Vadastuximab talirine

Last updated
Vadastuximab talirine
Vadastuximab talirine.svg
Monoclonal antibody
Type Whole antibody
Source Chimeric (mouse/human)
Target CD33
Clinical data
Other namesSGN-CD33A
ATC code
  • none
Identifiers
CAS Number
ChemSpider
  • none
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]

Contents

Development of vadastuximab talirine was discontinued in 2017 after a pivotal phase III clinical trial. [3]

Target, mAb, linker, and cytotoxin

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]

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]

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

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]

Related Research Articles

<span class="mw-page-title-main">Azacitidine</span>

Azacitidine, sold under the brand name Vidaza among others, is used for the treatment of myelodysplastic syndrome, myeloid leukemia, and juvenile myelomonocytic leukemia. It is a chemical analog of cytidine, a nucleoside in DNA and RNA. Azacitidine and its deoxy derivative, decitabine were first synthesized in Czechoslovakia as potential chemotherapeutic agents for cancer.

<span class="mw-page-title-main">Gemtuzumab ozogamicin</span>

Gemtuzumab ozogamicin, sold under the brand name Mylotarg, is an antibody-drug conjugate that is used to treat acute myeloid leukemia.

The interleukin-3 receptor (CD123) is a molecule found on cells which helps transmit the signal of interleukin-3, a soluble cytokine important in the immune system.

<span class="mw-page-title-main">Decitabine</span> Medication for the treatment of conditions where certain blood cells are dysfunctional,

Decitabine, sold under the brand name Dacogen among others, acts as a nucleic acid synthesis inhibitor. It is a medication for the treatment of myelodysplastic syndromes, a class of conditions where certain blood cells are dysfunctional, and for acute myeloid leukemia (AML). Chemically, it is a cytidine analog.

Lintuzumab (SGN-33) is a humanized monoclonal antibody used in the treatment of cancer. The drug had been developed by Seattle Genetics as a treatment for acute myeloid leukemia (AML), a condition which results in the deaths of 9,000 people a year in the United States. Lintuzumab targets the CD33 protein, which is expressed in AML and other myeloproliferative diseases, but does not appear in abundance on normal cells.

<span class="mw-page-title-main">CD33</span> Mammalian protein found in Homo sapiens

CD33 or Siglec-3 is a transmembrane receptor expressed on cells of myeloid lineage. It is usually considered myeloid-specific, but it can also be found on some lymphoid cells.

<span class="mw-page-title-main">CD135</span> Protein-coding gene in the species Homo sapiens

Cluster of differentiation antigen 135 (CD135) also known as fms like tyrosine kinase 3 (FLT-3), receptor-type tyrosine-protein kinase FLT3, or fetal liver kinase-2 (Flk2) is a protein that in humans is encoded by the FLT3 gene. FLT3 is a cytokine receptor which belongs to the receptor tyrosine kinase class III. CD135 is the receptor for the cytokine Flt3 ligand (FLT3L).

Milatuzumab is an anti-CD74 humanized monoclonal antibody for the treatment of multiple myeloma non-Hodgkin's lymphoma and chronic lymphocytic leukemia.

<span class="mw-page-title-main">Sapacitabine</span>

Sapacitabine is a chemotherapeutic drug developed by US biotechnology firm Cyclacel currently undergoing clinical trials against leukemia.

Brentuximab vedotin is an antibody-drug conjugate medication used to treat relapsed or refractory Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL), a type of T cell non-Hodgkin lymphoma. It selectively targets tumor cells expressing the CD30 antigen, a defining marker of Hodgkin lymphoma and ALCL. The drug is being jointly marketed by Millennium Pharmaceuticals outside the US and by Seattle Genetics in the US.

<span class="mw-page-title-main">Antibody-drug conjugate</span> Class of biopharmaceutical drugs

Antibody-drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As of 2019, some 56 pharmaceutical companies were developing ADCs.

<span class="mw-page-title-main">Midostaurin</span>

Midostaurin, sold under the brand name Rydapt & Tauritmo both by Novartis, is a multi-targeted protein kinase inhibitor that has been investigated for the treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and advanced systemic mastocytosis. It is a semi-synthetic derivative of staurosporine, an alkaloid from the bacterium Streptomyces staurosporeus.

Lirilumab (INN) is a human monoclonal antibody designed for the treatment of cancer. It binds to KIR2DL1/2L3.

Seagen Inc. is an American biotechnology company focused on developing and commercializing innovative, empowered monoclonal antibody-based therapies for the treatment of cancer. The company, headquartered in Bothell, Washington, is the industry leader in antibody-drug conjugates or ADCs, a technology designed to harness the targeting ability of monoclonal antibodies to deliver cell-killing agents directly to cancer cells. Antibody-drug conjugates are intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy, while potentially enhancing antitumor activity.

ImmunoGen, Inc. is a biotechnology company focused on the development of antibody-drug conjugate (ADC) therapeutics for the treatment of cancer. ImmunoGen was founded in 1981 and is headquartered in Waltham, Massachusetts.

<span class="mw-page-title-main">Venetoclax</span> Medication

Venetoclax, sold under the brand names Venclexta and Venclyxto, is a medication used to treat adults with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or acute myeloid leukemia (AML).

Denintuzumab mafodotin is a humanized monoclonal antibody-drug conjugate designed for the treatment of CD19-positive acute lymphoblastic leukemia and B-cell non-Hodgkin lymphoma. It consists of an anti-CD19 mAb linked to monomethyl auristatin F (MMAF), a cytotoxic agent. This drug was developed by Seattle Genetics.

<span class="mw-page-title-main">Loncastuximab tesirine</span>

Loncastuximab tesirine, sold under the brand name Zynlonta, is a monoclonal antibody conjugate medication used to treat large B-cell lymphoma. It is an antibody-drug conjugate (ADC) composed of a humanized antibody targeting the protein CD19.

Camidanlumab tesirine is an antibody-drug conjugate (ADC) composed of a human antibody that binds to the protein CD25, conjugated to a pyrrolobenzodiazepine dimer toxin. The experimental drug, developed by ADC Therapeutics is being tested in clinical trials for the treatment of B-cell Hodgkin's lymphoma (HL) and non-Hodgkin lymphoma (NHL), and for the treatment of B-cell acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).

GEMoaB is a biopharmaceutical company based in Dresden/Germany. The company has a broad pipeline of next generation immunotherapy product candidates for the treatment of advanced blood cancers and solid tumours in pre-clinical and clinical development. The company was founded in 2011 by the two university professors Gerhard Ehninger and Michael Bachmann.

References

  1. ↑ 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.
  2. ↑ "Pyrrolobenzodiazepine (PBD)". ADC Review / Journal of Antibody-drug Conjugates. 16 March 2015.
  3. 1 2 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.
  4. 1 2 3 "Vadastuximab talirine (SGN-CD33a) drug description". ADC Review / Journal of Antibody-drug Conjugates. 23 November 2015.
  5. ↑ Clinical trial number NCT01902329 for "A Safety Study of SGN-CD33A in AML Patients" at ClinicalTrials.gov
  6. ↑ 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.
  7. ↑ 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)
  8. ↑ 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
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.