Brentuximab verdotin was approved by the U.S. FDA in August 2011
for treatment of Hodgkin’s lymphoma (HL) in patients who have failed autologous stem cell transplant (ASCT) or ASCT ineligible patients who have
failed at least two prior chemotherapy regimens, and for second line treatment of systemic anaplastic large cell leukemia (ALCL).
Brentuximab verdotin is a chimeric (mouse V region/human
C region) CD30 binding monoclonal antibody (cAC10) that is
conjugated via cysteine residues to a small molecule comprising a cysteine
reactive dipeptide linker moiety and the microtubule polymerization
inhibitor monomethyl auristatin E(MMAE). The antibody component
of the drug binds to CD30 expressing tumor cells, and the active
cytotoxic component, MMAE, is released by proteolytic cleavage of the
dipeptide linker moiety.
Clinical Use
Brentuximab vedotin is an antibody drug conjugate that is comprised
of an anti-CD30 antibody and the potent tubulin based
inhibitor monomethyl auristatin E (MMAE). These two entities
are connected together via a linker consisting of a maleimide conjugation
handle that includes an enzyme-cleavable valine-citrulline-
para-aminobenzylcarbamate group. This conjugation handle
releases MMAE after internalization of the conjugate by the cancer cell that recognizes the antibody. Brentuximab vedotin was discovered
by Seattle Genetics who co-developed the conjugate with Millenium
Pharmaceuticals. Brentuximab vendotin has been approved
for the treatment of relapsed or refractory systemic anaplastic
large cell lymphoma (ALCL) and relapsed or refractory Hodgkin’s
lymphoma. Brentuximab vedotin is also undergoing clinical trials
for the treatment of CD30-expressing cutaneous T-cell lymphoma
and CD30-positive hematologic malignancies. Although brentuximab
vedotin is classified as a biologic, an exception has been made
to include it in this year’s review because the small molecule portion
of the conjugate was prepared by total synthesis.
