NAV

Polatuzumab vedotin

Identification

Summary

Polatuzumab vedotin is a CD79b antibody conjugate indicated to treat different types of large B-cell lymphoma.

Brand Names
Polivy
Generic Name
Polatuzumab vedotin
DrugBank Accession Number
DB12240
Background

Polatuzumab vedotin is a CD79b-directed antibody-drug conjugate that delivers monomethyl auristatin E (MMAE), an anti-mitotic agent, to cancer cells.5 The drug consists of three components - a humanized immunoglobulin G1 (IgG1) monoclonal antibody specific for human CD79b (polatuzumab), MMAE, and protease-cleavable linker called maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-vc-PAB) that covalently attaches MMAE to polatuzumab.5

Polatuzumab vedotin was granted accelerated FDA approval on June 10, 2019 3 and was approved by Health Canada on July 9, 2020.6

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Other protein based therapies
Protein Chemical Formula
C6670H10317N1745O2087S40
Protein Average Weight
150000.0 Da (approximate)
Sequences
Not Available
Synonyms
  • Polatuzumab vedotin
  • polatuzumab vedotin-piiq

Pharmacology

Indication

In the US, polatuzumab vedotin is used in combination with bendamustine and rituximab to treat adult patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, after at least two prior therapies.5 In Canada, this indication is approved for patients who are not eligible for autologous stem cell transplant and have received at least one prior therapy.6

In Canada, polatuzumab vedotin is also used in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) to treat adult patients with previously untreated large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), high grade B-cell lymphoma, Epstein-Barr viruspositive (EBV+) DLBCL NOS, and T-cell/histiocyte rich LBCL.6

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Polatuzumab vedotin is an anti-cancer agent that works to cause apoptosis in malignant B cells.5 In vitro, it exerted cytotoxic effects on most diffuse large B-cell lymphoma (DLBCL) cell lines: this effect was consistent across cell lines, regardless of the cell-of-origin subtypes and whether they harboured mutations in the CD79B gene or not.3 In mouse xenograft models, polatuzumab vedotin caused apoptosis and reduced proliferation of mature CD79b+ B-cell NHL cell lines.3

Polatuzumab vedotin can cause immunosuppression, including neutropenia and thrombocytopenia.1,5

Mechanism of action

Polatuzumab vedotin is an antibody-drug conjugate consisting of a CD79b-directed antibody, a microtubule-disrupting agent called monomethyl auristatin E (MMAE), and a cleavable linker that holds the components together.5 CD79 is a heterodimer composed of CD79a and CD79b. Responsible for signal transduction, CD79 forms a complex with the B cell receptor (BCR) and is almost exclusively expressed on B cells, including malignant B cells.3,4 Most importantly, CD79b gained increasing attention as a promising therapeutic target as it plays an essential role in BCR expression, transport, and functions such as B cell proliferation and differentiation.4

Once the antibody component binds to CD79b, polatuzumab vedotin is internalized, and lysosomal proteases cleave the linker to release MMAE in the cell. MMAE is a microtubule-disrupting anti-mitotic agent that exerts cytotoxic effects against malignant B cells. It binds to microtubules, inhibits mitosis by interfering with tubulin and tubulin polymerization, and induces apoptosis in dividing B cells.3,5,6

TargetActionsOrganism
AB-cell antigen receptor complex-associated protein beta chain
antibody
Humans
Absorption

After the first polatuzumab vedotin dose of 1.8 mg/kg, the mean (± SD) Cmax of antibody-conjugated MMAE and unconjugated MMAE were 803 (± 233) ng/mL and 6.82 (± 4.73) ng/mL, respectively.5 The mean AUCinf of antibody-conjugated MMAE and unconjugated MMAE were 1860 (± 966) day x ng/mL and 52.3 (± 18.0) day x ng/mL, respectively.5

Volume of distribution

The estimated central volume of distribution of polatuzumab vedotin based on population PK analysis is 3.15 L.5

Protein binding

MMAE is 71% to 77% bound to plasma proteins. Its blood-to-plasma ratio is 0.79 to 0.98, in vitro.5

Metabolism

Polatuzumab vedotin is expected to undergo catabolism into small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. MMAE is metabolized by CYP3A4/5.6

Route of elimination

Polatuzumab vedotin is predominantly excreted in feces, as well as in urine to some extent.2,6

Half-life

The terminal half-life of polatuzumab vedotin is approximately 12 days (95% CI: 8.1 to 19.5 days) at Cycle 6. The terminal half-life of unconjugated MMAE is approximately four days after the first dose of polatuzumab vedotin.5

Clearance

The predicted clearance of polatuzumab vedotin is 0.9 L/day.5

Adverse Effects
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Toxicity

Data regarding overdoses and LD50 are not readily available.

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
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interactions in your software
AbametapirThe serum concentration of Polatuzumab vedotin can be increased when it is combined with Abametapir.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Polatuzumab vedotin.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Polatuzumab vedotin.
AducanumabThe risk or severity of adverse effects can be increased when Polatuzumab vedotin is combined with Aducanumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Polatuzumab vedotin.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Polatuzumab vedotin.
AmiodaroneThe risk or severity of adverse effects can be increased when Amiodarone is combined with Polatuzumab vedotin.
AmivantamabThe risk or severity of adverse effects can be increased when Polatuzumab vedotin is combined with Amivantamab.
AmprenavirThe risk or severity of adverse effects can be increased when Amprenavir is combined with Polatuzumab vedotin.
AnifrolumabThe risk or severity of adverse effects can be increased when Anifrolumab is combined with Polatuzumab vedotin.
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Food Interactions
  • Exercise caution with grapefruit products. The active ingredient of polatuzumab vedotin, monomethyl auristatin E (MMAE), is a CYP3A4 substrate and grapefruit may increase MMAE plasma concentrations.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
PolivyInjection, powder, for solution30 mgIntravenousRoche Registration Gmb H2021-01-12Not applicableEU flag
PolivyPowder, for solution140 mg / vialIntravenousHoffmann La Roche2020-11-25Not applicableCanada flag
PolivyInjection, powder, for solution140 mgIntravenousRoche Registration Gmb H2021-01-12Not applicableEU flag
PolivyInjection, powder, lyophilized, for solution30 mg/1.88mLIntravenousGenentech, Inc.2019-06-10Not applicableUS flag
PolivyPowder, for solution30 mg / vialIntravenousHoffmann La Roche2021-10-26Not applicableCanada flag
PolivyInjection, powder, lyophilized, for solution140 mg/7.52mLIntravenousGenentech, Inc.2019-06-10Not applicableUS flag

Categories

ATC Codes
L01FX14 — Polatuzumab vedotin
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
KG6VO684Z6
CAS number
1313206-42-6

References

General References
  1. Tilly H, Morschhauser F, Bartlett NL, Mehta A, Salles G, Haioun C, Munoz J, Chen AI, Kolibaba K, Lu D, Yan M, Penuel E, Hirata J, Lee C, Sharman JP: Polatuzumab vedotin in combination with immunochemotherapy in patients with previously untreated diffuse large B-cell lymphoma: an open-label, non-randomised, phase 1b-2 study. Lancet Oncol. 2019 May 14. pii: S1470-2045(19)30091-9. doi: 10.1016/S1470-2045(19)30091-9. [Article]
  2. Han TH, Zhao B: Absorption, distribution, metabolism, and excretion considerations for the development of antibody-drug conjugates. Drug Metab Dispos. 2014 Nov;42(11):1914-20. doi: 10.1124/dmd.114.058586. Epub 2014 Jul 21. [Article]
  3. Deeks ED: Polatuzumab Vedotin: First Global Approval. Drugs. 2019 Sep;79(13):1467-1475. doi: 10.1007/s40265-019-01175-0. [Article]
  4. Assi R, Masri N, Dalle IA, El-Cheikh J, Ghanem H, Bazarbachi A: Polatuzumab Vedotin: Current Role and Future Applications in the Treatment of Patients with Diffuse Large B-Cell Lymphoma. Clin Hematol Int. 2021 Mar 13;3(1):21-26. doi: 10.2991/chi.k.210305.001. eCollection 2021 Mar. [Article]
  5. FDA Approved Drug Products: POLIVY (polatuzumab vedotin-piiq) for injection, for intravenous use [Link]
  6. Health Canada Approved Drug Products: POLIVY (polatuzumab vedotin) Intravenous Injection [Link]
PubChem Substance
347911301
RxNav
2174091
Wikipedia
Polatuzumab_vedotin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentDiffuse Large B-Cell Lymphoma (DLBCL)1
3RecruitingTreatmentDiffuse Large B-Cell Lymphoma (DLBCL)1
3RecruitingTreatmentNon-Hodgkin's Lymphoma (NHL)1
3RecruitingTreatmentRefractory Diffuse Large B Cell Lymphoma (DLBCL) / Relapsed Diffuse Large B-cell Lymphoma (DLBCL)1
3TerminatedTreatmentDiffuse Large B-Cell Lymphoma (DLBCL)1
2Active Not RecruitingTreatmentDiffuse Large B-Cell Lymphoma Unclassifiable / Recurrent Diffuse Large B-Cell Lymphoma / Recurrent Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma / Recurrent Transformed B-cell Non-Hodgkin Lymphoma / Refractory Diffuse Large B Cell Lymphoma (DLBCL) / Refractory Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma / Refractory Transformed B-cell Non-Hodgkin Lymphoma1
2Not Yet RecruitingTreatmentB-Cell Lymphoma / Hodgkin's Lymphoma / Relapsed B-Cell Non-Hodgkin Lymphoma1
2Not Yet RecruitingTreatmentDiffuse Large B-Cell Lymphoma (DLBCL)1
2Not Yet RecruitingTreatmentMantle Cell Lymphoma (MCL)1
2RecruitingTreatmentAggressive Non-Hodgkin's Lymphoma / Non-Hodgkin's Lymphoma, Relapsed / Refractory Non-Hodgkin's lymphoma1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous140 mg
Injection, powder, for solutionIntravenous30 MG
Injection, powder, lyophilized, for solutionIntravenous140 MG
Injection, powder, lyophilized, for solutionIntravenous140 mg/7.52mL
Injection, powder, lyophilized, for solutionIntravenous30 mg/1.88mL
Injection, solution, concentrateIntravenous140 mg/1vial
Powder, for solutionIntravenous140 mg / vial
Powder, for solutionIntravenous30 mg / vial
Powder140 mg
Injection, powder, lyophilized, for solutionIntravenous30 mg
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

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Details1. B-cell antigen receptor complex-associated protein beta chain
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antibody
Curator comments
The antibody component of polatuzumab vedotin targets the B-cell antigen receptor complex-associated protein beta chain, which causes the endocytosis of the drug-antibody complex.
General Function
Required in cooperation with CD79A for initiation of the signal transduction cascade activated by the B-cell antigen receptor complex (BCR) which leads to internalization of the complex, trafficking to late endosomes and antigen presentation. Enhances phosphorylation of CD79A, possibly by recruiting kinases which phosphorylate CD79A or by recruiting proteins which bind to CD79A and protect it from dephosphorylation.
Specific Function
Identical protein binding
Gene Name
CD79B
Uniprot ID
P40259
Uniprot Name
B-cell antigen receptor complex-associated protein beta chain
Molecular Weight
26047.65 Da
References
  1. FDA Approved Drug Products: POLIVY (polatuzumab vedotin-piiq) for injection, for intravenous use [Link]
  2. Health Canada Approved Drug Products: POLIVY (polatuzumab vedotin) Intravenous Injection [Link]

Enzymes

Details1. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Curator comments
Unconjugated monomethyl auristatin E, the active component of polatuzumab vedotin, is metabolized by CYP3A4.
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: POLIVY (polatuzumab vedotin-piiq) for injection, for intravenous use [Link]
  2. Health Canada Approved Drug Products: POLIVY (polatuzumab vedotin) Intravenous Injection [Link]
Details2. Cytochrome P450 3A5
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Curator comments
Unconjugated monomethyl auristatin E, the active component of polatuzumab vedotin, is metabolized by CYP3A5.
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Health Canada Approved Drug Products: POLIVY (polatuzumab vedotin) Intravenous Injection [Link]

Transporters

Details1. P-glycoprotein 1
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Curator comments
Monomethyl auristatin E (MMAE), the active component of polatuzumab vedotin, is a P-gp substrate in vitro.
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: POLIVY (polatuzumab vedotin-piiq) for injection, for intravenous use [Link]
  2. Health Canada Approved Drug Products: POLIVY (polatuzumab vedotin) Intravenous Injection [Link]

Drug created at October 20, 2016 21:42 / Updated at January 05, 2023 10:09