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Inter-individual genomic variations have recently become evident with advances in sequencing techniques and genome-wide array comparative genomic hybridization. Among such variations single nucleotide polymorphisms (SNPs) are widely studied and better defined because of availability of large-scale detection platforms. However, insertion–deletions, inversions, copy-number variations (CNVs) also populate our genomes. The large structural variations (>3 Mb) have been known for past 20 years, however, their link to health and disease remain ill-defined. CNVs are defined as the segment of DNA >1 kb in size, and compared with reference genome vary in its copy number. All these types of genomic variations are bound to have vital role in disease susceptibility and drug response. In this review, the discussion is confined to CNVs and their link to health, diseases and drug response. There are several CNVs reported till date, which have important roles in an individual's susceptibility to several complex and common disorders. This review compiles some of these CNVs and analyzes their involvement in diseases in different populations, analyses available evidence and rationalizes their involvement in the development of disease phenotype. Combined with SNP, additional genomic variations including CNV, will provide better correlations between individual genomic variations and health.

Cell surface protein, CD20, is extensively expressed on the surface of B cells. Antibodies targeting CD20 protein are being used to treat B-cell malignancies and B-cell mediated autoimmune diseases. Considering the cost of therapy with innovator monoclonal antibodies for these diseases, development of biosimilar products for the treatment of such diseases provides affordable solution to rising healthcare costs. Reference products of rituximab (six batches) were procured and stored as per manufacturer's instructions. Cell lines used in bioassay were procured from American Type Culture Collection and all other reagents used for analysis were of analytical grade. Primary structure was studied by intact mass analysis, peptide fingerprinting, peptide mass fingerprinting and sequence coverage analysis. Higher order structure was studied by circular dichroism, ultraviolet-visible spectroscopy, fluorescence spectroscopy, and disulfide bridge analysis. Different isoforms of reference product and SB-02 were identified using capillary isoelectric focusing and capillary zone electrophoresis. Glycosylation was studied by N-glycan mapping using LC-ESI-MS, point of glycosylation, released glycan analysis using ultra performance liquid chromatography (UPLC). Product related impurities such as oligomer content analysis and oxidized impurities were studied using size exclusion chromatography and reverse phase high performance liquid chromatography, respectively. Here, we report physicochemical and biological characterizations of Sun Pharma's proposed biosimilar (SB-02) to rituximab, a monoclonal anti-CD20 antibody approved for the treatment of non-Hodgkin's lymphoma and chronic lymphocytic leukemia. SB-02 and rituximab exhibited indistinguishable primary as well as higher-order structure upon analyzing with the array of analytical and extended characterization methods according to statistical methods. The molecule also displayed comparability to reference product in post-translational modifications and charge heterogeneity. In functional bioassays, SB-02 demonstrated comparable potency with respect to reference product. Our results indicate highly similar quality profile between SB-02 and rituximab.

Doc number: P50

Objectives: Copy number variations (CNV) are important source of human genetic variation, found to be widely prevalent than what was initially predicted. The involvement of CNVs in disease susceptibility and drug response is well reported in other populations but has not been studied to a larger extent in Indian population. The aim of the present study was to evaluate the distribution of copy number variable genes in Indian population and their link, if any, to health, disease and drug response along with development of a comprehensive resource of CNV frequency distribution among different populations. Methods: A total of 100 280 healthy controls and in variable number of patients from Indian population were genotyped. Genotyping of the copy number (CN) variable genes was carried by PCR-based methodologies (long range PCR, real-time PCR and PRT assay). Results: An indicative correlation with disease susceptibility and significant (p < 0.05) difference in the frequency distribution of the CNV variants was observed in our study. MTUS1 deletion variant was found to be significantly (p = 0.0207) associated with a decreased risk to breast cancer. A significant association between CCL3L1 copy number and risk to HIV-1 was also observed. The inter-ethnic comparison of CCL3L1 gene copy number frequency demonstrated significant difference worldwide, being highest in Africans. The common deletion frequency comprising LCE3B and LCE3C genes was found to be highest in European and American populations. The frequency of FCGR3B CN < 2 was found comparatively higher in Indians, Americans and Africans as compared to European Caucasians. Thus, inter-ethnic differences were observed among populations, highlighting varied frequency distribution pattern based on their distinct geographical location. Conclusion: This is our first attempt to create a comprehensive map of the frequency distribution of CNVs and its association to disease susceptibility in Indian population. This varied worldwide distribution can thus be relevant from clinical or evolutionary point of view in future.