Wednesday, June 7, 2023

ADCETRIS(Brentuximab vedotin)

ADCETRIS(Brentuximab vedotin)

Brentuximab vedotin (INN; trade name Adcetris) is an antibody drug conjugate medication used to treat relapsed or refractory Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL), a type of T cell non Hodgkin lymphoma. It selectively targets tumor cells expressing the CD30 antigen, a defining marker of Hodgkin lymphoma and ALCL. The drug is being jointly marketed by Millennium Pharmaceuticals outside the US and by Seattle Genetics in the US.

In August 2011, the U.S. Food and Drug Administration (FDA) granted accelerated approval to the biologics license application (BLA) submitted by Seattle Genetics for the use of brentuximab vedotin in the treatment of relapsed HL and ALCL.

In October 2012, the European Medicine Agency (EMA) gave it conditional for marketing authorization relapsed or refractory HL and ALCL.

In November 2017, the FDA approved brentuximab vedotin as a treatment for patients with cutaneous T-cell lymphoma (CTCL) who have received prior systemic therapy This approval is for patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) and CD30-expressing mycosis fungoides (MF).

In March 2018, the FDA approved brentuximab vedotin to treat adults with previously untreated stage III or IV classical Hodgkin lymphoma (cHL) in combination with chemotherapy.

In November 2018, the FDA expanded the approved use of brentuximab vedotin in combination with chemotherapy for adults with certain types of peripheral T-cell lymphoma (PTCL). This is the first FDA approval for treatment of newly diagnosed PTCL.

Approval in Australia

The Australian Pharmaceutical Benefits Advisory Committee (PBAC) considered a March 2014 application by the manufacturer for inclusion of brentuximab vedotin under a Pharmaceutical Benefits Scheme Section 100 (Efficient Funding of Chemotherapy) arrangement. While this application was accepted, the committee noted that on the basis of inadequate cost-benefit, the medicine would not be made available more generally for the first-line treatment of relapsed or refractory systemic anaplastic large cell lymphoma (sALCL).

Brentuximab vedotin consists of the chimeric monoclonal antibody brentuximab (cAC10, which targets the cell-membrane protein CD30) linked with maleimide attachment groups, cathepsin-cleavable linkers (valine-citrulline), and para- aminobenzyl carbamate spacers to three to five units of the antimitotic agent monomethyl auristatin E (MMAE, reflected by the ‘vedotin’ in the drug’s name).The peptide-based linker bonds the antibody to the cytotoxic compound in a stable manner so the drug is not easily released from the antibody under physiologic conditions to help prevent toxicity to healthy cells and ensure dosage efficiency. The peptide antibody-drug bond facilitates rapid and efficient drug cleavage inside the target tumor cell. The antibody cAC10 part of the drug binds to CD30 which often occurs on diseased cells but rarely on normal tissues. The antibody portion of the drug attaches to CD30 on the surface of malignant cells, delivering MMAE which is responsible for the anti-tumour activity. Once bound, brentuximab vedotin is internalised by endocytosis and thus selectively taken up by targeted cells. The vesicle containing the drug is fused with lysosomes and lysosomal cysteine proteases, particularly cathapesin AE, start to break down valine-citrulline linker and MMAE is no longer bound to the antibody and is released directly into the tumor environment


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