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

• Published in: International journal of molecular sciences Vol. 23; no. 14; p. 7565
• Main Authors: Singh, Sunanda, Murillo, Genoveva, Richner, Justin, Singh, Samara P., Berleth, Erica, Kumar, Vijay, Mehta, Rajendra, Ramiya, Vijay, Parihar, Ashutosh S.
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 08-07-2022; MDPI
• Subjects: Angiogenesis; Antibodies; Apoptosis; bi-specific; Cancer; Cancer therapies; Cell membranes; Cell proliferation; Cytoplasm; Drug resistance; Immunization; Intracellular; Intracellular signalling; K-Ras protein; Kinases; KRAS; Localization; Mutants; Mutation; PD-L1; Phosphorylation; Proteins; STAT3; Stat3 protein; Transcription factors; Tumors; VEGF; VHH
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23147565

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.