Polatuzumab vedotin
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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
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
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,6,7 Epstein-Barr virus-positive (EBV+) DLBCL NOS, and T-cell/histiocyte rich LBCL.6
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- 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
Target Actions Organism AB-cell antigen receptor complex-associated protein beta chain antibodyHumans - 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
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Polatuzumab vedotin can be increased when it is combined with Abametapir. Abciximab The risk or severity of adverse effects can be increased when Abciximab is combined with Polatuzumab vedotin. Adalimumab The risk or severity of adverse effects can be increased when Adalimumab is combined with Polatuzumab vedotin. Aducanumab The risk or severity of adverse effects can be increased when Polatuzumab vedotin is combined with Aducanumab. Alemtuzumab The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Polatuzumab vedotin. - 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
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Polivy Injection, powder, lyophilized, for solution 30 mg/1.88mL Intravenous Genentech, Inc. 2019-06-10 Not applicable US Polivy Powder, for solution 30 mg / vial Intravenous Hoffmann La Roche 2021-10-26 Not applicable Canada Polivy Injection, powder, lyophilized, for solution 140 mg/7.52mL Intravenous Genentech, Inc. 2019-06-10 Not applicable US Polivy Injection, powder, for solution 30 mg Intravenous Roche Registration Gmbh 2021-01-12 Not applicable EU Polivy Powder, for solution 140 mg / vial Intravenous Hoffmann La Roche 2020-11-25 Not applicable Canada
Categories
- ATC Codes
- L01FX14 — Polatuzumab vedotin
- Drug Categories
- Amino Acids, Peptides, and Proteins
- Antibodies
- Antibodies, Monoclonal
- Antibodies, Monoclonal, Humanized
- Antibody-drug Conjugates
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Blood Proteins
- Cancer immunotherapy
- CD79b-directed Antibody–Drug Conjugates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 Substrates
- Globulins
- Immunoglobulins
- Immunologic Factors
- Immunoproteins
- Immunotherapy
- Monoclonal antibodies and antibody drug conjugates
- Noxae
- P-glycoprotein substrates
- Proteins
- Serum Globulins
- Toxic Actions
- 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
- 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]
- 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]
- Deeks ED: Polatuzumab Vedotin: First Global Approval. Drugs. 2019 Sep;79(13):1467-1475. doi: 10.1007/s40265-019-01175-0. [Article]
- 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]
- FDA Approved Drug Products: POLIVY (polatuzumab vedotin-piiq) for injection, for intravenous use [Link]
- Health Canada Approved Drug Products: POLIVY (polatuzumab vedotin) Intravenous Injection [Link]
- FDA Approved Drug Products: POLIVY (polatuzumab vedotin-piiq) for injection, for intravenous use (April 2023) [Link]
- External Links
- PubChem Substance
- 347911301
- 2174091
- Wikipedia
- Polatuzumab_vedotin
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Recruiting Not Available Diffuse Large B-Cell Lymphoma (DLBCL) 1 somestatus stop reason just information to hide Not Available Unknown Status Not Available Diffuse Large B-Cell Lymphoma (DLBCL) 1 somestatus stop reason just information to hide 3 Active Not Recruiting Treatment Diffuse Large B-Cell Lymphoma (DLBCL) 2 somestatus stop reason just information to hide 3 Active Not Recruiting Treatment Non-Hodgkin's Lymphoma (NHL) 1 somestatus stop reason just information to hide 3 Recruiting Treatment Diffuse Large B-Cell Lymphoma (DLBCL) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, powder, for solution Intravenous 140 mg Injection, powder, for solution Intravenous 30 MG Injection, powder, lyophilized, for solution Intravenous 140 mg/7.52mL Injection, powder, lyophilized, for solution Intravenous 30 mg/1.88mL Injection, solution, concentrate Intravenous 140 mg/1vial Powder, for solution Intravenous 140 mg / vial Powder, for solution Intravenous 30 mg / vial Powder 140 mg Powder 30 mg Injection, powder, lyophilized, for solution Intravenous 140 mg Injection, powder, lyophilized, for solution Intravenous 30 mg - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Liquid
- Experimental Properties
- Not Available
Targets
- 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
Enzymes
- 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
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- 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
- A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Exhibits high catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes 6beta-hydroxylation of the steroid hormones testosterone, progesterone, and androstenedione (PubMed:2732228). Catalyzes the oxidative conversion of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics, including calcium channel blocking drug nifedipine and immunosuppressive drug cyclosporine (PubMed:2732228)
- Specific Function
- aromatase activity
- Gene Name
- CYP3A5
- Uniprot ID
- P20815
- Uniprot Name
- Cytochrome P450 3A5
- Molecular Weight
- 57108.065 Da
References
- Health Canada Approved Drug Products: POLIVY (polatuzumab vedotin) Intravenous Injection [Link]
Transporters
- 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
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
References
Drug created at October 20, 2016 21:42 / Updated at April 23, 2023 14:17