A novel peptide therapeutic targeting PD1 immune checkpoint with equipotent antagonism of both ligands and a potential for better management of immune-related adverse events

Sasikumar, Pottayil G.; Shrimali, Rajeev; Adurthi, Sreenivas; Ramachandra, Raghuveer K.; Satyam, Leena K.; Dhudashiya, Amit A.; Samiulla, Dodheri S.; Sunilkumar, K B; Ramachandra, Murali

doi:10.1186/2051-1426-1-s1-o24

Cited by 15 publications

(7 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It was recently reported that immune checkpoint inhibitors with a half-life of more than 15–20 days and a target binding rate of more than 70% after several months of treatment caused a series of severe side effects in clinical trials. 44 Although the mechanism has not been fully elucidated, some researchers speculated that the severe side effects may be associated with the long half-life of such drugs, suggesting that diabodies with a short half-life might decrease the risk of adverse reactions. In mouse models, no obvious difference was observed between the diabody-treated groups and the control group in terms of activity, weight, and eating behavior.…”

Section: Discussionmentioning

confidence: 99%

Development of bispecific anti-c-Met/PD-1 diabodies for the treatment of solid tumors and the effect of c-Met binding affinity on efficacy

et al. 2021

View full text Add to dashboard Cite

Although the blockade of the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/ PD-L1) pathway has become a promising treatment strategy for several types of cancers, the constitutive activation of c-Met in tumors may cause a low overall response rate to PD-1 inhibitors. Increasing evidence indicates that the dual inhibition of c-Met and PD-1 could improve the efficacy of anti-PD-1/PD-L1 monoclonal antibodies for tumor immunotherapy. In this study, we developed two bispecific singlechain diabodies targeting c-Met and PD-1 for the treatment of solid tumors based on protein homology modeling, and we identified that the binding affinity of diabody-mp to c-Met was 50-folds higher than that of diabody-pm. The results of in vitro studies revealed that both diabodies suppressed HGF-induced proliferation, migration, and invasion of tumor cells, inhibiting the activation of c-Met signaling by antagonizing HGF binding to c-Met. Moreover, they promoted T cell activation by blocking the PD-1 pathway, mediating tumor cellular cytotoxicity through T cell engagement. In vivo studies with mice models demonstrated that diabody-mp exhibited higher therapeutic efficacy than other structural antibodies, greatly enhancing the survival of c-Met-positive tumor-bearing mice compared to single or combined c-Met and PD-1 blockade therapy. Furthermore, diabody-mp, which had a higher c-Met binding affinity, showed better anti-tumoral activity than diabody-pm, which had a lower c-Met binding affinity. In conclusion, bispecific anti-PD-1/c-Met diabody-mp, with high c-Met-associated affinity, inhibited tumor growth by activating T cells, suggesting its therapeutic potential for c-Met-positive solid tumors.

show abstract

Section: Discussionmentioning

confidence: 99%

Development of bispecific anti-c-Met/PD-1 diabodies for the treatment of solid tumors and the effect of c-Met binding affinity on efficacy

et al. 2021

View full text Add to dashboard Cite

show abstract

“…AUNP‐12 has been proven to perform well on the antagonism of PD‐1 by subcutaneous administration and showed a safe toxicological profile. [ 77 ] Although peptide antagonists have better tumor penetration properties, short‐term retention in tumor tissues limits their application. Therefore, the authors applied subcutaneous injection of AUNP‐12‐loaded phospholipid‐based phase separation gel (PPSG) near the tumor to achieve long‐term sustained release of the antagonist.…”

Section: Strategies Of Bacteria‐based Cancer Immunotherapymentioning

confidence: 99%

Bacteria‐Based Cancer Immunotherapy

et al. 2021

View full text Add to dashboard Cite

In the past decade, bacteria‐based cancer immunotherapy has attracted much attention in the academic circle due to its unique mechanism and abundant applications in triggering the host anti‐tumor immunity. One advantage of bacteria lies in their capability in targeting tumors and preferentially colonizing the core area of the tumor. Because bacteria are abundant in pathogen‐associated molecular patterns that can effectively activate the immune cells even in the tumor immunosuppressive microenvironment, they are capable of enhancing the specific immune recognition and elimination of tumor cells. More attractively, during the rapid development of synthetic biology, using gene technology to enable bacteria to be an efficient producer of immunotherapeutic agents has led to many creative immunotherapy paradigms. The combination of bacteria and nanomaterials also displays infinite imagination in the multifunctional endowment for cancer immunotherapy. The current progress report summarizes the recent advances in bacteria‐based cancer immunotherapy with specific foci on the applications of naive bacteria‐, engineered bacteria‐, and bacterial components‐based cancer immunotherapy, and at the same time discusses future directions in this field of research based on the present developments.

show abstract

“…Unfortunately, despite impressive clinical activity, severe immune‐related adverse events (irAEs) due to the disruption of immune self‐tolerance have become evident in certain cases. Sustained target inhibition as a result of a long half‐life and strong target occupancy for months likely contribute to the irAEs observed in the clinic with antibodies against immune checkpoint proteins …”

Section: Checkpoint Inhibitorsmentioning

confidence: 99%

Cancer Immunotherapy: Selected Targets and Small‐Molecule Modulators

Weinmann

2016

ChemMedChem

107

View full text Add to dashboard Cite

There is a significant amount of excitement in the scientific community around cancer immunotherapy, as this approach has renewed hope for many cancer patients owing to some recent successes in the clinic. Currently available immuno-oncology therapeutics under clinical development and on the market are mostly biologics (antibodies, proteins, engineered cells, and oncolytic viruses). However, modulation of the immune system with small molecules offers several advantages that may be complementary and potentially synergistic to the use of large biologicals. Therefore, the discovery and development of novel small-molecule modulators is a rapidly growing research area for medicinal chemists working in cancer immunotherapy. This review provides a brief introduction into recent trends related to selected targets and pathways for cancer immunotherapy and their small-molecule pharmacological modulators.

show abstract

A novel peptide therapeutic targeting PD1 immune checkpoint with equipotent antagonism of both ligands and a potential for better management of immune-related adverse events

Abstract: Sasikumar et al.: A novel peptide therapeutic targeting PD1 immune checkpoint with equipotent antagonism of both ligands and a potential for better management of immune-related adverse events.

Cited by 15 publications

References 0 publications

Development of bispecific anti-c-Met/PD-1 diabodies for the treatment of solid tumors and the effect of c-Met binding affinity on efficacy

Development of bispecific anti-c-Met/PD-1 diabodies for the treatment of solid tumors and the effect of c-Met binding affinity on efficacy

Bacteria‐Based Cancer Immunotherapy

Cancer Immunotherapy: Selected Targets and Small‐Molecule Modulators

Contact Info

Product

Resources

About