab

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	Colorectal Neoplasms	1
3	Active Not Recruiting	Treatment	Melanoma	1
3	Not Yet Recruiting	Treatment	Advanced Melanoma	1
3	Not Yet Recruiting	Treatment	Melanoma	1
3	Recruiting	Treatment	Advanced Melanoma	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection	Intravenous
Injection, solution, concentrate	Intravenous
Solution	Intravenous

Prices

Not Available

Patents

Not Available

Properties

State: Liquid
Experimental Properties: Not Available

Targets

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Details1. Lymphocyte activation gene 3 protein

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Antibody

General Function: Lymphocyte activation gene 3 protein: Inhibitory receptor on antigen activated T-cells (PubMed:7805750, PubMed:8647185, PubMed:20421648). Delivers inhibitory signals upon binding to ligands, such as FGL1 (By similarity). FGL1 constitutes a major ligand of LAG3 and is responsible for LAG3 T-cell inhibitory function (By similarity). Following TCR engagement, LAG3 associates with CD3-TCR in the immunological synapse and directly inhibits T-cell activation (By similarity). May inhibit antigen-specific T-cell activation in synergy with PDCD1/PD-1, possibly by acting as a coreceptor for PDCD1/PD-1 (By similarity). Negatively regulates the proliferation, activation, effector function and homeostasis of both CD8(+) and CD4(+) T-cells (PubMed:7805750, PubMed:8647185, PubMed:20421648). Also mediates immune tolerance: constitutively expressed on a subset of regulatory T-cells (Tregs) and contributes to their suppressive function (By similarity). Also acts as a negative regulator of plasmacytoid dendritic cell (pDCs) activation (By similarity). Binds MHC class II (MHC-II); the precise role of MHC-II-binding is however unclear (PubMed:8647185).
Specific Function: Antigen binding
Gene Name: LAG3
Uniprot ID: P18627
Uniprot Name: Lymphocyte activation gene 3 protein
Molecular Weight: 57448.04 Da

References

FDA Approved Drug Products: Opdualag (nivolumab and relatlimab-rmbw) injection for intravenous use [Link]

Drug created at May 20, 2019 14:30 / Updated at February 14, 2024 00:55

Relatlimab

Identification

References:

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References