Mosunetuzumab

Identification

Summary

Mosunetuzumab is a humanized anti-CD20/CD3 bispecific antibody used to treat relapsed or refractory follicular lymphoma.

Brand Names

Lunsumio

Generic Name

Mosunetuzumab

DrugBank Accession Number

DB15434

Background

Mosunetuzumab is a humanized anti-CD20/CD3 bispecific antibody.⁴ It can recognize and bind two different targets simultaneously, CD20 on cancer B-cells and CD3 on T-cells, allowing it to redirect T-cell cytotoxic activity to cancer cells.¹ The standard of care for patients with B-cell lymphoma includes an anti-CD20 monoclonal antibody, such as rituximab, in combination with chemotherapy. However, patients with certain types of B-cell lymphoma, such as follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) or aggressive B-cell lymphoma, have a high probability of relapse or recurrence after treatment.^1,3 Mosunetuzumab has the potential to circumvent resistance to rituximab in patients with follicular lymphoma,^1,4 and unlike CAR-T therapies such as axicabtagene ciloleucel and tisagenlecleucel, it is an “off-the-shelf” alternative, readily available to patients.⁵ In June 2022, the European Medicines Agency approved mosunetuzumab for the treatment of adult patients with relapsed or refractory (R/R) FL who have received at least two prior systemic therapies.⁵ In January 2023, the use of mosunetuzumab was approved by the FDA under accelerated approval based on response rate.⁶

Type

Biotech

Groups

Approved, Investigational

Biologic Classification

Protein Based Therapies
Monoclonal antibody (mAb)

Protein Chemical Formula

C₆₅₁₅H₁₀₀₃₁N₁₇₂₅O₂₀₂₅S₄₃

Protein Average Weight

146300.0 Da (approximate)

Sequences

>CD3E Heavy Chain
EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIHWVRQAPGQGLEWIGWIYPGDGNTKY
NEKFKGRATLTADTSTSTAYLELSSLRSEDTAVYYCARDSYSNYYFDYWGQGTLVTVSSA
STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP
SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM
TKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQ
QGNVFSCSVMHEALHNHYTQKSLSLSPGK

>CD3E Light Chain
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSRTRKNYLAWYQQKPGQPPKLLIYWASTR
ESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCTQSFILRTFGQGTKVEIKRTVAAPSV
FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

>CD20 Heavy Chain
EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYNMHWVRQAPGKGLEWVGAIYPGNGDTSY
NQKFKGRFTISVDKSKNTLYLQMNSLRAEDTAVYYCARVVYYSNSYWYFDVWGQGTLVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ
YGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR
EEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS
RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

>CD20 Light Chain
DIQMTQSPSSLSASVGDRVTITCRASSSVSYMHWYQQKPGKAPKPLIYAPSNLASGVPSR
FSGSGSGTDFTLTISSLQPEDFATYYCQQWSFNPPTFGQGTKVEIKRTVAAPSVFIFPPS
DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL
SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

References:

KEGG: Mosunetuzumab (D11463) [Link]
Statement on a nonproprietary name adopted by the USAN Council: Mosunetuzumab [Link]

Download FASTA Format

Synonyms

Mosunetuzumab

External IDs

BTCT-4465A
BTCT4465A
RG-7828
RG7828
RO-7030816
RO7030816

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Pharmacology

Indication

Mosunetuzumab as monotherapy is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies.^4,6

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Relapsed or refractory follicular lymphoma		••••••••••••	•••••	•• ••••• ••• ••••• •••••••• •••••••••	•••••••••
Treatment of	Relapsed or refractory follicular lymphoma		••••••••••••	•••••	•• ••••• ••• ••••• •••••••• •••••••••	•••••••••

Contraindications & Blackbox Warnings

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Pharmacodynamics

Mosunetuzumab is an anti-CD20/CD3 bispecific antibody that leads to B-cell depletion (CD19 B-cell counts < 0.07 x 109/L) and hypogammaglobulinemia (IgG levels < 500 mg/dL).⁴ In patients with aggressive non-Hodgkin's lymphoma (NHL) treated with mosunetuzumab, the overall response rate (ORR) was 37.4%, and the complete remission (CR) rate was 19.5%, while patients with indolent NHL treated with mosunetuzumab had an ORR of 62.7% and a CR rate of 43.3%.² The response to mosunetuzumab in a high-risk group of patients with progression of follicular lymphoma within 24 months after initiating frontline treatment (n=29) was also beneficial; the ORR was 75.9% and the CR rate was 55.2%.²

Patients treated with mosunetuzumab may develop cytokine release syndrome (CRS), including life-threatening reactions. CRS mainly occurred on days 1 and 15 of cycle 1. To avoid CRS, patients should receive corticosteroids, antipyretics and antihistamines prior to mosunetuzumab therapy.⁴ Serious infections such as pneumonia, bacteremia, and sepsis or septic shock have been reported in patients treated with mosunetuzumab, and caution should be exercised in patients with a history of recurring or chronic infections. Tumour flare and tumour lysis syndrome (TLS) have also been reported in patients treated with mosunetuzumab.⁴

Mechanism of action

Mosunetuzumab is a full-length, humanized anti-CD20/CD3 bispecific antibody that targets CD20-expressing B-cells.^1,4 Unlike B-cell-targeting monoclonal antibodies, such as rituximab, mosunetuzumab can recognize and bind two different targets, CD20 on cancer B-cells and CD3 on T-cells in a 1:1 ratio.^1,2 Mosunetuzumab is a conditional agonist; the targeted killing of CD20-expressing B-cells is observed only when this drug is simultaneously bound to CD20 on B-cells and CD3 on T-cells. Mosunetuzumab recruits T-cells and leads to their activation by promoting the formation of an immunologic synapse between a target B-cell and a cytotoxic T-cell. The activation of T-cells leads to the directed release of perforin and granzymes through the immunologic synapsis, which ultimately induces B-cell lysis and cell death.⁴

Target	Actions	Organism
AB-lymphocyte antigen CD20	binder	Humans
AT-cell surface glycoprotein CD3 epsilon chain	binder	Humans

Absorption

Between 0.05 and 60 mg, mosunetuzumab follows a dose-proportional pharmacokinetic profile. The population pharmacokinetics of intravenous mosunetuzumab are described with a two-compartment pharmacokinetic model with time-dependent clearance.⁴ After two cycles of mosunetuzumab (42 days, given by intravenous infusion), patients reached a C_max of 17.9 µg/mL at the end of dose of Cycle 2 Day 1. The average AUC of two cycles of mosunetuzumab was 126 µg⋅day/mL.⁴ In patients with relapsed or refractory B-cell non-Hodgkin's lymphoma treated with mosunetuzumab, serum concentration reached the C_max at the end of the intravenous infusion and declined in a bi-exponential fashion.⁴ The steady-state values of mosunetuzumab were reached at cycle 4 (63 ‒ 84 days). Steady-state AUC and C_max were 52.9 day⋅μg/mL and 7.02 μg/mL, respectively.⁶

Mosunetuzumab is expected to have a bioavailability close to 100% when given intravenously. In clinical trials, mosunetuzumab administered subcutaneously had a slow absorption rate and high bioavailability (>75%).² The pharmacokinetics of mosunetuzumab was similar in Asian and non-Asian subjects. Compared to males, the steady-state clearance of mosunetuzumab in females is marginally lower (approximately 13%), and dose adjustment based on gender is not required.⁴

Volume of distribution

The estimated central volume of distribution for mosunetuzumab administered via intravenous infusion is 5.49 L.^4,6

Protein binding

Mosunetuzumab is a bispecific antibody; therefore, protein binding studies were not carried out.⁴

Metabolism

Mosunetuzumab is a protein therapeutic; it is expected to be degraded into small peptides and amino acids via catabolic pathways.⁴

Route of elimination

Since mosunetuzumab is an immunoglobulin G (IgG) antibody, it is expected to be mainly eliminated via intracellular catabolism. Hepatic or renal impairment is not expected to influence the elimination of mosunetuzumab.⁴

Half-life

Mosunetuzumab has a terminal half-life of 16.1 days,^4,6 and an apparent half-life between 6 and 11 days.¹

Clearance

The mean steady-state plateau clearance (CL_ss) of mosunetuzumab is 1.08 L/day, and its baseline clearance (CL_base) is 0.584 L/day.^4,6

Adverse Effects

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Toxicity

In case of a mosunetuzumab overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment should be instituted.⁴ Patients experiencing an overdose are at an increased risk of severe adverse effects such as cytokine release syndrome (CRS), febrile neutropenia, neutropenia and pneumonia.^1,4

Preclinical single- and repeat-dose toxicity studies of up to 26 weeks in duration found that transient CRS was developed mostly after the first dose of mosunetuzumab. Findings suggest that this effect is pharmacologically-mediated and reversible.⁴ The effect of mosunetuzumab on male and female reproductive organs was evaluated in sexually mature cynomolgus monkeys given an intravenous infusion dose equivalent to the one recommended in patients. Up to 26 weeks, mosunetuzumab did not have an effect on male or female reproductive organs.⁴ Preclinical studies evaluating the effect of mosunetuzumab on developmental toxicity have not been conducted. Due to the low placental transfer of antibodies during the first trimester, mosunetuzumab is not expected to have a teratogenic effect. However, it can lead to a higher risk of opportunistic infections, which may cause fetal loss.⁴

Pathways

Not Available

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Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

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
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Abatacept	The risk or severity of adverse effects can be increased when Abatacept is combined with Mosunetuzumab.
Abciximab	The risk or severity of bleeding can be increased when Abciximab is combined with Mosunetuzumab.
Abemaciclib	The metabolism of Abemaciclib can be decreased when combined with Mosunetuzumab.
Acalabrutinib	The metabolism of Acalabrutinib can be decreased when combined with Mosunetuzumab.
Acenocoumarol	The metabolism of Acenocoumarol can be decreased when combined with Mosunetuzumab.

Food Interactions

Not Available

Products

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International/Other Brands

Lunsumio (Roche)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Lunsumio	Concentrate	1 mg/1mL	Intravenous	Genentech, Inc.	2022-12-22	Not applicable
Lunsumio	Injection, solution, concentrate	30 mg	Intravenous	Roche Registration Gmb H	2022-06-28	Not applicable
Lunsumio	Concentrate	30 mg/30mL	Intravenous	Genentech, Inc.	2022-12-22	Not applicable
Lunsumio	Injection, solution, concentrate	1 mg	Intravenous	Roche Registration Gmb H	2022-06-28	Not applicable

Chemical Identifiers

UNII: LDJ89SS0YG
CAS number: 1905409-39-3

References

Synthesis Reference

Ast, O., et al. (2018). Bispecific T cell activating antigen binding molecules (U.S. Patent No. 9,914,776 B2). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/e5/93/68/6ded0d607c0070/US9914776.pdf

General References

Budde LE, Assouline S, Sehn LH, Schuster SJ, Yoon SS, Yoon DH, Matasar MJ, Bosch F, Kim WS, Nastoupil LJ, Flinn IW, Shadman M, Diefenbach C, O'Hear C, Huang H, Kwan A, Li CC, Piccione EC, Wei MC, Yin S, Bartlett NL: Single-Agent Mosunetuzumab Shows Durable Complete Responses in Patients With Relapsed or Refractory B-Cell Lymphomas: Phase I Dose-Escalation Study. J Clin Oncol. 2022 Feb 10;40(5):481-491. doi: 10.1200/JCO.21.00931. Epub 2021 Dec 16. [Article]
Salvaris R, Ong J, Gregory GP: Bispecific Antibodies: A Review of Development, Clinical Efficacy and Toxicity in B-Cell Lymphomas. J Pers Med. 2021 Apr 29;11(5). pii: jpm11050355. doi: 10.3390/jpm11050355. [Article]
Sun LL, Ellerman D, Mathieu M, Hristopoulos M, Chen X, Li Y, Yan X, Clark R, Reyes A, Stefanich E, Mai E, Young J, Johnson C, Huseni M, Wang X, Chen Y, Wang P, Wang H, Dybdal N, Chu YW, Chiorazzi N, Scheer JM, Junttila T, Totpal K, Dennis MS, Ebens AJ: Anti-CD20/CD3 T cell-dependent bispecific antibody for the treatment of B cell malignancies. Sci Transl Med. 2015 May 13;7(287):287ra70. doi: 10.1126/scitranslmed.aaa4802. [Article]
European Medicines Agency (EMA) Summary of Product Characteristics: Lunsumio (mosunetuzumab) solution for intravenous infusion [Link]
Globe News Wire: European Commission approves Roche’s first-in-class bispecific antibody Lunsumio for people with relapsed or refractory follicular lymphoma [Link]
FDA Approved Drug Products: LUNSUMIO (mosunetuzumab-axgb) injection for intravenous use [Link]

External Links

RxNav: 2625122
Wikipedia: Mosunetuzumab

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
3	Recruiting	Treatment	Marginal Zone Lymphoma (MZL)	1
3	Recruiting	Treatment	Non-Hodgkin's Lymphoma (NHL)	1
3	Recruiting	Treatment	Relapsed or Refractory Follicular Lymphoma	1
2	Recruiting	Treatment	Aggressive Non-Hodgkin's Lymphoma / Non-Hodgkin's Lymphoma, Relapsed / Refractory Non-Hodgkin's lymphoma	1
2	Recruiting	Treatment	B-Cell Lymphoma / Follicular Lymphoma ( FL) / Marginal Zone Lymphoma (MZL)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Concentrate	Intravenous	1 mg/1mL
Concentrate	Intravenous	30 mg/30mL
Injection, solution, concentrate	Intravenous	1 mg
Injection, solution, concentrate	Intravenous	30 mg

Prices

Not Available

Patents

Not Available

Properties

State: Solid
Experimental Properties: Not Available

Targets

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Details1. B-lymphocyte antigen CD20

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

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

European Medicines Agency (EMA) Summary of Product Characteristics: Lunsumio (mosunetuzumab) solution for intravenous infusion [Link]

Details2. T-cell surface glycoprotein CD3 epsilon chain

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Binder
Curator comments: CD3 chain not specified in drug label. However, the majority of monoclonal antibodies bind to the CD3 epsilon chain.

General Function: Transmembrane signaling receptor activity
Specific Function: The CD3 complex mediates signal transduction, resulting in T cell activation and proliferation. Required for normal immune responses (PubMed:15546002, PubMed:8490660).
Gene Name: CD3E
Uniprot ID: P07766
Uniprot Name: T-cell surface glycoprotein CD3 epsilon chain
Molecular Weight: 23147.09 Da

References

Tunnacliffe A, Olsson C, de la Hera A: The majority of human CD3 epitopes are conferred by the epsilon chain. Int Immunol. 1989;1(5):546-50. doi: 10.1093/intimm/1.5.546. [Article]
European Medicines Agency (EMA) Summary of Product Characteristics: Lunsumio (mosunetuzumab) solution for intravenous infusion [Link]

Drug created at May 20, 2019 15:30 / Updated at January 13, 2023 10:08

Mosunetuzumab

Identification

References:

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References

References