Engineering the hinge region of human IgG1 Fc-fused bispecific antibodies to improve fragmentation resistance

Suzuki, Sho; Annaka, Hiroaki; Konno, S.; Kumagai, Izumi; Asano, Ryutaro

doi:10.1038/s41598-018-35489-y

Cited by 22 publications

(16 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Fc fusion protein, in which Fc domain of IgG isotypes is joined to recombinant protein, is considered as a promising platform for novel peptide agents ( 17 ). Drugs derived from peptide often suffer from short serum half-life owing to their low molecular mass and fast renal clearance ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

RETRACTED: The Design, Characterizations, and Tumor Angiogenesis Inhibition of a Multi-Epitope Peptibody With bFGF/VEGFA

et al. 2020

View full text Add to dashboard Cite

Tumor angiogenesis is dependent on growth factors, and inhibition of their pathways is one of the promising strategies in cancer therapy. However, resistance to single pathway has been a great concern in clinical trials so that it necessitates multiple targetable factors for developing tumor angiogenesis inhibitors. Moreover, the strategy of Fc fusion protein is an attractive platform for novel peptide agents, which gains increasing importance with FDA approval because of better immunogenicity and stability. Here, we applied the Fc fusion protein concept to bFGF/VEGFA pathways and designed a multi-epitope Peptibody with immunogenic peptides derived from human bFGF and VEGFA sequences. Immunization with Peptibody could elicit high-titer anti-bFGF and anti-VEGFA antibodies, activate T cells, and induce Th1/Th2-type cytokines. In in vitro experiments, the isolated anti-Peptibody antibody inhibited the proliferation and migration of A549 cells and human umbilical vein endothelial cells (HUVECs) by decreasing the MAPK/Akt/mTOR signal pathways. In the murine tumor model, pre-immunization with Peptibody suppressed the tumor growth and neovascularization of lung cancer by decreasing the production of bFGF/VEGFA/PDGF, the MAPK/Akt/mTOR signal pathways, and the activation of suppressive cells in tumor sites. Further, the biological characterizations of the recombinant Peptibody were investigated systematically, including protein primary structure, secondary structure, stability, and toxicity. Collectively, the results highlighted the strategy of bFGF/VEGFA pathways and Fc fusion protein in suppressing tumor progression and angiogenesis, which emphasized the potential of multiple targetable factors for producing enduring clinical responses in tumor patients.

show abstract

Section: Introductionmentioning

confidence: 99%

RETRACTED: The Design, Characterizations, and Tumor Angiogenesis Inhibition of a Multi-Epitope Peptibody With bFGF/VEGFA

et al. 2020

View full text Add to dashboard Cite

show abstract

“…We selected three antigenic epitopes from human bFGF and three antigenic epitopes from human VEGFA through phage display and bioinformatic prediction [12]. Moreover, Fc domain of IgG can fuse to recombinant peptides, which is well-known as a promising platform with FDA approval [13]. The low molecular weight and fast renal clearance will cut down the serum half-life of peptide drugs [14].…”

Section: Introductionmentioning

confidence: 99%

Large‐scale production, purification, and function of a tumor multi‐epitope vaccine: Peptibody with bFGF/VEGFA

Zhang

Jiang

Chen

et al. 2020

Engineering in Life Sciences

View full text Add to dashboard Cite

In tumor tissue, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor A (VEGFA) promote tumorigenesis by activating angiogenesis, but targeting single factor may produce drug resistance and compensatory angiogenesis. The Peptibody with bFGF/VEGFA was designed to simultaneously blockade these two factors. We were aiming to produce this Fc fusion protein in a large scale. The biological characterizations of Peptibody strains were identified as Escherichia coli and the fermentation mode was optimized in the shake flasks and 10‐L bioreactor. The fermentation was scaled up to 100 L, with wet cell weight (WCW) 126 g/L, production 1.41 g/L, and productivity 0.35 g/(L·h) of IPTG induction. The target protein was isolated by cation‐exchange, hydrophobic and Protein A chromatography, with total recovery of 60.28% and HPLC purity of 86.71%. The host cells protein, DNA, and endotoxin residues were within the threshold. In mouse model, immunization of Peptibody vaccine could significantly suppressed the tumor growth and angiogenesis, with inhibition rate of 57.73 and 39.34%. The Peptibody vaccine could elicit high‐titer anti‐bFGF and anti‐VEGFA antibodies, which inhibited the proliferation and migration of Lewis lung cancer cell cells by decreasing the Akt/MAPK signal pathways. Therefore, the Peptibody with bFGF/VEGFA might be used as a therapeutic tumor vaccine. The large‐scale process we developed could support its industrial production and pre‐clinical study in the future.

show abstract

“…Another BCMAxCD3 bispecific antibody teclistamab (JNJ-64007957) has been shown to be well-tolerated in a monkey model [ 70 ] and has been included in two clinical trials in RRMM—a phase I dose-escalation study (NCT03145181) and a phase I trial in combination with subcutaneous daratumumab (NCT04108195) plus the CD3xGPRC5D bispecific construct talquetamab. PF-06863135 (PF-3135), a BCMA-CD3 formatted BiTE derived from hinge-mutation engineering of an IgG2a backbone, is presently in a phase I trial (NCT03269136) for RRMM [ 71 , 72 , 73 ]. Another humanized IgG T-cell engager under clinical scrutiny is CC-93269 (NCT03486067), whose two arms bind in a 2 + 1 format—bivalently to BCMA and monovalently to CD3ε [ 74 ].…”

Section: T-cell-engaging Bispecific Antibodiesmentioning

confidence: 99%

B-Cell Maturation Antigen (BCMA) as a Target for New Drug Development in Relapsed and/or Refractory Multiple Myeloma

Abramson

2020

IJMS

View full text Add to dashboard Cite

During the past two decades there has been a major shift in the choice of agents to treat multiple myeloma, whether newly diagnosed or in the relapsed/refractory stage. The introduction of new drug classes, such as proteasome inhibitors, immunomodulators, and anti-CD38 and anti-SLAMF7 monoclonal antibodies, coupled with autologous stem cell transplantation, has approximately doubled the disease’s five-year survival rate. However, this positive news is tempered by the realization that these measures are not curative and patients eventually relapse and/or become resistant to the drug’s effects. Thus, there is a need to discover newer myeloma-driving molecular markers and develop innovative drugs designed to precisely regulate the actions of such putative targets. B cell maturation antigen (BCMA), which is found almost exclusively on the surfaces of malignant plasma cells to the exclusion of other cell types, including their normal counterparts, has emerged as a specific target of interest in this regard. Immunotherapeutic agents have been at the forefront of research designed to block BCMA activity. These agents encompass monoclonal antibodies, such as the drug conjugate belantamab mafodotin; bispecific T-cell engager strategies exemplified by AMG 420; and chimeric antigen receptor (CAR) T-cell therapeutics that include idecabtagene vicleucel (bb2121) and JNJ-68284528.

show abstract

Engineering the hinge region of human IgG1 Fc-fused bispecific antibodies to improve fragmentation resistance

Cited by 22 publications

References 50 publications

RETRACTED: The Design, Characterizations, and Tumor Angiogenesis Inhibition of a Multi-Epitope Peptibody With bFGF/VEGFA

RETRACTED: The Design, Characterizations, and Tumor Angiogenesis Inhibition of a Multi-Epitope Peptibody With bFGF/VEGFA

Large‐scale production, purification, and function of a tumor multi‐epitope vaccine: Peptibody with bFGF/VEGFA

B-Cell Maturation Antigen (BCMA) as a Target for New Drug Development in Relapsed and/or Refractory Multiple Myeloma

Contact Info

Product

Resources

About