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]
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| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Chimeric (mouse/human) |
| Target | CD33 |
| Clinical data | |
| Other names | SGN-CD33A |
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| Identifiers | |
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Development of vadastuximab talirine was discontinued in 2017 after a pivotal phase III clinical trial.[3]
Target, mAb, linker, and cytotoxin
editThe 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]
Clinical trials
editThe 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]
Orphan drug designation
editVadastuximab 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]
References
edit- ^ Sutherland MS, Walter RB, Jeffrey SC, Burke PJ, Yu C, Harrington KH, et al. (November 2012). "SGN-CD33A: A novel CD33-directed antibody-drug conjugate, utilizing pyrrolobenzodiazepine dimers, demonstrates preclinical antitumor activity against multi-drug resistant human AML". Blood. 120 (21): 3589. doi:10.1182/blood.V120.21.3589.3589.
- ^ "Pyrrolobenzodiazepine (PBD)". ADC Review / Journal of Antibody-drug Conjugates. 16 March 2015.
- ^ a b Hartley JA (July 2021). "Antibody-drug conjugates (ADCs) delivering pyrrolobenzodiazepine (PBD) dimers for cancer therapy". Expert Opinion on Biological Therapy. 21 (7): 931–943. doi:10.1080/14712598.2020.1776255. PMID 32543981. S2CID 219725417.
- ^ a b c "Vadastuximab talirine (SGN-CD33a) drug description". ADC Review / Journal of Antibody-drug Conjugates. 23 November 2015.
- ^ Clinical trial number NCT01902329 for "A Safety Study of SGN-CD33A in AML Patients" at ClinicalTrials.gov
- ^ Stein EM, Stein A, Walter RB, Fathi AT, Lancet JE, Kovacsovics TJ, et al. (November 2014). "Interim analysis of a phase 1 trial of SGN-CD33A in patients with CD33-positive acute myeloid leukemia (AML)". Blood. 124 (21): 623. doi:10.1182/blood.V124.21.623.623.
- ^ Kennedy DA, Alley SC, Zhao B, Feldman EJ, O'Meara M, Sutherland M (April 2015). Abstract DDT02-04: SGN-CD33A: Preclinical and phase 1 interim clinical trial results of a CD33-directed PBD dimer antibody-drug conjugate for the treatment of acute myeloid leukemia (AML). Proceedings: AACR 106th Annual Meeting 2015. Philadelphia, PA. doi:10.1158/1538-7445.AM2015-DDT02-04.Abstract DDT02-04: SGN-CD33A: Preclinical and phase I interim clinical trial results of a CD33-directed PBD dimer antibody-drug conjugate for the treatment of acute myeloid leukemia (AML)
- ^ Clinical trial number NCT02785900 for "Vadastuximab Talirine (SGN-CD33A; 33A) Combined With Azacitidine or Decitabine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia (CASCADE)" at ClinicalTrials.gov