In Silico Inhibition of Three Cancer Inducing Receptors, IL-6, CTLA-4, and B7-2 by Dostarlimab may explain the 100% Complete Recovery Rate in MMRd Locally Advanced Rectal Cancer seen in Pivotal ‘Immunoablative’ Neoadjuvant Immunotherapy Clinical Trial. A Cancer Therapy Breakthrough.

Dostarlimab is antitumor drug that mainly prescribed for treating endometrial cancer (cancer of the lining of the uterus or womb) that is mismatch repair deficient (dMMR) in patients whose cancer has returned, or it has spread or cannot be removed by surgery. Dostarlimab is a type of humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L2 and PD-L1. Surprisingly, it was showed that a dozen of patients with colorectal cancer (A total of 12 patients) have experienced complete response to this type of treatment after 12 months completion of dostarlimab therapy. A recent clinical trial conducted by researchers at Memorial Sloan Kettering Cancer Center (MSK) has found Dostarlimab to cure 100% of the CRC patients who were given this drug. According to literature, the primary mechanism by which Dostarlimab could achieve this breakthrough is due to its ability to block PD-1(B7-H1). Surprisingly, we insilico, discovered that Dostarlimab exhibited a high binding affinity (329 kcal/mol) with good quality model (LGScore (4.540) to IL-6R and this binding affinity is comparable with its binding affinity to B7-2 receptors (-332.35 kcal/mol) (LGScore(2.540). Moreover, we discovered that Dostarlimab could bind to CTLA-4 with binding affinity (-305.91 kcal/mol). As a result, this means that dostarlimab not only bind with high affinity to B7-2 or BH-3(PD-1) but also to IL-6R and CATLA4. According to our novel results dostarlimab could experimentally inhibit IL-6, CTLA-4 and B7 receptors and this may explain the 100% Remission Rate observed in this small clinical trial and considered as one of its novel mechanisms in treating CR cancer particularly via inhibiting of IL-6 and CATLA4. Docking study of each IL- 6, CTLA-4 and B7-2 receptors and Dostarlimab were carried out using HDOCK server (http://hdock.phys.hust.edu.cn/). The binding mode of Tislelizumab Fab antibody and B7-2, CTLA-4, IL6 proteins which its retrieved form the PDB https://www.rcsb.org/ with accession number (7CGW, 1NCN, 7ELX, 5FUC) respectively CONCLUSIONS Surprisingly, our docking results discovered that Tislelizumab could potentially inhibit three receptors that could implicated in suppressing antitumor immunity and promoting cancer growth and invasion. Herein Tislelizumab was found to bind to IL-6 and B7 (PD-1) with comparable high binding affinities in addition to CATLA4 which is a major factor that inhibit activation of cancer killing T cells. As a result, it's not surprising that Tislelizumab succeeded to cure 100% of the CRC patients who were given this drug because of its triple inhibitory action. Numerous studies have showed that the predominant role of IL-6 in tumor is the promotion of cancer growth via the interaction of IL-6 and its receptor-activated JAKs with following induction/activation of STAT3 through tyrosine phosphorylation driving PD-L1 Y112 phosphorylation. When CTLA-4 is bound to another protein called B7(B7-2), it helps keep T cells from killing other cells, including cancer cells. The immune functions of the B7 family of proteins. B7-1 and B7- 2 molecules expressed on APCs exhibit positive or negative functions via interaction with either cognate stimulatory receptor, CD28, or inhibitory receptor, CTLA-4, respectively. This study paves the way towards understanding the complex mechanism of Dostarlimab in CRC, and may lead to the discovery of new mechanisms of Dostarlimab for different types of cancer