NAV

Glofitamab

Identification

Summary

Glofitamab is a bispecific monoclonal antibody directed against CD20 and CD3 which is used for the treatment of relapsed or refractory diffuse large B-cell lymphoma.

Generic Name
Glofitamab
DrugBank Accession Number
DB16371
Background

Glofitamab is a full-length bispecific monoclonal antibody with affinity for both CD20 and CD3 surface antigens found on B- and T-cells, respectively. It has a 2:1 configuration, with bivalency towards CD20 and monovalency towards CD3, and works by recruiting T-cells directly to the surface of cancerous B-cells.3,2

Glofitamab was approved by Health Canada in March 2023 for the treatment of certain patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), becoming the first CD20/CD3 bispecific monoclonal antibody approved for DLBCL.5 The most common type of non-Hodgkin lymphoma,4 DLBCL is relatively sensitive to chemotherapy and generally responsive to first-line treatment regimens like CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)4 - despite this, as many as 40% of patients will experience relapsed or refractory disease.5,1 In the context of relapsed or refractory DLBCL, glofitamab provides an alternative treatment option for patients having failed other systemic therapies or for whom targeted therapies - such as CAR-T cell therapy - are inappropriate.

In June 2023, the FDA approved the use of glofitamab for the treatment of patients with relapsed or refractory DLBCL not otherwise specified or large B-cell lymphoma (LBCL) arising from follicular lymphoma, after two or more lines of systemic therapy under accelerated approval based on response rate and durability of response.6,7

Glofitamab was granted conditional marketing authorization in July 2023 by the EMA for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. This approval is based on the positive results obtained from the phase I/II NP30179 study, where 35.2% of study participants achieved a complete response.9

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
Not Available
Protein Average Weight
194000.0 Da (Peptide chains only, without heavy chain C terminal lysine residues, with N terminal glutamines converted into pyroglutamates due to cyclization)
Sequences
>SUBUNIT_1
QVQLVQSGAEVKKPGSSVKVSCKASGYAFSYSWINWVRQAPGQGLEWMGRIFPGDGDTDY
NGKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNVFDGYWLVYWGQGTLVTVSSA
STKGPSVFPLAPSSKSTSGGTAALGCLVEDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDEKVEPKSCDGGGGSGGGGSQAVVTQE
PSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQEKPGQAFRGLIGGTNKRAPGTPARFSGS
LLGGKAALTLSGAQPEDEAEYYCALWYSNLWVFGGGTKLTVLSSASTKGPSVFPLAPSSK
STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL
GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI
SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
LNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFY
PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH
NHYTQKSLSLSPGK
>SUBUNIT_2
QVQLVQSGAEVKKPGSSVKVSCKASGYAFSYSWINWVRQAPGQGLEWMGRIFPGDGDTDY
NGKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNVFDGYWLVYWGQGTLVTVSSA
STKGPSVFPLAPSSKSTSGGTAALGCLVEDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDEKVEPKSCDKTHTCPPCPAPEAAGGP
SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVCTLPPSRDEL
TKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQ
QGNVFSCSVMHEALHNHYTQKSLSLSPGK
>SUBUNIT_3
DIVMTQTPLSLPVTPGEPASISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQMSNLV
SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCAQNLELPYTFGGGTKVEIKRTVAAPSV
FIFPPSDRKLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SUBUNIT_4
DIVMTQTPLSLPVTPGEPASISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQMSNLV
SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCAQNLELPYTFGGGTKVEIKRTVAAPSV
FIFPPSDRKLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SUBUNIT_5
EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGLEWVSRIRSKYNNYAT
YYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFGNSYVSWFAYWGQGTL
VTVSSASVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES
VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. NIH Inxight: Glofitamab [Link]
Download FASTA Format
Synonyms
  • Anti-CD20/CD3 bispecific monoclonal antibody RO7082859
  • Glofitamab
External IDs
  • RG-6026
  • RG6026
  • RO-7082859
  • RO7082859
  • WHO 11145
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Pharmacology

Indication

Glofitamab is indicated in Canada for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from follicular lymphoma, or primary mediastinal B-cell lymphoma (PMBCL), who have received two or more lines of systemic therapy and are ineligible to receive or cannot receive CAR-T cell therapy or have previously received CAR-T cell therapy. This indication has been authorized pending the results of trials designed to verify glofitamab's clinical benefit.3

The FDA approved glofitamab under accelerated approval for the treatment of adult patients with relapsed or refractory DLBCL not otherwise specified or large B-cell lymphoma (LBCL) arising from follicular lymphoma, after two or more lines of systemic therapy.7

Glofitamab was also approved by the EMA to treat adult patients with relapsed or refractory diffuse large B-cell lymphoma after two or more lines of systemic therapy.8

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofDiffuse large b-cell lymphoma (dlbcl)•••••••••••••••••••••• •• ••••• •• •••••••• •••••••• •••••••••• ••• ••••• •••• ••••••••••••••••• ••••••••• •••••••••••
Treatment ofLarge b cell lymphoma•••••••••••••••••••••• •• ••••• •• •••••••• ••••••••••••••••
Treatment ofPrimary mediastinal (thymic) large b cell lymphoma (pmbcl)••••••••••••••••••••••••••• ••• ••••• •••• •••••••• ••••• •• ••••• •• •••••••• ••••••••••••••••• ••••••••• •••••••••••
Treatment ofRefractory diffuse large b cell lymphoma (dlbcl)••••••••••••••••••••••••••• ••• ••••• •••• •••••••• ••••• •• ••••• •• •••••••• ••••••••••••••••• ••••••••• •••••••••••
Treatment ofRefractory diffuse large b-cell lymphoma, not otherwise specified•••••••••••••••••••••• •• ••••• •• •••••••• ••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

In clinical trials, 10/152 patients exposed to glofitamab experienced a prolonged QTc interval (post-baseline QTc >450 ms), although only one of these cases was determined to be clinically significant and no patients were required to discontinue treatment due to QTc prolongation.3

Glofitamab can cause cytokine release syndrome (CRS) which may be serious or life-threatening in some patients.3 To limit the risk of CRS, prescribing information states that all patients must receive pre-treatment with obinutuzumab seven days prior to beginning treatment with glofitamab. In addition, patients should be well-hydrated and should receive a premedication regimen comprising a glucocorticoid, analgesic/antipyretic, and/or antihistamine, dependent on the patient and the cycle.3 The dose of glofitamab should be titrated gradually and according to prescribing information to further limit the risk of CRS, and patients should be monitored for 10 hours following the first infusion and as required thereafter.

Mechanism of action

Glofitamab is a bispecific monoclonal antibody targeted towards CD20 surface antigens - found on B-cells - and CD3 protein complexes found on the surface of T-cells.3 It binds bivalently to CD20 and monovalently to CD3, thereby creating an immunological synapse that serves to recruit T-cells to CD20-expressing B-cells. This simultaneous binding allows for potent T-cell activation and proliferation which ultimately results in the lysis of the target B-cells.3

TargetActionsOrganism
AB-lymphocyte antigen CD20
binder
antibody
Humans
AT-cell surface glycoprotein CD3
binder
antibody
Humans
Absorption

According to population pharmacokinetic analysis, the geometric mean Cmax of glofitamab on day 1 after the first infusion of 2.5 mg was 0.674 µg/mL. At the end of cycle 2 - following the step-up dosing to a final dose of 30 mg - the geometric mean Cmax was estimated via population pharmacokinetic modeling to be 7.67 µg/mL.3

Non-compartmental analysis following a single dose of 10 mg showed a geometric mean Cmax of 2.34 µg/mL, Tmax of 8.05, and AUCinf of 244 hr*µg/mL.3

Volume of distribution

Following intravenous administration, population pharmacokinetic modeling estimated the central and peripheral volumes of distribution to be 3.33 L and 2.18 L, respectively, with an intercompartmental clearance of 0.674 L/day.3

Protein binding

Not Available

Metabolism

The metabolism of glofitamab has not been directly studied. As with other therapeutic antibodies, it is likely metabolized primarily via catabolism to smaller peptides and amino acids.3

Route of elimination

Not Available

Half-life

The transition from non-linear to linear clearance phase was estimated to take approximately 1.56 days, after which the effective linear half-life of glofitamab is approximately 6.54 days.3

Clearance

Glofitamab's serum concentration-time data are best described by a two-compartment model and both time-independent and time-varying clearance parameters. Population pharmacokinetic modeling estimated a time-independent clearance parameter of 0.602 L/day, and an initial time-varying clearance parameter of 0.396 L/day.3

Adverse Effects
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Toxicity

There was no experience with overdosage of glofitamab in clinical trials.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
Integrate drug-drug
interactions in your software
1,2-BenzodiazepineThe serum concentration of 1,2-Benzodiazepine can be increased when it is combined with Glofitamab.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Glofitamab.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Glofitamab.
AbirateroneThe serum concentration of Abiraterone can be increased when it is combined with Glofitamab.
AbrocitinibThe serum concentration of Abrocitinib can be increased when it is combined with Glofitamab.
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ColumviInjection, solution, concentrate10 mgIntravenousRoche Registration Gmb H2023-07-22Not applicableEU flag
ColumviSolution2.5 mg / 2.5 mLIntravenousHoffmann La Roche2023-07-05Not applicableCanada flag
ColumviInjection, solution, concentrate2.5 mgIntravenousRoche Registration Gmb H2023-07-22Not applicableEU flag
ColumviSolution10 mg / 10 mLIntravenousHoffmann La Roche2023-07-05Not applicableCanada flag
ColumviSolution, concentrate2.5 mg/2.5mLIntravenousGenentech, Inc.2023-06-15Not applicableUS flag

Categories

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
06P3KLK2J8
CAS number
2229047-91-8

References

General References
  1. Wang C, Liu Y: Glofitamab therapy for diffuse large B cell lymphoma: latest updates from the 2022 ASH Annual Meeting. J Hematol Oncol. 2023 Mar 10;16(1):20. doi: 10.1186/s13045-023-01420-w. [Article]
  2. Gonzalez Barca E: Role of Bispecific Antibodies in Relapsed/Refractory Diffuse Large B-Cell Lymphoma in the CART Era. Front Immunol. 2022 Jul 19;13:909008. doi: 10.3389/fimmu.2022.909008. eCollection 2022. [Article]
  3. Health Canada Product Monograph: Columvi (glofitamab) concentrate for solution for intravenous infusion [Link]
  4. Canadian Cancer Society: Diffuse large B-cell lymphoma [Link]
  5. BioSpace: COLUMVI® (Glofitamab for Injection) Receives Health Canada Authorization with Conditions for Adult Patients with Relapsed or Refractory Diffuse Large B-cell Lymphoma [Link]
  6. Globe News Wire: FDA approves Roche’s Columvi, the first and only bispecific antibody with a fixed-duration treatment for people with relapsed or refractory diffuse large B-cell lymphoma [Link]
  7. FDA Approved Drug Products: COLUMVI (glofitamab-gxbm) injection for intravenous use (June 2023) [Link]
  8. EMA Approved Drug Products: Columvi (glofitamab) injection, for intravenous use [Link]
  9. European Commission approves Roche's fixed-duration Columvi (glofitamab) for people with relapsed or refractory diffuse large B-cell lymphoma [Link]
RxNav
2639782
Wikipedia
Glofitamab

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingTreatmentDiffuse Large B-Cell Lymphoma (DLBCL)1
3RecruitingTreatmentLarge B Cell Lymphoma1
3RecruitingTreatmentLymphoma1
2Active Not RecruitingTreatmentRefractory Diffuse Large B Cell Lymphoma (DLBCL) / Refractory Indolent Adult Non-Hodgkin Lymphoma / Refractory Mantle Cell Lymphoma / Refractory Primary Mediastinal Large B-Cell Cell Lymphoma / Refractory Transformed B-cell Non-Hodgkin Lymphoma1
2Not Yet RecruitingOtherDiffuse Large B-Cell Lymphoma (DLBCL)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
ConcentrateIntravenous10 mg/10mL
Injection, solution, concentrateIntravenous10 mg
Injection, solution, concentrateIntravenous2.5 mg
SolutionIntravenous10 mg / 10 mL
SolutionIntravenous2.5 mg / 2.5 mL
Solution, concentrateIntravenous2.5 mg/2.5mL
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

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Details1. B-lymphocyte antigen CD20
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
Antibody
General Function
Mhc class ii protein complex binding
Specific Function
This protein may be involved in the regulation of B-cell activation and proliferation.
Gene Name
MS4A1
Uniprot ID
P11836
Uniprot Name
B-lymphocyte antigen CD20
Molecular Weight
33076.99 Da
References
  1. Health Canada Product Monograph: Columvi (glofitamab) concentrate for solution for intravenous infusion [Link]
Details2. T-cell surface glycoprotein CD3 (Protein Group)
Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Binder
Antibody
General Function
Transmembrane signaling receptor activity
Specific Function
The CD3 complex mediates signal transduction.
Components:
NameUniProt ID
T-cell surface glycoprotein CD3 delta chainP04234
T-cell surface glycoprotein CD3 epsilon chainP07766
T-cell surface glycoprotein CD3 gamma chainP09693
T-cell surface glycoprotein CD3 zeta chainP20963
References
  1. Health Canada Product Monograph: Columvi (glofitamab) concentrate for solution for intravenous infusion [Link]

Drug created at December 21, 2020 19:33 / Updated at July 25, 2023 16:37