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VHH-based CAR-T Cell Therapy Targeting BCMA

For Multiple Myeloma Treatment

Home / Available Projects / VHH-based CAR-T Cell Therapy Targeting BCMA

  • Overview
  • Target
  • Drug Modality
  • Indication
  • Mechanism of Action
  • Status
  • Data
Drug Name PR-18-01
Description

The overexpression of B-cell maturation antigen (BCMA) is associated with multiple myeloma (MM) cells, hence BCMA has been suggested as one of the most promising target antigens. PR-18-01 is chimeric antigen receptor T cell (CAR-T) therapeutics targeting BCMA, using humanized single-domain antibody (VHH) that derived from the alpaca with high affinity. Different from single-chain variable fragments (scFvs) as an antigen targeting moiety, CARs composed of VHHs may likely overcome the obstacle including host immunogenic responses and engineered T cell disappearance.

The results of the preliminary clinical trial demonstrated the promising efficacy and acceptable safety of PR-18-01. IND clearance of PR-18-01 for clinical trial has been received from the NMPA, and the IND application is also submitting to the FDA.

Target B-cell maturation antigen (BCMA)
Drug Modality CAR-T cell
Indication Multiple myeloma
Product Category Cellular immunotherapy
Mechanism of Action Genetically modified T cells are activated by CARs recognizing BCMA to kill MM cells
Status Clinical trial
Patent Granted

Collaboration Opportunity

Protheragen Inc. is actively seeking partnership for PR-18-01. Potential collaboration can be strategic alliance, licensing, or marketing agreement.

We look forward to hearing from you.

B-cell Maturation Antigen (BCMA)

Introduction B-cell maturation antigen (BCMA), also known as tumor necrosis factor receptor superfamily member 17 (TNFRSF17), is preferentially expressed in mature B lymphocytes and may be important for B cell development and autoimmune response. Its ligands include B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL).
Approved Name TNF receptor superfamily member 17
Official Symbol TNFRSF17
Gene Type Protein coding
Synonyms BCM; BCMA; CD269; TNFRSF13A
Ensembl ENSG00000048462
Gene ID 608
mRNA Refseq NM_001192
Protein Refseq NP_001183
OMIM 109545
UniProt ID Q02223
Chromosome Location 16p13.13

Clinical Resources

Gene Function BCMA mRNA and protein are highly expressed in malignant cells, as validated by multiple gene expression profiling. BCMA expression is positively regulated by B-lymphocyte-induced maturation protein 1, a gene controlling proliferation of plasma cells.
Pathway BCMA specifically binds to the tumor necrosis factor superfamily, member 13b, activating NF-kappaB and MAPK8/JNK. BCMA also binds to various TRAF family members to transduce signals for cell survival and proliferation.
Major Conditions Leukemia; lymphomas; multiple myeloma

CAR-T Cell

PR-18-01 was produced by transducing autologous T cells with a lentiviral vector encoding a second-generation CAR incorporating an anti-BCMA single-domain antibody, CD8 strand region, a transmembrane region and a CD137 (4-1BB) costimulatory domain, and a CD3-zeta signaling domain.

Multiple Myeloma

Multiple myeloma (MM), also known as myeloma, is a B cell-dependent hematological malignancy caused by excessive clonal proliferation of terminally differentiated plasma cells in bone marrow. MM is the second most common hematological malignancy, with the first being non-Hodgkin’s lymphoma, although it is nonetheless a rare disorder, accounting for less than 2% of all cancers.

According to the Global Burden of Disease study, approximately 154,000 new cases of MM were diagnosed worldwide in 2015 and resulting in an estimated 101,100 deaths. MM is a highly treatable, albeit ultimately incurable, neoplastic disorder, so the goal is extended survival.

Current treatments include drug therapy (targeted therapy, immunomodulator, chemotherapy), radiation therapy, autologous bone marrow transplantation, and supportive care. Patients should be ideally treated on an individualized basis according to a risk-adapted approach that balances efficacy with potential side effects. The introduction of many new drugs has dramatically changed the outcome of MM patients. But despite a significant improvement in overall survival, MM remains largely incurable due to the resistant and refractory nature of the disease.

Genetically Modified T Cells Activated by CAR Recognizing BCMA to Kill Multiple Myeloma Cells

PR-18-01 is a CAR-T cell therapy that targets BCMA for the treatment of multiple myeloma. PR-18-01 was generated from autologous T cells collected from patient, modified to express CAR fusing anti-BCMA single-domain antibody, expanded in vitro, and then given to the patient by infusion.

When the CAR specifically binds to BCMA on the multiple myeloma cells, T cell is activated through signal transduction. Activated CAR-T cells kill tumor cells through several mechanisms, including extensive stimulated cell proliferation, increased degree of cytotoxicity, and increased secretion of factors to affect other cells, such as cytokines, interleukins, and growth factors.

The Status of PR-18-01

As of November 2019, PR-18-01 were tested as a treatment for 34 relapsed MM patients. After at least 5 months of follow-up period, PR-18-01 was demonstrated to be an effective and safe therapy. PR-18-01 has received IND clearance by the NMPA for clinical trial and the IND application has also been submitted to the FDA.


Binding Affinity of Single-domain Antibody to BCMA

One single-domain antibody (VHH) was engineered and developed as antigen recognition domain in PR-18-01 anti-BCMA CAR-T cell. Biocore assay showed that the affinity of VHH to BCMA was 1.14nM, indicating only one VHH domain already had enough binding ability for CAR-T cell to recognize the BCMA positive tumor cells.


Clinical Efficacy of Patients Treated with Different Doses of PR-18-01

Different dosages have a similar efficacy. The best ORR is 88.2% (30/34). CR/sCR rate is 52.9% (18/34). These results demonstrated promising efficacy and safety of PR-18-01, anti-BCMA CAR-T with the humanized VHH, in treating patients with relapsed/refractory multiple myeloma.

Diane Hong Business Development Manager
1-516-927-7606
info@protheragen.com

Protheragen’s business is growing rapidly after founded in Ronkonkoma, New York in 2009. More offices have been established at different locations across China and the US ever since.

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