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Monoclonal antibody | |
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Type | Whole antibody |
Source | Chimeric (mouse/human) |
Target | CD33 |
Clinical data | |
Other names | SGN-CD33A |
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UNII |
Vadastuximab talirine is an antibody-drug conjugate (ADC) directed to CD33 (siglec-3) which is a transmembrane receptor expressed on cells of myeloid lineage. The experimental drug, being developed by Seattle Genetics, was in clinical trials for the treatment of acute myeloid leukemia (AML).[1][2]
Development of vadastuximab talirine was discontinued in 2017 after a pivotal phase III clinical trial.[3]
The drug target, CD33, is expressed on most AML cells. The CD33 antibody is attached to a highly potent DNA binding agent, a pyrrolobenzodiazepine (PBD) dimer (SGD-1882), via a proprietary site-specific conjugation chemistry via a cleavable (valine-alanine dipeptide as cathepsin B cleavage site) maleimidocaproyl type linker, to a monoclonal antibody with engineered cysteines (EC-mAb). Vadastuximab talirine contains two site-specific drug attachment engineered cysteines. This use of engineered cysteine residues at the sites of drug linker attachment results in a drug loading of approximately 2 PBD dimers per antibody. PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the site-specific conjugation technology (EC-mAb) allows uniform drug-loading of the cell-killing PBD agent to the anti-CD33 antibody.[4]
The drug has concluded phase I clinical trials for acute myeloid leukemia.[5] Interim results were presented in Dec 2014.[6] and published April 2015.[7]
Based on interim data from ongoing phase I clinical trials presented at the 57th Annual Meeting of the American Society of Hematology (ASH), researchers at Seattle Genetics have planned a phase III clinical trial to begin in 2016. This phase III study is expected to evaluate vadastuximab talirine in combination with hypomethylating agents (HMAs; azacitidine, decitabine) in previously untreated older AML patients. The drug is also being evaluated broadly across multiple lines of therapy in patients with myeloid malignancies, including in ongoing and planned phase I and II clinical trials for newly diagnosed or relapsed AML and for newly diagnosed myelodysplastic syndrome or MDS.[4]
A phase III clinical trial of Vadastuximab talirine in combination with hypomethylating agents, was terminated, however, in June 2017 due to a higher rate of deaths resulting from fatal infections.[3][8]
Vadastuximab talirine was granted orphan drug designation by both the U.S. Food and Drug Administration (FDA) and the European Commission for the treatment of AML.[4]