A Multispecific Checkpoint Inhibitor Nanofitin with a Fast Tumor Accumulation Property and Anti-Tumor Activity in Immune Competent Mice
Immune checkpoint inhibitors have revolutionized cancer treatment but remain limited by on-target/off-tumor effects that narrow their therapeutic window. Although PD-L1 is mainly expressed by tumor cells, these effects could reduce bloodstream availability and tumor accumulation of PD-L1 inhibitors....
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-03-01
|
| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/15/4/471 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850155911535919104 |
|---|---|
| author | Perrine Jacquot Javier Muñoz-Garcia Antoine Léger Antoine Babuty Manon Taupin Laurie Fradet Fabio Dupont Marie-Françoise Heymann Mathieu Cinier Dominique Heymann |
| author_facet | Perrine Jacquot Javier Muñoz-Garcia Antoine Léger Antoine Babuty Manon Taupin Laurie Fradet Fabio Dupont Marie-Françoise Heymann Mathieu Cinier Dominique Heymann |
| author_sort | Perrine Jacquot |
| collection | DOAJ |
| description | Immune checkpoint inhibitors have revolutionized cancer treatment but remain limited by on-target/off-tumor effects that narrow their therapeutic window. Although PD-L1 is mainly expressed by tumor cells, these effects could reduce bloodstream availability and tumor accumulation of PD-L1 inhibitors. Enhancing tumor specificity through bispecific proteins targeting two tumor-associated antigens offers a promising strategy. This study evaluated a bispecific Nanofitin, B10–B11, targeting PD-L1 and EGFR. In vitro, B10–B11 efficiently bound to human A431 and murine CT26 cell lines, validating these models for in vivo studies. Nanofitins’ accumulation in tumors and their anti-tumor efficacy were assessed, respectively, in A431 xenograft and CT26 immunocompetent mouse models. In both experiments, B10–B11 was compared with its albumin binding fused counterpart (B10–B11-ABNF). This study showed that the dual-targeting approach with the bispecific Nanofitin enhanced in vitro PD-L1 neutralization compared to the monomeric form and led to in vivo anti-tumor activity evidenced by reduced tumor growth and increased CD3+ T cells and F4/80+ macrophages in tumors. This activity was further correlated with Nanofitin’s tumor accumulation at 7 h post-injection, which was highest for the B10–B11-ABNF. This study highlights the potential of bispecific Nanofitins, particularly with albumin binding to enable rapid and uniform tumor accumulation of effective PD-L1 immunotherapy. |
| format | Article |
| id | doaj-art-e0f48f93d57b47d3a75ac535bb157ff0 |
| institution | OA Journals |
| issn | 2218-273X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj-art-e0f48f93d57b47d3a75ac535bb157ff02025-08-20T02:24:45ZengMDPI AGBiomolecules2218-273X2025-03-0115447110.3390/biom15040471A Multispecific Checkpoint Inhibitor Nanofitin with a Fast Tumor Accumulation Property and Anti-Tumor Activity in Immune Competent MicePerrine Jacquot0Javier Muñoz-Garcia1Antoine Léger2Antoine Babuty3Manon Taupin4Laurie Fradet5Fabio Dupont6Marie-Françoise Heymann7Mathieu Cinier8Dominique Heymann9Affilogic SAS, 24 rue de la Rainière, 44300 Nantes, FranceUMR6286, US2B, CNRS, Nantes Université, 44322 Nantes, FranceAffilogic SAS, 24 rue de la Rainière, 44300 Nantes, FranceUMR6286, US2B, CNRS, Nantes Université, 44322 Nantes, FranceResearch Pathology Platform, Institut de Cancérologie de l’Ouest, 44805 Saint-Herblain, FranceUMR6286, US2B, CNRS, Nantes Université, 44322 Nantes, FranceAffilogic SAS, 24 rue de la Rainière, 44300 Nantes, FranceUMR6286, US2B, CNRS, Nantes Université, 44322 Nantes, FranceAffilogic SAS, 24 rue de la Rainière, 44300 Nantes, FranceUMR6286, US2B, CNRS, Nantes Université, 44322 Nantes, FranceImmune checkpoint inhibitors have revolutionized cancer treatment but remain limited by on-target/off-tumor effects that narrow their therapeutic window. Although PD-L1 is mainly expressed by tumor cells, these effects could reduce bloodstream availability and tumor accumulation of PD-L1 inhibitors. Enhancing tumor specificity through bispecific proteins targeting two tumor-associated antigens offers a promising strategy. This study evaluated a bispecific Nanofitin, B10–B11, targeting PD-L1 and EGFR. In vitro, B10–B11 efficiently bound to human A431 and murine CT26 cell lines, validating these models for in vivo studies. Nanofitins’ accumulation in tumors and their anti-tumor efficacy were assessed, respectively, in A431 xenograft and CT26 immunocompetent mouse models. In both experiments, B10–B11 was compared with its albumin binding fused counterpart (B10–B11-ABNF). This study showed that the dual-targeting approach with the bispecific Nanofitin enhanced in vitro PD-L1 neutralization compared to the monomeric form and led to in vivo anti-tumor activity evidenced by reduced tumor growth and increased CD3+ T cells and F4/80+ macrophages in tumors. This activity was further correlated with Nanofitin’s tumor accumulation at 7 h post-injection, which was highest for the B10–B11-ABNF. This study highlights the potential of bispecific Nanofitins, particularly with albumin binding to enable rapid and uniform tumor accumulation of effective PD-L1 immunotherapy.https://www.mdpi.com/2218-273X/15/4/471bispecific Nanofitinprogrammed cell death-ligand 1 (PD-L1)epidermal growth factor receptor (EGFR)on-target/off-tumor effecttumoral accumulation |
| spellingShingle | Perrine Jacquot Javier Muñoz-Garcia Antoine Léger Antoine Babuty Manon Taupin Laurie Fradet Fabio Dupont Marie-Françoise Heymann Mathieu Cinier Dominique Heymann A Multispecific Checkpoint Inhibitor Nanofitin with a Fast Tumor Accumulation Property and Anti-Tumor Activity in Immune Competent Mice Biomolecules bispecific Nanofitin programmed cell death-ligand 1 (PD-L1) epidermal growth factor receptor (EGFR) on-target/off-tumor effect tumoral accumulation |
| title | A Multispecific Checkpoint Inhibitor Nanofitin with a Fast Tumor Accumulation Property and Anti-Tumor Activity in Immune Competent Mice |
| title_full | A Multispecific Checkpoint Inhibitor Nanofitin with a Fast Tumor Accumulation Property and Anti-Tumor Activity in Immune Competent Mice |
| title_fullStr | A Multispecific Checkpoint Inhibitor Nanofitin with a Fast Tumor Accumulation Property and Anti-Tumor Activity in Immune Competent Mice |
| title_full_unstemmed | A Multispecific Checkpoint Inhibitor Nanofitin with a Fast Tumor Accumulation Property and Anti-Tumor Activity in Immune Competent Mice |
| title_short | A Multispecific Checkpoint Inhibitor Nanofitin with a Fast Tumor Accumulation Property and Anti-Tumor Activity in Immune Competent Mice |
| title_sort | multispecific checkpoint inhibitor nanofitin with a fast tumor accumulation property and anti tumor activity in immune competent mice |
| topic | bispecific Nanofitin programmed cell death-ligand 1 (PD-L1) epidermal growth factor receptor (EGFR) on-target/off-tumor effect tumoral accumulation |
| url | https://www.mdpi.com/2218-273X/15/4/471 |
| work_keys_str_mv | AT perrinejacquot amultispecificcheckpointinhibitornanofitinwithafasttumoraccumulationpropertyandantitumoractivityinimmunecompetentmice AT javiermunozgarcia amultispecificcheckpointinhibitornanofitinwithafasttumoraccumulationpropertyandantitumoractivityinimmunecompetentmice AT antoineleger amultispecificcheckpointinhibitornanofitinwithafasttumoraccumulationpropertyandantitumoractivityinimmunecompetentmice AT antoinebabuty amultispecificcheckpointinhibitornanofitinwithafasttumoraccumulationpropertyandantitumoractivityinimmunecompetentmice AT manontaupin amultispecificcheckpointinhibitornanofitinwithafasttumoraccumulationpropertyandantitumoractivityinimmunecompetentmice AT lauriefradet amultispecificcheckpointinhibitornanofitinwithafasttumoraccumulationpropertyandantitumoractivityinimmunecompetentmice AT fabiodupont amultispecificcheckpointinhibitornanofitinwithafasttumoraccumulationpropertyandantitumoractivityinimmunecompetentmice AT mariefrancoiseheymann amultispecificcheckpointinhibitornanofitinwithafasttumoraccumulationpropertyandantitumoractivityinimmunecompetentmice AT mathieucinier amultispecificcheckpointinhibitornanofitinwithafasttumoraccumulationpropertyandantitumoractivityinimmunecompetentmice AT dominiqueheymann amultispecificcheckpointinhibitornanofitinwithafasttumoraccumulationpropertyandantitumoractivityinimmunecompetentmice AT perrinejacquot multispecificcheckpointinhibitornanofitinwithafasttumoraccumulationpropertyandantitumoractivityinimmunecompetentmice AT javiermunozgarcia multispecificcheckpointinhibitornanofitinwithafasttumoraccumulationpropertyandantitumoractivityinimmunecompetentmice AT antoineleger multispecificcheckpointinhibitornanofitinwithafasttumoraccumulationpropertyandantitumoractivityinimmunecompetentmice AT antoinebabuty multispecificcheckpointinhibitornanofitinwithafasttumoraccumulationpropertyandantitumoractivityinimmunecompetentmice AT manontaupin multispecificcheckpointinhibitornanofitinwithafasttumoraccumulationpropertyandantitumoractivityinimmunecompetentmice AT lauriefradet multispecificcheckpointinhibitornanofitinwithafasttumoraccumulationpropertyandantitumoractivityinimmunecompetentmice AT fabiodupont multispecificcheckpointinhibitornanofitinwithafasttumoraccumulationpropertyandantitumoractivityinimmunecompetentmice AT mariefrancoiseheymann multispecificcheckpointinhibitornanofitinwithafasttumoraccumulationpropertyandantitumoractivityinimmunecompetentmice AT mathieucinier multispecificcheckpointinhibitornanofitinwithafasttumoraccumulationpropertyandantitumoractivityinimmunecompetentmice AT dominiqueheymann multispecificcheckpointinhibitornanofitinwithafasttumoraccumulationpropertyandantitumoractivityinimmunecompetentmice |