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.
Authors: Elkazzaz mahmoud , Haikal Abdullah , Shamkh Israa M , Ahmed Amr 
Published: September 2022

Abstract
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