Vadastuximab talirine

Vadastuximab talirine
Monoclonal antibody
Type	Whole antibody
Source	Chimeric (mouse/human)
Target	CD33
Clinical data
ATC code	none
Identifiers
CAS Number	1436390-64-5
ChemSpider	none

Vadastuximab talirine or SGN-CD33A is an antibody-drug conjugate or ADC directed to CD33 or Siglec-3 is a transmembrane receptor expressed on cells of myeloid lineage. The trial drug, being developed by Seattle Genetics and currently in clinical trials, is designed for the treatment of acute myeloid leukemia (AML).^[1]^[2] Acute myeloid leukemia remains a major challenge in the treatment of hematologic oncology. According to the American Cancer Society, an estimated 13,780 new cases and 10,200 deaths occurred in the United States in 2012.^[3]

Target, antibody, linker and cytotoxin

The drug target, CD33, is expressed on most AML cells. The CD33 antibody is attached to a potent DNA binding agent, a pyrrolobenzodiazepine (PBD) dimer (SGD-1882), 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 such cysteines. This use of engineered cysteine residues at the sites of drug linker attachment results in a drug loading of approximately two 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]

Chemical structure of "talirine" (drawn black), attached to a cysteine in the antibody's (vadastuximab's) peptide backbone (drawn blue).^[4]

Clinical trials

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]

The phase 3 HMA combination trial (called CASCADE) was halted early (June 2017) due to safety concerns.^[8]

Orphan drug designation

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]

References

Monoclonal antibodies for tumors

Tumor
("-t(u[m])-")

Human ("-tumu-")	Adecatumumab^§ Ascrinvacumab^§ Cixutumumab^§ Conatumumab^§ Daratumumab Drozitumab^§ Duligotumab^§ Dusigitumab^§ Enfortumab vedotin^§ Enoticumab^§ Figitumumab^§ Ganitumab^† Glembatumumab vedotin^§ Intetumumab^§ Ipilimumab Iratumumab^§ Icrucumab^§ Lexatumumab^§ Lucatumumab^§ Mapatumumab^§ Narnatumab^§ Necitumumab Nesvacumab^§ Ofatumumab Olaratumab^† Panitumumab Patritumab^§ Pritumumab^§ Radretumab^§ Ramucirumab Rilotumumab^† Robatumumab^§ Seribantumab^§ Tarextumab^§ Teprotumumab^§ Tovetumab^§ Vantictumab^§ Vesencumab^§ Votumumab^§ Zalutumumab^† "-melu-" (melanoma) Flanvotumab^§
Mouse ("-tumo-")	Altumomab pentetate Anatumomab mafenatox Arcitumomab Bectumomab Blinatumomab Detumomab Ibritumomab tiuxetan Minretumomab Mitumomab Moxetumomab pasudotox Naptumomab estafenatox Nofetumomab merpentan Pemtumomab^† Pintumomab Racotumomab Satumomab pendetide Solitomab Taplitumomab paptox Tenatumomab Tositumomab 3F8 "-govo-" (ovarian tumor) Abagovomab Igovomab Oregovomab "-pro-" (prostate tumor) Capromab pendetide "-colo-" (colonic tumor) Edrecolomab Nacolomab tafenatox
Chimeric ("-tuxi-")	Amatuximab^§ Bavituximab^§ Brentuximab vedotin Cetuximab Derlotuximab biotin^§ Dinutuximab Ensituximab^§ Futuximab^§ Girentuximab^† Indatuximab ravtansine^§ Isatuximab^† Margetuximab^† Rituximab^# Siltuximab Ublituximab^§ "-mexi-" (melanoma): Ecromeximab^§
Humanized ("-tuzu-")	Abituzumab^§ Alemtuzumab Bevacizumab Bivatuzumab mertansine^§ Brontictuzumab^§ Cantuzumab mertansine^§ Cantuzumab ravtansine^§ Citatuzumab bogatox^§ Clivatuzumab tetraxetan Dacetuzumab^§ Demcizumab^§ Dalotuzumab^§ Denintuzumab mafodotin^§ Elotuzumab Emactuzumab^§ Emibetuzumab^§ Enoblituzumab^§ Etaracizumab^§ Farletuzumab^§ Ficlatuzumab^§ Gemtuzumab ozogamicin^‡ Imgatuzumab^§ Inotuzumab ozogamicin^† Labetuzumab^§ Lifastuzumab vedotin^§ Lintuzumab^§ Lorvotuzumab mertansine^§ Lumretuzumab^§ Matuzumab^§ Milatuzumab^§ Nimotuzumab^† Obinutuzumab Ocaratuzumab^§ Otlertuzumab^§ Onartuzumab^§ Oportuzumab monatox^§ Parsatuzumab^§ Pertuzumab Pinatuzumab vedotin^§ Polatuzumab vedotin^§ Sibrotuzumab^§ Simtuzumab^§ Tacatuzumab tetraxetan^§ Tigatuzumab^§ Trastuzumab Tucotuzumab celmoleukin^§ Vandortuzumab vedotin^§ Vanucizumab^§ Veltuzumab^§ Vorsetuzumab mafodotin^§ "-gozu-" (ovarian tumor) Sofituzumab vedotin^§
Rat/mouse hybrid ("-tumaxo-")	Catumaxomab Ertumaxomab^§
Chimeric + humanized ("-tuxizu-")	Depatuxizumab mafodotin^§ Ontuxizumab^§
Veterinary ("-tuvet-")	Blontuvetmab^§ Tamtuvetmab^§

^#WHO-EM
^‡Withdrawn from market
Clinical trials:
- ^†Phase III
- ^§Never to phase III

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Vadastuximab talirine

Target, antibody, linker and cytotoxin

Clinical trials

Orphan drug designation

See also

References