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Biosimilar

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Biosimilar

Protheragen is specialized in developing biosimilar candidates for the treatment of various cancers, autoimmune and metabolic diseases to cover significant unmet need. Through close collaboration with distinguished scientists, we have been committed to developing biosimilar candidates with promising quality and similarity to original drugs.

With the expiration of patent protection for a range of biologics, there is a rising expectation within the global biopharmaceutical community concerning the construction of biosimilars due to the following reasons. First, the biosimilars are considered a more affordable way to benefit the health of millions of patients, and second, the reduced production cost and lowering of capital investment in manufacturing facility makes biosimilar development a lower-risk way to enter the market and gain credibility as a biopharmaceutical developer. Biosimilars will be rapidly growing in the biopharmaceutical industry.

Pipeline

Biosimilar Generic Name Target Protein Format Major indication Est. Patent Expiration (USA) Est. Patent Expiration (EU)
Pro-S01 Adalimumab TNF-α IgG1κ, human RA, Crohn’s disease 2016 2018
Pro-S02 Etanercept TNF-α; 
TN-β
FcFP; IgG1-Fc fused to TNFR p75 exodomain RA 2028 2014
Pro-S03 Infliximab TNF-α IgG1κ, chimeric RA, Crohn’s disease 2013 2014
Pro-S04 Rituximab CD20 IgG1κ, chimeric NHL, RA 2018 2015
Pro-S05 Bevacizumab  VEGF IgG1κ, humanized Colorectal cancer 2019 2018
Pro-S06 Trastuzumab HER2/Neu IgG1κ, humanized Breast cancer 2019 2014

Pro-S01, Biosimilar of Adalimumab

Adalimumab, a monoclonal antibody that targets tumor necrosis factor (TNF), is marketed as a treatment for a variety of conditions caused or exacerbated by TNF in the body.

The protein format of adalimumab is a full-human IgG1 kappa antibody. Binding specifically to TNF-alpha (TNF-α), adalimumab can block the interaction of TNF-α with TNF receptors on cells. TNF, a potent pro-inflammatory cytokine, is generated as a precursor transmembrane protein by cells such as macrophages, lymphocytes, and vascular endothelial cells. After processing, a soluble form of TNF is released. Adalimumab has been shown to exert its biological effects through antibody-dependent cell-mediated cytotoxicity, complement-mediated cytotoxicity, apoptosis, and cell cycle arrest.

Adalimumab was first approved in the United States in December 2002 as a treatment for rheumatoid arthritis (RA), and it received subsequent approvals for the treatment of Crohn’s disease, juvenile idiopathic and psoriatic arthritis, ankylosing spondylitis, ulcerative colitis and psoriasis. The patents are expired in the US and EU in 2016-2018.

Pro-S02, Biosimilar of Etanercept

Etanercept is the first and most widely known Fc fusion protein product (FcFP). Proteins that are constructed by fusing the Fc domain of an IgG to a receptor protein, cytokine, peptide, scFv, or domain antibody are known as Fc fusion proteins (FcFPs). The etanercept is an exemplified FcFP, in which the human-soluble TNF receptor (TNFR2) p75 exodomain was fused to an Fc domain. The Fc-fusion structure of etanercept confer longer half-life on the fusion protein, achieving a half-life in humans of about 100 hours. Moreover, due to the incorporation of p75 as the binding domain, etanercept binds to both TNF-α and TNF-β, a factor that differentiates it from infliximab, adalimumab, golimumab, and certolizumab pegol, all of which bind only TNF-α.

Etanercept was approved by the FDA in 1998, making it the first FcFP to be approved for marketing. The major indication of etanercept is for the treatment of rheumatoid arthritis, psoriasis, and several other inflammation-related conditions.

Pro-S03, Biosimilar of Infliximab

Infliximab was developed as a potential therapeutic agent for various inflammatory chronic diseases that are believed to be driven by the proinflammatory cytokine tumor necrosis factor alpha (TNFα).

As a chimeric antibody, infliximab was genetically engineered by fusing the variable region of the murine antibody A2 that binds with high selectivity and specificity human TNFα to the constant region of human immunoglobulin G1κ (IgG1κ) using recombinant DNA technology. It had been expected that the chimeric antibody had a better immunogenic and pharmacokinetic profile than the murine antibody.

Infliximab binds the soluble TNF-α homotrimer and its membrane-bound precursor to neutralizes the function of TNF-α. The major indication of infliximab is for the treatment of chronic inflammatory conditions, including rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis. Infliximab was first approved in the USA in 1998, and currently, several biosimilars have been approved in the EU, Japan, and USA.

Pro-S04, Biosimilar of Rituximab

Rituximab, the first chimeric IgG in the market, is a genetically engineered human/mouse chimeric monoclonal antibody that is specific for the CD20 antigen on the surface of B cells. It is a fusion of the light- and heavy-chain variable (antigen-binding) domains of 2B8 (a murine monoclonal anti-CD20 antibody) and human kappa light-chain and gamma 1 heavy-chain constant regions chimeric monoclonal antibody produced by recombinant technology.

Binding to its target CD20 antigen, rituximab functions to kill and deplete the targeted B cell by the human effector mechanisms. CD20 is a transmembrane surface antigen, which is expressed only by B-cell precursors and mature B cells. This antigen appears to be involved in the regulation of growth and differentiation of B lymphocyte. Further, CD20 could play an important role in the influx of calcium across cell membranes, sustaining intracellular calcium concentration and allowing activation of B cells.

The major indication of rituximab is for the treatment of non-Hodgkin’s lymphoma (B-cell lymphoma) and chronic lymphocytic leukemia (CLL). Rituximab was approval by American and European regulatory authorities in 1997 and 1998, respectively.

Pro-S05, Biosimilar of Bevacizumab

Bevacizumab, a humanized immunoglobulin G1κ (IgG1κ) antibody targeting human vascular endothelial growth factor A (VEGF-A), inhibits angiogenesis by blocking VEGF-A from interacting with its receptors, Flt-1 (VEGFR-1) and kinase insert domain receptor (KDR, VEGFR-2), on the surface of endothelial cells. Neutralization of these ligand/receptor interactions has downstream effects on vascular permeability, patterning, and development in tumors. Bevacizumab has been shown to block binding of both major isoforms, VEGF-121 and VEGF-165 that result from alternative splicing or proteolytic cleavage of VEGF-A. Additionally, bevacizumab has been shown to bind VEGF-165b, an antiangiogenic form of VEGF-A that has the identical length of VEGF-165 but differs in the C-terminal amino acid sequence.

The major indication of Bevacizumab is for the treatment of solid tumors, including CRC, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), breast cancer, ovarian cancer, and glioblastoma.

Bevacizumab received its first marketing approval in 2004 in USA for the treatment of metastatic CRC in combination with chemotherapy.

Pro-S06, Biosimilar of Trastuzumab

Trastuzumab, a humanized antibody with 5% murine sequence, has been shown to markedly inhibit the growth of breast tumors. The target of trastuzumab is the Human epidermal growth factor receptor 2 (HER2). HER2 is a member of the epidermal growth factor receptor (EGFR/ErbB) family, and is overexpressed in approximately 20–30% of breast cancers. This is associated with aggressive tumor behavior and denotes a poorer prognosis, with Her2-positive patients having a median survival of 3 years compared to 6–7 years for those who are negative.

Trastuzumab directly bind to the extracellular domain of HER2, and is considered to activate immune-mediated response, such as the antibody-dependent cell-mediated cytotoxicity (ADCC) effect caused by the interaction of the Fc domain of trastuzumab and the Fc gamma Receptor on natural killer (NK) cells.

Approval was granted by the US Food and Drug Administration (FDA) in September 1998 and by the European Medicines Agency in September 2000 for the use of trastuzumab in women with HER2-positive MBC, making the trastuzumab the first commercially available mAb-based therapy for the treatment of breast cancer. Trastuzumab is currently available in more than 150 countries worldwide.

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