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Brentuximab Vedotin (SGN35) Drug Description

Brentuximab vedotin (also known as SGN-035; Adcetris® by Seattle Genetics Inc.) is an antibody-drug conjugate (ADC) or immunoconjugate directed to CD30, which is expressed in classical hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). CD30 (tumor necrosis factor receptor superfamily, member 8; TNFRSF8) is a type I transmembrane receptor which shares sequence homology in the extracellular domain with other members of the tumor necrosis factor (TNF) receptor superfamily.

CD30 is highly expressed on the Reed Sternberg cells, the large, often multinucleated cells with a peculiar morphology and an unusual immunophenotype, that does not resemble any normal cell in the body and which form the hallmark of Hodgkin’s disease (HD).

On normal tissues, CD30 has a restricted expression profile limited to activated T cells, activated B cells, and activated natural killer cells. This expression profile makes CD30 an ideal target for monoclonal antibody (mAb)-based therapies of Hodgkin’s disease.[1][2]

Brentuximab vedotin, links the chimeric anti-CD30 monoclonal (cAC10), derived from the fusion of the variable heavy and light region of the murine anti-CD30 antibody AC10 with the constant gamma1-heavy and kappa-light region of the human immunoglobulin, via a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), a synthetic derivative of dolastatin 10, a natural cytostatic pseudo peptide which was originally isolated from the marine shell-less mollusk Dorabella auricularia.

The linker system in brentuximab vedotin, which consists of a thiolreactive maleimidocaproyl spacer, the dipeptide valine–citrulline linker, and a self-immolative, p-amino-benzyloxycarbonyl or PABC, spacer, is designed to be stable in the bloodstream.

After binding to CD30 on the cell surface initiates internalization. Upon internalization into CD30-expressing tumor cells, monomethyl auristatin E, which exerts its potent cytostatic effect by inhibiting microtubule assembly, tubulin-dependent GTP hydrolysis and polymerization, released via proteolytic cleavage [2][3][4]

Finally, after binding to tubulin, monomethyl auristatin E disrupts the microtubule network within the cell, which, in turn, induces cell cycle arrest and results in apoptotic death of the CD30-expressing tumour cell.

Structure

Figure 1.0: Structure of mAb(cAC10)-Val-Cit-PABC-MMAE (Brentuximab vedotin)

Brentuximab vedotin has an approximate molecular weight of 153 kDa (149.2–152.8 kDa) . Approximately 4 molecules of monomethyl auristatin E  are attached to each antibody molecule. the drug is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian Chinese Hamster Ovary or CHO cells. The small molecule components are produced by chemical synthesis.

Brentuximab vedotin

Figure 2.0: Brentuximab vedotin is an antibody-drug conjugate consisting of the antibody cAC10, specific for human CD30, the highly potent antimicrotubule agent monomethyl auristatin E (MMAE), and a protease cleavable linker that covalently attaches MMAE to cAC10.

Pharmacodynamics
Brentuximab vedotin causes apoptosis of tumor cells by preventing cell cycle progression of the G2 to M phase through disruption of the cytosolic mictrotuble network.

Absorption
Brentuximab vedotin is administered only as an intravenous infusion resulting in 100% absorption.

Protein binding
Monomethyl auristatin E has a plasma protein binding range of 68-82%. Highly-protein bound drugs are not likely to displace it.

Metabolism
Only a small fraction of monomethyl auristatin E or MMAE is metabolized primarily via oxidation by CYP3A4 and CYP3A5.

Route of elimination
Monomethyl auristatin E is eliminated by the feces (with 72% unchanged) and urine.

Half Life
The terminal half-life is 4-6 days.

Clearance
Monomethyl auristatin E is cleared by the liver but not quantitative studies have been performed.

Toxicity
The most severe toxic reaction seen in patients is progressive multifocal leukoencephalopathy. Other toxicities include bone marrow suppression, infusion reactions, peripheral neuropathy, Stevens-Johnson syndrome, and tumor lysis syndrome.

Approval
To date, the drug is indicated for the treatment in relapsed HL and sALCL.  The drug is currently not approved for consolidation therapy in HL patients immediately after ASCT.[5]

Approval includes:

  • Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)
  • HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens
  • Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen

These indications are approved under accelerated approval based on overall response rate. An improvement in patient-reported outcomes or survival has not been established. Based on the regulatory authority, approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

A large number of ongoing clinical trials (phase I – IV) are being conducted.  Brentuximab vedotin is marketed Adcetris® by Seattle Genetics Inc. in North America and Takeda Oncology in the rest of the world.

Click here for an overview of other clinical trials with brentuximab vedotion.

Prescribing Information

Medically Necessary
Based on the The National Comprehensive Cancer Network® (NCCN®), an alliance of 26 of the world’s leading cancer centers, brentuximab vedotin is considered medically necessary for the treatment of individuals with:

  • Hodgkin Lymphoma (HL) and any of the following
    • After failure of autologous hematopoietic stem cell transplant (AHSCT); or
    • After failure of at least two prior multi-agent chemotherapy regimens in individuals who are not AHSCT candidates; or
    • As cytoreduction prior to either autologous or allogeneic stem cell transplantation for relapsed or refractory Hodgkin lymphoma; or
    • As early consolidation therapy after an autologous stem cell transplantation for individuals with any of the following:
      • Primary refractory Hodgkin lymphoma (failure to achieve complete remission, as determined by investigator); or
      • Relapsed Hodgkin lymphoma with an initial remission duration of less than 12 months; or
      • Extranodal involvement at the start of pre-transplantation salvage chemotherapy.
  • Anaplastic Large Cell Lymphoma (ALCL)
    • systemic Anaplastic Large Cell Lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.
    • CD30+ cutaneous ALCL.
  • Brentuximab vedotin is considered investigational and not medically necessary when the above criteria are not met and for all other indications including, but not limited to, mycosis fungoides and Sezáry syndrome.

Reference

[1] Küppers R, Hansmann ML. The Hodgkin and Reed/Sternberg cell. Int J Biochem Cell Biol. 2005 Mar;37(3):511-7.
[2] Wahl AF, Klussman K, Thompson JD, Chen JH, Francisco LV, Risdon G, Chace DF, Siegall CB, Francisco JA. et al. The anti-CD30 monoclonal antibody SGN-30 promotes growth arrest and DNA fragmentation in vitro and affects antitumor activity in models of Hodgkin’s disease. Cancer Res. 2002 Jul 1;62(13):3736-42.
[3] Francisco JA, Cerveny CG, Meyer DL, Mixan BJ, Klussman K, Chace DF, Rejniak SX, et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003 Aug 15;102(4):1458-65. Epub 2003 Apr 24.
[4] Bai R, Pettit GR, Hamel E. Dolastatin 10, a powerful cytostatic peptide derived from a marine animal. Inhibition of tubulin polymerization mediated through the vinca alkaloid binding domain. Biochem Pharmacol. 1990 Jun 15;39(12):1941-9.
[5] ADCETRIS Prescribing Information. Seattle Genetics, Inc (Bothell, WA). November 2014. 


Photo: Brentuximab Vedotin (SGN35) Packaging Illustration 1.0: Structure of Brentuximab Vedotin Courtesy: Seattle Genetics, Inc. Illustration 2.0: Schematic Brentuximab vedotin. Courtesy EMEA/Committee for Medicinal Products for Human Use (CHMP). Used with permission.

Last Editorial Review: August 1, 2016.

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