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▲TG-Bio has joined hands with more than 600 industry colleagues and will open in April ▲About 50% of soft tissue sarcomas in children and adolescents are rhabdomyosarcoma (RMS), and there are two main subtypes: embryonic rhabdomyosarcoma (ERMS) and alveolar type Rhabdomyosarcoma (ARMS) accounts for 60% and 20% of all cases, respectively.
Rhabdomyosarcoma has a poor prognosis, and the overall survival rate for advanced rhabdomyosarcoma is less than 20%.
The main types of rhabdomyosarcoma (Document 1) FGFR4 and tumor fibroblast growth factor receptor 4 (FGFR4) belong to the receptor tyrosine kinase family.
The human FGFR4 gene is located on the long arm of chromosome 5 (5q35.
1), spanning a genomic region of approximately 11 kb.
The FGFR4 gene has five transcript variants, of which three encode 802 amino acid FGFR4 subtype 1, with a molecular weight of about 95-110kDa (affected by the level of glycosylation).
The basic protein domain structure of FGFR4 consists of four parts, including a signal peptide, three extracellular immunoglobulin (Ig) domains, a transmembrane domain and an intracellular tyrosine kinase domain.
The ligand of FGFR4 is FGF19.
The combination of the two activates signal pathways, promotes cell survival, differentiation, and participates in myogenesis and muscle regeneration.
FGFR4 lacks expression in normal muscles and is specifically overexpressed in rhabdomyosarcoma and other tumors, such as hepatocellular carcinoma, squamous cell carcinoma of the head and neck, and basal-like breast cancer.
Therefore, FGFR4 is a promising candidate drug target for targeted therapy of rhabdomyosarcoma.
FGF19-FGFR4 signaling pathway (Document 2) FGFR4 single-domain antibody development Single-domain antibody has a small molecular weight and good tissue penetration.
For some solid tumors, it can reach the deep layer of the tumor tissue and have a better therapeutic effect.
It has won the academic and scientific research circles.
extensive attention.
France’s No.
1 University of Arts and Sciences in Paris and Honing Biosciences have developed single-domain antibodies against FGFR4, and the corresponding results have been published in Cancers (Ref.
3).
Phage display and FGFR4 single domain monoclonal antibody (SDAb) sequence preselected schematic diagram Experimental results single domain antibody in vitro binding verification A flow cytometry detection of single domain antibody and cell surface FGFR4 selective binding B combined with recombinant FGF19 and single domain antibody The FGFR4 activation test was performed on Rh30 cells.
The affinity of the single domain antibody to the recombinant protein was measured by surface plasmon resonance spectroscopy.
Dynamic light scattering was used to detect the size of the liposome encapsulating the single domain antibody, and the single domain antibody in the liposome was detected by western blot.
In vitro binding of FGFR4 targeting liposomes to verify the construction of CAR-T by single domain antibodies and its killing effect on rhabdomyosarcoma cells.
Summary of the editor.
Rhabdomyosarcoma is a malignant tumor that is more common in children, accounting for about 50% of children’s soft tissue tumors.
The prognosis is poor.
FGFR4 is specifically expressed in tumors and is not expressed in normal muscle tissues, avoiding the side effects of off-tumor, and is a good target for drug development.
The FGFR4 single-domain antibody was developed by the University of Arts and Sciences in Paris, France, which was further made into liposome-encapsulated drugs and used as CAR-T.
Both showed good binding activity and anti-tumor activity in vitro, demonstrating the potential for further development. References 1.
Farah Ramadan et al, Signaling pathways in Rhabdomyosarcoma invasion and metastasis, Cancer and Metastasis Reviews https://doi.
org/10.
1007/s10555-020-09860-32.
Yanan Liu et al, Dissecting the Role of the FGF19 -FGFR4 Signaling Pathway in Cancer Development and Progression, Front.
Cell Dev.
Biol.
, 20 February 2020 3.
Nagjie Alijaj et al, Novel FGFR4-Targeting Single-Domain Antibodies for Multiple Targeted Therapies against Rhabdomyosarcoma, Cancers 2020, 12, 3313; doi :10.
3390/cancers12113313 Copyright statement welcomes personal forwarding and sharing.
Any other media or website that needs to reprint or quote the copyrighted content of this website must be authorized and marked "Reprinted from: Biopharmaceutical Editor" in a prominent position.
Rhabdomyosarcoma has a poor prognosis, and the overall survival rate for advanced rhabdomyosarcoma is less than 20%.
The main types of rhabdomyosarcoma (Document 1) FGFR4 and tumor fibroblast growth factor receptor 4 (FGFR4) belong to the receptor tyrosine kinase family.
The human FGFR4 gene is located on the long arm of chromosome 5 (5q35.
1), spanning a genomic region of approximately 11 kb.
The FGFR4 gene has five transcript variants, of which three encode 802 amino acid FGFR4 subtype 1, with a molecular weight of about 95-110kDa (affected by the level of glycosylation).
The basic protein domain structure of FGFR4 consists of four parts, including a signal peptide, three extracellular immunoglobulin (Ig) domains, a transmembrane domain and an intracellular tyrosine kinase domain.
The ligand of FGFR4 is FGF19.
The combination of the two activates signal pathways, promotes cell survival, differentiation, and participates in myogenesis and muscle regeneration.
FGFR4 lacks expression in normal muscles and is specifically overexpressed in rhabdomyosarcoma and other tumors, such as hepatocellular carcinoma, squamous cell carcinoma of the head and neck, and basal-like breast cancer.
Therefore, FGFR4 is a promising candidate drug target for targeted therapy of rhabdomyosarcoma.
FGF19-FGFR4 signaling pathway (Document 2) FGFR4 single-domain antibody development Single-domain antibody has a small molecular weight and good tissue penetration.
For some solid tumors, it can reach the deep layer of the tumor tissue and have a better therapeutic effect.
It has won the academic and scientific research circles.
extensive attention.
France’s No.
1 University of Arts and Sciences in Paris and Honing Biosciences have developed single-domain antibodies against FGFR4, and the corresponding results have been published in Cancers (Ref.
3).
Phage display and FGFR4 single domain monoclonal antibody (SDAb) sequence preselected schematic diagram Experimental results single domain antibody in vitro binding verification A flow cytometry detection of single domain antibody and cell surface FGFR4 selective binding B combined with recombinant FGF19 and single domain antibody The FGFR4 activation test was performed on Rh30 cells.
The affinity of the single domain antibody to the recombinant protein was measured by surface plasmon resonance spectroscopy.
Dynamic light scattering was used to detect the size of the liposome encapsulating the single domain antibody, and the single domain antibody in the liposome was detected by western blot.
In vitro binding of FGFR4 targeting liposomes to verify the construction of CAR-T by single domain antibodies and its killing effect on rhabdomyosarcoma cells.
Summary of the editor.
Rhabdomyosarcoma is a malignant tumor that is more common in children, accounting for about 50% of children’s soft tissue tumors.
The prognosis is poor.
FGFR4 is specifically expressed in tumors and is not expressed in normal muscle tissues, avoiding the side effects of off-tumor, and is a good target for drug development.
The FGFR4 single-domain antibody was developed by the University of Arts and Sciences in Paris, France, which was further made into liposome-encapsulated drugs and used as CAR-T.
Both showed good binding activity and anti-tumor activity in vitro, demonstrating the potential for further development. References 1.
Farah Ramadan et al, Signaling pathways in Rhabdomyosarcoma invasion and metastasis, Cancer and Metastasis Reviews https://doi.
org/10.
1007/s10555-020-09860-32.
Yanan Liu et al, Dissecting the Role of the FGF19 -FGFR4 Signaling Pathway in Cancer Development and Progression, Front.
Cell Dev.
Biol.
, 20 February 2020 3.
Nagjie Alijaj et al, Novel FGFR4-Targeting Single-Domain Antibodies for Multiple Targeted Therapies against Rhabdomyosarcoma, Cancers 2020, 12, 3313; doi :10.
3390/cancers12113313 Copyright statement welcomes personal forwarding and sharing.
Any other media or website that needs to reprint or quote the copyrighted content of this website must be authorized and marked "Reprinted from: Biopharmaceutical Editor" in a prominent position.
