Vadastuximab talirine, also know as SGN-CD33A, is a novel Antibody-drug Conjugate or ADC targeted to CD33. The novel drug, being developed by Seattle Genetics, is utilizing this company’s newest ADC technology.
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 cathepsine 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. [1] 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. [2]
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.
Structure
Clinical Trials
Vadastuximab talirine is designed to be stable in the bloodstream and to release its potent DNA binding agent upon internalization into CD33-expressing cells. Seattle Genetics has initiated a number of clinical trials to evaluate vadastuximab talirine in ongoing phase I and phase I/II clinical trials for patients with acute myeloid leukemia, also called acute myelocytic leukemia or AML. [3]
Based on interim data from the ongoing phase I clinical trial, a phase III clinical trial is planned to begin in 2016. The phase III study will evaluate vadastuximab talirine in combination with hypomethylating agents (HMAs; azacitidine, decitabine) in previously untreated older AML patients. The drug is also 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 (MDS).
Impressive activity
In a number of clinical trials, vadastuximab talirine displayed impressive activity in elderly treatment-naïve patients who were not candidates for induction chemotherapy. In an article published in The Hematologist (May – June 2017 | Volume 4, Issue 3), Daniel A. Pollyea, MD, MS, Associate Professor, Division of Hematology, University of Colorado School of Medicine, Aurora, CO, writes that with a Complete Response (CR) or a Complete Response with incomplete cell recovery (CRi) rate of 73% when paired with a hypomethylator, these results are comparable to what might be expected from induction chemotherapy in younger patients.
Pollyea further explains that the minimal residual disease negativity rate of the responses (50%) suggest that the remissions were deep and that with a 30-day mortality rate was 2%, a fraction of what would be expected if a similarly aged group would have been treated with intensive chemotherapy is remarkable. He also explains that patients who achieved remissions were able to proceed to transplantation, representing a bridge to a definitive therapy in appropriate instances.
Orphan Drug Designation
Vadastuximab talirine has received granted Orphan Drug Designation by both the U.S. Food and Drug Administration (FDA) and the European Commission for the treatment of AML. In the United States, an orphan drug designation is intended to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 individuals.
References
[1] International Nonproprietary Names for Pharmaceutical Substances (INN). WHO Drug Information, Vol. 29, No. 2, 2015. Page 271-272; Published by INN Programme, WHO, Geneva, Switzerland.
[2] Kung Sutherland MS, Walter RB, Jeffrey SC, Burke PJ, Yu C, Kostner H, Stone I, Ryan MC, Sussman D, et al. SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood. 2013 Aug 22;122(8):1455-63. doi: 10.1182/blood-2013-03-491506. Epub 2013 Jun 14.
[3] Phase I/II Clinical Trial of Vadastuximab Talirine Initiated in Patients with Relapsed or Refractory AML ADC Review / Journal of Antibody-drug Conjugates. November 23, 2015. Publication Online. http://adc.expert/1SWAPI9 Last accessed November 23, 2015.
Illustration: Structure of vadastuximab talirine Courtesy: WHO – World Health Organization.
Last Editorial Review: November 23, 2017.
