To support the analytical development of biomolecules, such as biopharmaceuticals, biosimilars, and monoclonal antibodies, VelaLabs offers methods in accordance with ICH Q6B guidelines, including method feasibility followed by method qualification and comparability.
The analytical portfolio for antibodies covers the Fab part e.g. target binding by ELISA, SPR, FACS and the Fc related part e.g. Fc gamma receptor binding by SPR, C1q binding by ELISA and biological assays that are related to the mode of action e.g. anti-proliferation, CDC, ADCC, apoptosis. For Fab-fragments, the Fc related assays do not apply. For the analysis of glycosylation patterns of proteins, VelaLabs offers lectin microarray technology.
New statistical tool for Biosimilarity testing
As a leading analytical service provider and biotech laboratory in the field of biosimilars, VelaLabs supports many customer projects involving biosimilar clone screening as well as comparability studies. Our clients need to select the right clones with minimal analytical effort and highly consistent data. With our inCyght® software, we now have a tool to explore which clones or process conditions perform most similarly to the originator product. Furthermore, we can explore which process parameters and settings achieve the highest biosimilarity score.
VelaLabs expertise covers a variety of biomolecules. Examples are listed below. A respective fact sheet may be downloaded for free. We know the market and have a competitive field available for all of these biomolecules. The competitive fields are researched with state-of-the-art methods and are routinely updated. For our customers the sheets are available upon request, however, we are willing to share our knowledge for a cost contribution with other interested parties.
Please contact office(at)vela-labs.at for inquiries.
Adalimumab (Humira®) is a human monoclonal IgG1/kappa antibody used in the treatment of e.g. Rheumatoid Arthritis, Psoriatic Arthritis, or Crohn’s disease. Humira was the third tumor necrosis factor (TNF) -α inhibitor on the market, but the first fully human antibody directed towards this target. Adalimumab consists of a tetramer of two heavy and two light chains with one N-glycosylation site per heavy chain. The extended patent of the originator owned by AbbVie expired in 2016 in the US and will expire in the EU in 2018; however, in the last few years AbbVie has secured about 70 (US) patents covering Humira formulations, manufacturing techniques and methods to treat multiple diseases. These additional patents expire between 2022 and 2034 and AbbVie will pursue litigation to try to keep biosimilars off the US market until at least 2022.
Alemtuzumab (Lemtrada®), marketed also under the trade names Campath®, MabCampath® and Campath-1H®, is a monoclonal antibody that binds to cluster of differentiation (CD)52, a cell-surface antigen present on T and B cells. Alemtuzumab depletes circulating T and B cells through antibody-dependent cellular cytolysis and complement-mediated lysis. CD52 is present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes are derived.
Alemtuzumab is indicated for the second-line treatment of chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL) and T-cell lymphoma under the trade names Campath®, MabCampath® and Campath-1H®, and in the treatment of multiple sclerosis as Lemtrada®. It is also indicated for some conditioning regimens for bone marrow transplantation, kidney transplantation and islet cell transplantation.
It has to be noted that MabCampath® originally approved for CLL in 2007 was withdrawn from the markets in the US and EU in 2012 to prepare for a higher-priced relaunch of Lemtrada® aimed at Multiple Sclerosis. Basic patents for the molecule have been already expired. A complication of therapy with alemtuzumab is that it increases the risk for opportunistic infections.
Bevacizumab (Avastin®) is a humanized monoclonal IgG1/kappa antibody that inhibits vascular endothelial growth factor A (VEGF-A) and is used to treat various cancers including colorectal, lung, breast, kidney, and glioblastomas. As a typical IgG1 antibody, bevacizumab is comprised of a tetramer of two heavy and two light chains with one N-glycosylation site per heavy chain. Bevacizumab patents will expire in 2019 in the US and in the EU in 2022.
Cetuximab (Erbitux®) is an epidermal growth factor receptor (EGFR) inhibitor used for the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer and head and neck cancer. It is a chimeric (mouse/human) monoclonal antibody. The main patents for cetuximab expired in the EU in 2014 and in the US in 2016.
Denosumab (Prolia® Xgeva®) is a human monoclonal antibody for the treatment of osteoporosis, treatment-induced bone loss, bone metastases, multiple myeloma, and giant cell tumor of bone. It is the first FDA approved receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor. RANKL has been identified to affect the immune system and control bone regeneration and remodeling. Denosumab was approved for use in postmenopausal women at risk of osteoporosis under the trade name Prolia®, and as Xgeva® for the prevention of skeleton-related events in patients with bone metastases from solid tumors. Expiry dates for patents related to denosumab range from 2017 to 2023 in the US and from 2017 to 2021 in the EU.
Golimumab (Simponi®) is a fully human anti-TNF-α IgG1? monoclonal antibody. Simponi®. is indicated in adults as an adjunct to methotrexate treatment for rheumatoid arthritis, alone or as an adjunct to methotrexate treatment for active psoriatic arthritis and as a single agent for active ankylosing spondylitis and ulcerative colitis. Starting from 2009, EMA and FDA have approved Simponi® for its first indications. Patents for Simponi® will expire in 2024 in US as well as in EU.
Infliximab (Remicade®) is a chimeric (mouse/human) IgG1/kappa monoclonal antibody. Like etanercept and adalimumab, infliximab is a TNF-α blocker. Infliximab is indicated for treatment of a variety of autoimmune diseases, e.g. Crohn's disease, Ulcerative Colitis and Rheumatoid Arthritis. It is composed of human constant and murine variable regions with a molecular weight of approx. 144 kDa. The main patent of Remicade® expired in the EU in 2015 and will expire in the US in 2018. J&J, the owner of the originator molecule is trying to delay the entry of biosimilars with additional patents, however, is struggling to defend their validity at court.
Natalizumab (Tysabri®) is a humanized monoclonal antibody against the cellular adhesion molecule α4-integrin. Natalizumab is used in the treatment of Multiple Sclerosis and Crohn's disease. Tysabri® got its first approval by FDA in 2004 for MS and subsequently for CD. In EU it was approved for MS in 2006. The Tysabri® patents expired in 2015 in the EU as well as in the US.
Nivolumab, (Opdivo®), is a fully human monoclonal IgG4 antibody. Nivolumab blocks programmed cell death 1 ligand 1 or programmed cell death 1 ligand 2 (PD-L1 or PD-L2) from binding to PD-1, a protein on the surface of activated T cells. Opdivo® is indicated, among other cancer types, as a first or second line treatment for inoperable or metastatic melanoma. Nivolumab got its first approval in 2014 in the US. Several patent families around this drug are filed, with expiration dates of up to 2027 in US and 2026 in EU.
Omalizumab (Xolair®) reduces sensitivity to inhaled or ingested allergens, especially in the control of moderate to severe allergic Asthma, which does not respond to high doses of corticosteroids. It is a recombinant humanized IgG1k monoclonal antibody that specifically binds to free human immunoglobulin E (IgE) in the blood and interstitial fluid and to the membrane-bound form of IgE (mIgE) on the surface of mIgE-expressing B -lymphocytes. Omalizumab is Indicated for moderate-to-severe persistent asthma and for chronic idiopathic urticaria in patients who remain symptomatic despite H1 antihistamine treatment. Xolair® was developed by Genentech (Roche) in collaboration with Novartis. It was approved in US in 2003 and in EU in 2005. Key patents on Xolair® already expired.
Ranibizumab (Lucentis®) is a humanized monoclonal antibody fragment created from the same parent mouse antibody as bevacizumab. It is indicated for the treatment of neovascular (wet) age-related macular degeneration, macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, and myopic choroidal neovascularization. Its effectiveness is similar to that of bevacizumab, however, it is much cheaper.
Ranibizumab binds to the receptor binding site of active forms of vascular endothelial growth factor A (VEGF-A), including the biologically active, cleaved form of this molecule, VEGF110. The binding of ranibizumab to VEGF-A prevents the interaction of VEGF-A with its receptors (VEGFR1 and VEGFR2) on the surface of endothelial cells, reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation. In 2006 it got its first FDA approval and in 2007 in the EU. The patents on Lucentis® will expire in the US in 2020 and in the EU in 2022.
Rituximab (Rituxan®, MabThera®) is a chimeric IgG1/kappa monoclonal antibody targeting CD20, which is primarily found on the surface of B -cells. Rituximab is used for the treatment of many lymphomas and leukemias, transplant rejection and some autoimmune disorders. Rituximab is also used off-label to treat difficult cases of Multiple Sclerosis, Systemic Lupus Erythematosus and autoimmune anemias. Rituximab destroys both normal and malignant B -cells that have CD20 on their surfaces, and is therefore used to treat diseases, which are characterized by having too many overactive or dysfunctional B -cells. Rituxan® patents expired in 2013 in the EU and in 2016 in the US.
Tocilizumab (Actemra®) is a recombinant humanized IgG1 monoclonal antibody targeting the interleukin-6 receptor (IL-6R). Tocilizumab recognizes both the membrane-bound and the soluble form of IL-6R and thus is able to block IL-6 functions. Actemra/RoActemra® is indicated for RA, active polyarticular juvenile idiopathic arthritis, giant cell arteritis, cytokine release syndrome, and systemic sclerosis. In Japan, it is also approved for treatment of Castleman’s disease.
The patents on Actemra/RoActemra® expired in US in 2015 and in Europe in 2017. The originator product from Roche was approved in US in 2010 and in 2009 in Europe.
Trastuzumab (Herceptin®) is a humanized monoclonal antibody that interferes with the HER2/neu receptor. Trastuzumab is used to treat certain breast cancers. As a typical IgG1 antibody, trastuzumab is comprised of a tetramer of two heavy and two light chains with one N-glycosylation site per heavy chain. Patents for Herceptin® expired in the EU in 2014 and will expire in 2019 in the US.
Ustekinumab (Stelara®) is an IgG1 kappa human monoclonal antibody. It is directed against Interleukin-12 and Interleukin-23, which are regulating inflammatory processes. It is indicated for treating patients with moderate to severe Plaque Psoriasis and also to treat active Psoriatic Arthritis alone or with Methotrexate. Ustekinumab has been approved in Europe in 2008 and in the US in 2009. The patent protection for Stelara® will be until 2023 in US and 2024 in EU.
Abatacept (Orencia®) is a fusion protein composed of the Fc region of the immunoglobulin IgG1 fused to the extracellular domain of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). It is down-regulating activation of T-cells by binding to the CD80 and CD86 ligand proteins. Abatacept is useful in delaying the progression of structural damage and reducing symptoms of Rheumatoid Arthritis. The patents on Orencia® will expire in the US in October 2019 and in Europe in December 2017
Etanercept (Enbrel®) is a receptor fusion protein used in the treatment of Rheumatoid Arthritis, Polyarticular Juvenile Idiopathic Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis and Plaque Psoriasis. Etanercept is consisting of the extracellular ligand-binding domain of human 75kD (p75) tumor necrosis factor receptor (TNFR) linked to Fc-part of human IgG1. The protein structure is characterized by a high degree of N- and O-glycosylation. In addition, an N- and C-terminal sequence heterogeneity adds to the complexity of the protein analysis. The main patents on Enbrel® in the US expired in 2012 and in the EU in 2015. Many companies are already developing biosimilar versions of this drug and some of these are already on the market in Asia and India. However, Amgen selling the originator hopes to hold off biosimilars until 2029 with new patents.
Follicle stimulating hormone (FSH) consists of two non-covalently linked glycoproteins designated as alpha- and beta- subunits, which have 92 and 111 amino acids, respectively. The molecular weight is 22.7 kD. Follitropin is the corresponding recombinantly produced molecule and is marketed as follitropin alpha (Gonal F®) and follitropin beta (Puregon®). The amino acid sequences of follitropin alpha and beta are identical to that of FSH, however, there are differences in glycosylation patterns.
FSH is synthesized and secreted by gonadotrophs of the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and luteinizing hormone (LH) act synergistically in reproduction. Specifically, an increase in FSH secretion by the anterior pituitary causes ovulation. Market approval was in 2004 and basic patents have already been expired.
Granulocyte Colony Stimulating Factor (G-CSF, Neupogen®) is a cytokine, which is involved in triggering the production of white blood cells (neutrophils) and their release from the bone marrow. Filgrastim is a recombinant form of G-CSF. It is a 175-amino-acid polypeptide with two disulfide bridges and expressed in E.coli. There are already a number of Filgrastim biosimilars and biobetters on the market.
Human growth hormone (HGH, Nutropin®, Humatrope®, Genotropin®, Norditropin®, Saizen®), also known as somatotropin, is a 191-amino acid, single-chain polypeptide that is synthesized and secreted by somatotropic cells within the lateral wings of the anterior pituitary gland. It is anabolic and stimulates growth, cell reproduction, and cell regeneration. HGH is used as replacement therapy in persons with HGH deficiency. Human pituitary-derived hormone was available since the late 1950s and 1981 Genetech developed the first recombinant product. Patents already expired and a variety of biosimilars are marketed (Omnitrope®, Valtropin®) or in development.
Interferon-β1a (IFN-β1a, Avonex®) is a cytokine in the interferon family used to treat the relapsing-remitting and secondary-progressive forms of Multiple Sclerosis (MS). The beneficial effect of IFN-β in MS probably results from a variety of modulatory actions, such as a for example modulation of IgG synthesis, an increase of Interleukin -10 levels, and the inhibition of Interleukin-1β and TNF-α. Avonex® was approved in 1996 and biosimilars are already on the market, e.g. CinnoVex®.
Pegfilgrastim is a variant of G-CSF (Neulasta®) coupled to a polyethylene glycol (PEG) molecule. The PEG form has a longer half-life, thus reducing the necessity of daily injections. Pegfilgrastim patents already expired in US in 2015 and in EU in 2017. Biosimilars are already in development at companies such as Apobiologix, Cinfa Biotech, USV, Intas, and Sandoz.
Parathyroid hormone (PTH, Natpara®, Preos®, Preotact®),is a polypeptide containing 84 amino acids (9.4 kD). The 34 N-terminal amino acids are solely required for the bioactive conformation. Teriparatide (Forteo®) consisting of these 34 amino acids has the same efficacy as PTH.
PTH secreted by the chief cells of the parathyroid glands is the primary regulator of calcium and phosphate metabolism in bone and kidney. It is acting upon the PTH-1 receptor in bone and kidney, and the PTH-2 receptor in the central nervous system, pancreas, testis, and placenta. PTH increases serum calcium.
PTH is marketed by Shire as Natpara®. The originator product of teriparatide, Eli Lilly’s Forteo®, was approved by FDA in 2002 and by EMA in 2003. In contrast to PTH, biosimilars of teriparatide are already marketed, approved for market or in development.