| Candidate ID: | R1569 |
| Source ID: | DB15699 |
| Source Type: | approved |
| Compound Type: |
biotech
|
| Compound Name: |
Brexucabtagene autoleucel
|
| Synonyms: |
Brexucabtagene autoleucel
|
| Molecular Formula: |
--
|
| SMILES: |
--
|
| DrugBank Description: |
Mantle cell lymphoma is a heterogeneous sub-category of non-Hodgkin's lymphoma that can be classified as either an aggressive nodal or an indolent leukemic non-nodal variant. Despite the introduction of Bruton's tyrosine kinase (BTK) inhibitors such as and , the prognosis for MCL patients remains poor and those that relapse following BTK inhibitor therapy have few treatment options.
More recently, chimeric antigen receptor (CAR) T cell therapies have been developed that modify a patient's own T cells using viral transduction to bind to and destroy cancerous cells. These therapies differ in manufacturing methodology, viral vector, chimeric antigen choice, and the internal co-stimulatory domains of the chimeric antigen. Similar to , brexucabtagene autoleucel employs a murine anti-CD19 single-chain variable fragment (scFv) linked to internal CD28- and CD3ζ-derived co-stimulatory domains. However, the preparation of brexucabtagene autoleucel, previously referred to as KTE-X19, uses a method of T cell enrichment that decreases the prevalence of CD19-expressing tumour cells in the CAR T cell preparation.
Brexucabtagene autoleucel was granted accelerated approval for the treatment of relapsed and refractory MCL by the FDA on July 24, 2020, and is currently available through Kite Pharma Inc. under the tradename TECARTUS.
|
| CAS Number: |
--
|
| Molecular Weight: |
|
| DrugBank Indication: |
Brexucabtagene autoleucel is a modified autologous chimeric antigen receptor (CAR) T cell immunotherapy indicated for the treatment of relapsed or refractory mantle cell lymphoma (MCL) in adult patients. It is additionally indicated for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
Brexucabtagene autoleucel has been granted accelerated approval based on results from a single-arm, open-label, multicentre clinical trial; continued approval may be contingent on confirmatory trials.
|
| DrugBank Pharmacology: |
Brexucabtagene autoleucel is an autologous T cell immunotherapy employing a CD19-directed chimeric antigen receptor (CAR) to direct modified T cells to bind to and subsequently destroy cancerous B cells. Like other CAR T cell therapies, brexucabtagene autoleucel has a durable response; in the single-arm ZUMA-2 trial, the median time to peak CAR T cell levels was 15 days, and 60% of assayed patients had detectable levels of CAR T cells at 24 months following the single infusion.
As brexucabtagene autoleucel recognizes both normal and cancerous B cells, adverse effects related to B cell depletion are expected, including severe and prolonged cytopenia, severe infections, neurological effects, hypogammaglobulinemia, and the potential to develop secondary malignancies. Patients should be advised not to drive or operate heavy machinery for eight weeks following infusion. Hypersensitivity reactions may occur during infusion.
|
| DrugBank MoA: |
Mantle cell lymphoma (MCL) is a heterogeneous sub-category of B cell non-Hodgkin's lymphoma typified by overexpression of cyclin D1 and SOX-11 as well as mutations in numerous genes including _TP53_; overall, these changes lead to increased cell growth, apoptosis inhibition, and cell-adhesion-mediated drug resistance. Based on the 2016 World Health Organization guidelines, MCL can be generally subdivided into aggressive nodal and indolent leukemic non-nodal subtypes. Bruton's tyrosine kinase (BTK) inhibitors can be used following a relapse of front-line therapy, but patients who relapse after BTK inhibitor therapy have a poor prognosis.
Chimeric antigen receptors (CARs) are synthetic immunoreceptors that can be introduced into T cells _ex vivo_ using viral transduction and that allow for major histocompatibility complex (MHC)-independent direction of T cells to any cell possessing the complementary antigen. Brexucabtagene autoleucel employs a murine anti-CD19 single-chain variable fragment (scFv) linked to internal CD28- and CD3ζ-derived co-stimulatory domains. Brexucabtagene autoleucel is prepared from the patient's own peripheral blood mononuclear cells using a leukapheresis methodology that excludes CD19-expressing tumour cells to avoid potential activation and exhaustion of CAR T cells during manufacturing. Collected cells are activated with anti-CD3 and anti-CD28 antibodies along with IL-2, transduced with a replication-incompetent retroviral vector, and subsequently expanded prior to infusion.
Once infused into the patient, the CAR T cells bind to CD19 antigens on the surface of both normal and cancerous B cells, leading to CAR T cell activation and expansion. Activated CAR T cells secrete cytokines and chemokines including, but not limited to, IL-6, IL-8, IL-10, IL-15, TNF-α, IFN-γ, and soluble IL-2 (sIL2Rα), leading to tumour cell lysis and anti-tumour activity.
|
| Targets: |
B-lymphocyte antigen CD19 binder
|
| Inclusion Criteria: |
Therapeutic strategy associated
|
