How ADCT-301 works
Lymphoma is a cancer that affects the lymphatic system, particularly the white blood cells called lymphocytes that help the body fight infections and other diseases. The two main types of lymphomas are HL and NHL, which can be distinguished by the type of lymphocytes affected and their appearance under a microscope.
CD25 over-expression has been demonstrated in HL and many types of NHL, including follicular lymphoma and diffuse large B-cell lymphoma, while its expression in healthy tissues is restricted. This makes CD25 protein an attractive target for anti-cancer therapy.
As an antibody-drug conjugate, ADCT-301 consists of a human monoclonal anti-CD25 antibody, licensed from Genmab, linked to a toxin based on PBD (pyrrolobenzodiazepine). Following ADCT-301 administration, the CD25-specific antibody portion binds to CD25 found on the surface of tumor cells, allowing the drug to enter the cell. Then, the two portions of the drug dissociate and the PBD toxin is released inside the cell where it binds to DNA, causing it to become cross-linked (its building blocks bind together). This means that the DNA no longer can replicate, leading to the death of the cancer cell. The linker component that connects the antibody to the toxin ensures the toxin is not released into the body before it is inside the cancer cells, avoiding or reducing the adverse effects usually seen with conventional chemotherapy agents.
ADCT-301 in clinical trials
Preclinical data from studies performed in cell lines and mouse models confirmed the mechanism of action of ADCT-301 and demonstrated the potent antitumor activity of the drug against CD25-expressing blood tumors. These data supported the clinical testing of this drug in patients with CD25-expressing tumors.
ADCT-301 is being evaluated in an ongoing Phase 1 clinical trial (NCT02432235) in patients with relapsed or refractory HL and NHL. The study will include 90 adults from several U.S. and U.K. institutions and aims to evaluate the tolerability, safety, drug dynamics and effectiveness of intravenous infusion of ADCT-301. Preliminary results from 37 patients demonstrated the drug leads to good overall response rates and low toxicity, with favorable tolerability and effectiveness. The study is still open for enrollment.
In addition to lymphoma, the drug also is being studied in an ongoing Phase 1 trial (NCT02588092) for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). This study also is recruiting participants.
According to the preliminary results of the clinical trial for the treatment of lymphoma, the most common adverse events reported for ADCT-301 therapy are skin symptoms and decreased numbers of blood cells.
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