Cargando…

A Broad-Based Characterization of a Cell-Penetrating, Single Domain Camelid Bi-Specific Antibody Monomer That Targets STAT3 and KRAS Dependent Cancers

STAT3 and KRAS regulate cell proliferation, survival, apoptosis, cell migration, and angiogenesis. Aberrant expression of STAT3 and mutant active forms of KRAS have been well-established in the induction and maintenance of multiple cancers. STAT3 and KRAS mutant proteins have been considered anti-ca...

Descripción completa

Detalles Bibliográficos
Autores principales: Singh, Sunanda, Murillo, Genoveva, Richner, Justin, Singh, Samara P., Berleth, Erica, Kumar, Vijay, Mehta, Rajendra, Ramiya, Vijay, Parihar, Ashutosh S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9323098/
https://www.ncbi.nlm.nih.gov/pubmed/35886918
http://dx.doi.org/10.3390/ijms23147565
_version_ 1784756466884804608
author Singh, Sunanda
Murillo, Genoveva
Richner, Justin
Singh, Samara P.
Berleth, Erica
Kumar, Vijay
Mehta, Rajendra
Ramiya, Vijay
Parihar, Ashutosh S.
author_facet Singh, Sunanda
Murillo, Genoveva
Richner, Justin
Singh, Samara P.
Berleth, Erica
Kumar, Vijay
Mehta, Rajendra
Ramiya, Vijay
Parihar, Ashutosh S.
author_sort Singh, Sunanda
collection PubMed
description STAT3 and KRAS regulate cell proliferation, survival, apoptosis, cell migration, and angiogenesis. Aberrant expression of STAT3 and mutant active forms of KRAS have been well-established in the induction and maintenance of multiple cancers. STAT3 and KRAS mutant proteins have been considered anti-cancer targets; however, they are also considered to be clinically “undruggable” intracellular molecules, except for KRAS(G12C). Here we report a first-in-class molecule, a novel, single domain camelid VHH antibody (15 kDa), SBT-100, that binds to both STAT3 and KRAS and can penetrate the tumor cell membrane, and significantly inhibit cancer cell growth. Additionally, SBT-100 inhibits KRAS GTPase activity and downstream phosphorylation of ERK in vitro. In addition, SBT-100 inhibits the growth of multiple human cancers in vitro and in vivo. These results demonstrate the feasibility of targeting hard-to-reach aberrant intracellular transcription factors and signaling proteins simultaneously with one VHH to improve cancer therapies.
format Online
Article
Text
id pubmed-9323098
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-93230982022-07-27 A Broad-Based Characterization of a Cell-Penetrating, Single Domain Camelid Bi-Specific Antibody Monomer That Targets STAT3 and KRAS Dependent Cancers Singh, Sunanda Murillo, Genoveva Richner, Justin Singh, Samara P. Berleth, Erica Kumar, Vijay Mehta, Rajendra Ramiya, Vijay Parihar, Ashutosh S. Int J Mol Sci Article STAT3 and KRAS regulate cell proliferation, survival, apoptosis, cell migration, and angiogenesis. Aberrant expression of STAT3 and mutant active forms of KRAS have been well-established in the induction and maintenance of multiple cancers. STAT3 and KRAS mutant proteins have been considered anti-cancer targets; however, they are also considered to be clinically “undruggable” intracellular molecules, except for KRAS(G12C). Here we report a first-in-class molecule, a novel, single domain camelid VHH antibody (15 kDa), SBT-100, that binds to both STAT3 and KRAS and can penetrate the tumor cell membrane, and significantly inhibit cancer cell growth. Additionally, SBT-100 inhibits KRAS GTPase activity and downstream phosphorylation of ERK in vitro. In addition, SBT-100 inhibits the growth of multiple human cancers in vitro and in vivo. These results demonstrate the feasibility of targeting hard-to-reach aberrant intracellular transcription factors and signaling proteins simultaneously with one VHH to improve cancer therapies. MDPI 2022-07-08 /pmc/articles/PMC9323098/ /pubmed/35886918 http://dx.doi.org/10.3390/ijms23147565 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Singh, Sunanda
Murillo, Genoveva
Richner, Justin
Singh, Samara P.
Berleth, Erica
Kumar, Vijay
Mehta, Rajendra
Ramiya, Vijay
Parihar, Ashutosh S.
A Broad-Based Characterization of a Cell-Penetrating, Single Domain Camelid Bi-Specific Antibody Monomer That Targets STAT3 and KRAS Dependent Cancers
title A Broad-Based Characterization of a Cell-Penetrating, Single Domain Camelid Bi-Specific Antibody Monomer That Targets STAT3 and KRAS Dependent Cancers
title_full A Broad-Based Characterization of a Cell-Penetrating, Single Domain Camelid Bi-Specific Antibody Monomer That Targets STAT3 and KRAS Dependent Cancers
title_fullStr A Broad-Based Characterization of a Cell-Penetrating, Single Domain Camelid Bi-Specific Antibody Monomer That Targets STAT3 and KRAS Dependent Cancers
title_full_unstemmed A Broad-Based Characterization of a Cell-Penetrating, Single Domain Camelid Bi-Specific Antibody Monomer That Targets STAT3 and KRAS Dependent Cancers
title_short A Broad-Based Characterization of a Cell-Penetrating, Single Domain Camelid Bi-Specific Antibody Monomer That Targets STAT3 and KRAS Dependent Cancers
title_sort broad-based characterization of a cell-penetrating, single domain camelid bi-specific antibody monomer that targets stat3 and kras dependent cancers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9323098/
https://www.ncbi.nlm.nih.gov/pubmed/35886918
http://dx.doi.org/10.3390/ijms23147565
work_keys_str_mv AT singhsunanda abroadbasedcharacterizationofacellpenetratingsingledomaincamelidbispecificantibodymonomerthattargetsstat3andkrasdependentcancers
AT murillogenoveva abroadbasedcharacterizationofacellpenetratingsingledomaincamelidbispecificantibodymonomerthattargetsstat3andkrasdependentcancers
AT richnerjustin abroadbasedcharacterizationofacellpenetratingsingledomaincamelidbispecificantibodymonomerthattargetsstat3andkrasdependentcancers
AT singhsamarap abroadbasedcharacterizationofacellpenetratingsingledomaincamelidbispecificantibodymonomerthattargetsstat3andkrasdependentcancers
AT berletherica abroadbasedcharacterizationofacellpenetratingsingledomaincamelidbispecificantibodymonomerthattargetsstat3andkrasdependentcancers
AT kumarvijay abroadbasedcharacterizationofacellpenetratingsingledomaincamelidbispecificantibodymonomerthattargetsstat3andkrasdependentcancers
AT mehtarajendra abroadbasedcharacterizationofacellpenetratingsingledomaincamelidbispecificantibodymonomerthattargetsstat3andkrasdependentcancers
AT ramiyavijay abroadbasedcharacterizationofacellpenetratingsingledomaincamelidbispecificantibodymonomerthattargetsstat3andkrasdependentcancers
AT pariharashutoshs abroadbasedcharacterizationofacellpenetratingsingledomaincamelidbispecificantibodymonomerthattargetsstat3andkrasdependentcancers
AT singhsunanda broadbasedcharacterizationofacellpenetratingsingledomaincamelidbispecificantibodymonomerthattargetsstat3andkrasdependentcancers
AT murillogenoveva broadbasedcharacterizationofacellpenetratingsingledomaincamelidbispecificantibodymonomerthattargetsstat3andkrasdependentcancers
AT richnerjustin broadbasedcharacterizationofacellpenetratingsingledomaincamelidbispecificantibodymonomerthattargetsstat3andkrasdependentcancers
AT singhsamarap broadbasedcharacterizationofacellpenetratingsingledomaincamelidbispecificantibodymonomerthattargetsstat3andkrasdependentcancers
AT berletherica broadbasedcharacterizationofacellpenetratingsingledomaincamelidbispecificantibodymonomerthattargetsstat3andkrasdependentcancers
AT kumarvijay broadbasedcharacterizationofacellpenetratingsingledomaincamelidbispecificantibodymonomerthattargetsstat3andkrasdependentcancers
AT mehtarajendra broadbasedcharacterizationofacellpenetratingsingledomaincamelidbispecificantibodymonomerthattargetsstat3andkrasdependentcancers
AT ramiyavijay broadbasedcharacterizationofacellpenetratingsingledomaincamelidbispecificantibodymonomerthattargetsstat3andkrasdependentcancers
AT pariharashutoshs broadbasedcharacterizationofacellpenetratingsingledomaincamelidbispecificantibodymonomerthattargetsstat3andkrasdependentcancers