مقالات پذیرفته شده در هفتمین کنگره بین المللی زیست پزشکی
Antibody engineering of Edrecolomab to increase affinity with B7-H3 antigen in colorectal cancer treatment
Antibody engineering of Edrecolomab to increase affinity with B7-H3 antigen in colorectal cancer treatment
sahar shahgholi,1Seyed Mohsen Mir Ismaili,2,*fatemeh sefid,3
1. science and art university, yazd, Iran 2. Associate Professor of Science and Art, Yazd 3. science and art university, yazd, Iran, Shahid Sadoughi University of Medical Sciences and Health Services
Introduction: Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. The majority of CRC cases and deaths attributable to modifiable are caused by risk factors, including diet (29%), physical inactivity (16%), alcohol intake (13%), smoking (11%), and excess body weight (5%) [1]. Angiogenesis also plays an important role in the occurrence and development of CRC[2]. in which VEGFA is a key driver of angiogenesis that is secreted from many types of cells including malignant cells [3]. B7-H3, an important immune checkpoint molecule, was highly expressed in CRC tissues and was involved in immune escape and tumor progression[4]. Targeting angiogenesis is an effective therapeutic strategy for various malignancies, including CRC[5]. Edrecolomab (monoclonal antibody 17-1A) is a murine monoclonal antibody that represents a novel therapeutic approach and has the potential to become a treatment of choice as monotherapy in colon cancer and in combination with chemotherapy colon cancer[6]. Edercolomab has been shown to have improved efficacy and safety in the treatment of various types of cardiovascular, cancer, respiratory, hematology, autoimmune diseases, and infections[7]. Antibodies (Abs) are glycoproteins belonging to the immunoglobulin (Ig) superfamily that are secreted by B cells to identify and neutralize foreign organisms or antigens. monoclonal antibodies (MAbs)comprise two heavy and two light chains and are grouped into different isotypes dependent on which type of heavy chain they contain. Therapeutic monoclonal Abs (mAbs) are typically of the γ-immunoglobulin (or IgG) isotype [8]
structural bioinformatics methods such as homology modelling, protein–protein docking or protein interface prediction are already used for rational antibody design[9].
In this research, by designing a monoclonal antibody and examining its affinity with B7-H3 antigen, we were able to introduce it as an effective therapeutic candidate, in order to reduce angiogenesis in colorectal cancer.
Methods: Edrecolomab monoclonal antibody was obtained from NCBI database at http://www.ncbi.nlm.nih.gov and as well as from Protein Data Bank with PDB ID at https://www. rcsb.org/ was used. The sequence of light and heavy chain with access code M15047.1 Mouse Ig gamma active m RNA from hybridism 17-1A/ as heavy chain and M15046.1 Mouse Ig kappa active m RNA from hybridism 17-1A. chain was selected as light source and antigen sequence with GI access code: 427931085.
he proABC is a web server for predicting the residues in antibody-binding site, which are involved in antigen recognition (http://www.biocomputing.it/proABC). Checking functional amino acids in protein with A Bodybuilder software, the best formats for VH and VL parts can be checked separately [10].
predicted based on solvent accessible surface areas, a new scale for interface propensities, and a cluster algorithm to locate surface exposed areas with high interface propensities with InterProSurf software from our web server at http://curie.utmb.edu/prosurf.html. [11]
SIFT server were used to predict (http://sift.jcvi.org/) whether an amino acid substitution affects protein function. [12]
Docking was performed using HADDOCK 2.2/. This scrutiny was used to determine the interaction and orientation between the two molecules to determine the correct binding between the antigen and the antibodies at http://haddock.science.uu.nl/services/HADDOCK 2.2 [13].
Results: HADDOCK software is a docking method based on the information of complex biomolecule models advances its information based on protein-protein face-to-face regions [14]
After these steps, the structures are classified with the reported software and the best structure is classified in the first cluster. The highest score given by the software represents the affinity of the antibody with the antigen, which was assigned to variant 13 here.
Cluster size from the clustering algorithm is an accurate and scalable method for detecting and predicting protein complexes in a network [15]. identification of repeats and motifs to understand their function at the level of a protein sequence is created by RSMD [16] electrostatic force occurs even before direct protein-protein contact is formed, may cause complex formation [17]. The protein-protein interaction is, in particular, the relationship between the area and the chemical nature of the interaction in binding the antibody to the antigen [18].
Conclusion: According to the results of molecular docking, it showed the binding affinity of Edercolomab antibody and engineered B7-H3 antigen, which was obtained from the reaction between the ligand and the binding site of the antibody. Edercolomab may inhibit the Angiogenic factor of VEGF and can be a good candidate for colorectal cancer treatment.