| Autor: |
Toh Y, Wu L, Tu J, Liang Z, Aldana AM, Li L, Wen JJ, Pan S, Julie RH, Hensel ME, Hodo CL, Finch RA, Carmon KS, Liu QJ |
| Jazyk: |
angličtina |
| Zdroj: |
BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 11. Date of Electronic Publication: 2024 Oct 11. |
| DOI: |
10.1101/2024.10.08.616548 |
| Abstrakt: |
Antibody-drug conjugates (ADCs) have emerged as a major modality of targeted cancer therapy, yet no ADC has been approved for colorectal cancer (CRC). LGR4/5/6 (leucine-rich repeat containing, G protein-coupled receptor 4, 5, 6) are three related receptors that are expressed at high levels together or alternately in nearly all cases of CRC. ADCs targeting LGR5 have been shown to have robust anti-tumor potency, but not all CRC cells express LGR5 and LGR5-positive tumor cells may lose LGR5 expression due to cancer cell plasticity. R-spondin 4 (RSPO4) is a natural protein ligand of LGR4/5/6 with high affinity for all three receptors. We fused a mutant form of RSPO4 that retains high affinity binding to LGR4/5/6 to IgG1 Fc to create a peptibody designated R462. Conjugation of R462 with a camptothecin analog (CPT2) at eight drugs per peptibody led to the synthesis of R462-CPT2 that showed highly potent cytotoxic activity in vitro in CRC cell lines expressing any of LG4/5/6. In cell line xenograft and PDX models of CRC, R462-CPT2 demonstrated robust anti-tumor effect. Importantly, R462-CPT2 showed no major adverse effect at therapeutically effective dose levels. These results strongly support the use of RSPO ligand drug-conjugates that target LGR4/5/6 simultaneously for the treatment of CRC. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
