VelaLabs expertise covers a variety of biomolecules including biosimilars. Examples for some of these biomolecules are presented in our Biosimilar Review.
A respective fact sheet may be downloaded for free. Currently fact sheets for abatacept, adalimumab, aflibercept, alemtuzumab, bevacizumab, cetuximab, darbepoetin, denosumab, eculizumab, epoetin, etanercept, FSH, G-CSF, golimumab, HGH, infliximab, insulin, interferon-beta-1a, ipilimumab, natalizumab, nivolumab, omalizumab, pegfilgrastim, pembrolizumab, pertuzumab, PTH, ramucirumab, ranibizumab, rituximab, tocilizumab, trastuzumab, and ustekinumab are available (see also below).
As we also know the market, we 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. An example for a competitive field is shown for adalimumab in our Biosimilar Review.
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 of anti-proliferation, CDC, ADCC, and apoptosis). For Fab-fragments, the Fc related assays do not apply. For the analysis of glycosylation patterns of proteins, VelaLabs offers lectin microarray technology.
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Adalimumab (Humira®) is a human monoclonal IgG1/kappa antibody indicated for 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 patent of the originator owned by AbbVie expired in 2016 in the US and 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 pursued litigation to keep biosimilars off the US market until at least 2022.
Alemtuzumab (Lemtrada®) depletes circulating T- and B-cells through antibody-dependent cellular cytolysis and complement-mediated lysis. Alemtuzumab was originally indicated for second-line treatment of chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL) and normal T-cell lymphoma under trade names Campath®, MabCampath® and Campath-1H®. Currently it is indicated for the treatment of multiple sclerosis as Lemtrada®. It is also applied for some conditioning regimens for bone marrow transplantation, kidney transplantation, and islet cell transplantation. Basic patents for Lemtrada® already expired in 2017.
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. Avastin® patents expired in 2019 in the US and will expire in the EU in 2022.
Cetuximab (Erbitux®) is an epidermal growth factor receptor (EGFR) inhibitor indicated for the treatment of certain types of metastatic colorectal cancer, metastatic non-small cell lung cancer and head and neck cancer with or without radiotherapy or platinum-based chemotherapy. 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 indicated for the treatment of patients with osteoporosis at high risk for fracture, giant cell tumor of bone, hypercalcemia in malignancy and for the prevention of skeletal-related events in patients with bone metastases from solid tumors. 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. Expiry dates of basic Prolia® patents related to the antibody and treatment of patients range from 2017 to 2023 in US and from 2017 to 2021 in EU.
Eculizumab (Soliris®) is a humanized monoclonal antibody. It binds to the complement component 5 (C5), which is a terminal molecule in the complement cascade. Eculizumab inhibits the cleavage of C5 by C5 convertase into C5a and C5b and subsequent generation of the terminal complement attack complex C5b-9. Paroxysmal nocturnal hemoglobinuria (PNH) patients are deficient in terminal complement inhibitors. Eculizumab thus inhibits terminal complement mediated intravascular hemolysis and therefore the destruction of erythrocytes. Soliris® is indicated for treatment of patients with PNH to reduce hemolysis. It is also indicated for treatment of patients with atypical haemolytic uremic syndrome (aHUS) to inhibit complement mediated thrombotic micro-angiopathy. Patents on Soliris® will expire in USA in 2021 and in Europe in 2020.
Golimumab (Simponi®) is a fully human anti-tumor necrosis factor (TNF)-α IgG1қ 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. 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. Remicade® is indicated for treatment of Crohn’s disease, psoriatic arthritis, ulcerative colitis, psoriasis, ankylosing spondylitis, and rheumatoid arthritis used together with methotrexate. The main patent of Remicade® expired in 2015 (EU) and in US in 2018. J&J (Janssen Biotech), the owner of the originator molecule is trying to delay the market entry of biosimilars with additional patents, however, is struggling to defend their validity at court.
Ipilimumab (Yervoy®) is targeting the immune checkpoint T-lymphocyte-associated protein 4 (CTLA-4). It was the first immune checkpoint inhibitor to be approved for the treatment of cancer. Yervoy® is indicated for unresectable or metastatic melanoma, as an adjuvant in the treatment of cutaneous melanoma, to treat microsatellite-high or mismatch repair deficient metastatic colorectal cancer, hepatocellular carcinoma, and in combination with nivolumab (Opdivo®) for advanced renal cell carcinoma. Yervoy® patents will expire in the US in 2023 and in the EU in 2021.
Natalizumab (Tysabri®) is a humanized monoclonal IgG4 antibody directed against α4 integrin, a cellular adhesion molecule. It is the first antibody in the class of selective adhesion molecule inhibitors. Tysabri® is indicated as monotherapy for treatment of relapsing forms of multiple sclerosis (MS) and in adult patients with moderately to severely active Crohn’s disease (CD) with evidence of inflammation, which have had an inadequate response or intolerance to conventional CD therapies. 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 ligand 1 or 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. This includes advanced non-small cell lung cancer, metastatic melanoma, advanced renal cell carcinoma, squamous cell carcinoma of the head and neck. Several patent families are filed, with expiration dates of up to 2027 in US and 2026 in EU.
Omalizumab (Xolair®) is a recombinant humanized IgG1 kappa monoclonal antibody, which binds to free human immunoglobulin E (IgE) and to membrane-bound form of IgE (mIgE) on the surface of mIgE-expressing B lymphocytes. Xolair® is indicated for moderate to severe persistent asthma and for chronic idiopathic urticaria in patients who remain symptomatic despite H1 antihistamine treatment. Key patents on Xolair® already expired in 2017.
Pembrolizumab (Keytruda®) is a humanized monoclonal IgG4 antibody and is targeted to the cellular programmed cell death protein -1 (PD-1). Programmed cell death ligand 1 or ligand 2 (PD-L1 or PD-L2) is upregulated on 40–50 % of melanomas and has limited expression otherwise. Both ligands bind to PD-1, a protein on the surface of activated T-cells. If PD-L1 binds to PD-1, a T-cell becomes inactive and inhibited from attacking a tumor.The inhibitory effect results from promotion of apoptosis in antigen specific T cells while simultaneously blocking apoptosis in suppressor T-cells. Pembrolizumab binds to PD-1, thus blocks PD-L1 or PD-L2 from binding to PD-1, and T-cells can again attack tumor cells. Keytruda® is indicated for, among other cancer types (more than 30 indications), melanoma, non-small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, gastric cancer, cervical cancer, hepatocellular carcinoma, and primary mediastinal large B-cell lymphoma. Patents for Keytruda® have expiry dates of up to 2036 in US and 2028 in EU.
Pertuzumab (Perjeta®) is a recombinant humanized monoclonal antibody that targets the dimerization domain II of human epidermal growth factor 2 (HER2) expressed on the cell surface. When HER2 is over-induced and dimerized with HER3, cell growth accelerates, which can lead to tumor formation. Whereas similar mAb trastuzumab binds to domain IV of the extracellular segment of HER2 receptor, pertuzumab binds to domain II located on the opposite side. Dimerization of HER2 / HER3 and activation of signaling pathways is thus prevented. Perjeta® is approved in combination with Herceptin® (trastuzumab) and docetaxel chemotherapy for the treatment of HER2-positive metastatic breast cancer not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Patent expiry for Perjeta® will be in 2026 (US) and 2024 (EU).
Ramucirumab (Cyramza®) is a fully human monoclonal IgG1 / kappa antibody.Similar to bevacizumab, ramucirumab inhibits angiogenesis (formation of new blood vessels) by binding to a specific epitope on the extracellular domain of vascular endothelial growth factor receptor -2 (VEGFR-2) and blocking the interaction of VEGF-A, VEGF-C, or VEGF-D with its receptors. Cyramza® is indicated for gastric cancer, gastro -oesophageal junction adeno- carcinoma, metastatic colorectal cancer, non-small cell lung cancer that has spread to other parts of the body or in patients whose cancer involves mutations in EGFRs, and hepatocellular carcinoma in patients with a high blood level of alpha fetoprotein. Cyramza® patents will expire in the US in November 2025 and in the EU in May 2023.
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. 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. 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 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® is applied for treatment of many lymphomas and leukemias, transplant rejection and some autoimmune disorders. Rituxan® is also used off-label to treat difficult cases of multiple sclerosis, systemic lupus erythematosus and autoimmune anemias. 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 rheumatoid arthritis, active poly-articular, 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.
Trastuzumab (Herceptin®) is a humanized monoclonal antibody that interferes with the human epidermal growth factor 2 (HER2)/neu receptor. The HER2 pathway promotes cell growth and cell division via HER2 receptor. When HER2 is over-induced and dimerized, cell growth accelerates, which can lead to tumor formation. Trastuzumab binds to domain IV of the extracellular segment of HER2 receptor preventing it from dimerization and activation of its signaling pathways. Herceptin® is indicated for the treatment of HER2-positive metastatic breast cancer patients. It is also approved for adjuvant treatment of HER2 over-expressing breast cancer and metastatic gastric cancer. Primary patents for Herceptin® expired in 2014 in EU and in US in 2019.
Ustekinumab (Stelara®) is an IgG1 kappa human monoclonal antibody. Ustekinumab blocks interleukin IL-12 and IL-23, which activate T helper cells (Th cells). Specifically it is targeting the p40 shared subunit of IL-12 and IL-23, which subsequently cannot bind to their distinct receptors. Stelara® is indicated for treating patients with moderate to severe plaque psoriasis, and also to treat active psoriatic arthritis alone or with methotrexate. In 2016, it was also approved to treat Crohn’s disease. 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 linked to the extracellular domain of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). It is down-regulating the activation of T-cells by binding to the CD80 and CD86 ligand proteins. Orencia® is indicated for reducing symptoms in adult patients with moderately to severely active rheumatoid arthritis. It is also indicated for juvenile idiopathic arthritis and adult psoriatic arthritis. Patents on Orencia® expired in US in October 2019 and in Europe in December 2017.
Aflibercept (Eylea®, Zaltrap®) is a recombinant fusion protein consisting of vascular endothelial growth factor (VEGF) – binding portion from the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of a human IgG1 immunoglobulin. Like ranibizumab, aflibercept is an inhibitor of VEGF. It binds to the receptor binding site of active forms of VEGF-A, including the biologically active, cleaved form of this molecule, VEGF-110. Eylea® (aflibercept) is indicated for the treatment of neovascular (wet) age-related macular degeneration, macular edema following retinal vein occlusion, diabetic macular edema, and diabetic retinopathy. Zaltrap® (ziv-aflibercept) is indicated in combination with 5-fluorouracil, leucovorin, irinotecan (cytostatic medication) for metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing therapy. The basic US patent for aflibercept will expire in 2020, European patents will expire in 2021.
Etanercept (Enbrel®) is a dimeric human receptor fusion protein consisting of the extracellular ligand-binding domain of human 75 kDa (p75) tumor necrosis factor receptor (TNFR) linked to the Fc-part of human IgG1. The Fc-part of etanercept contains CH2 domain, CH3 domain and the hinge region. Etanercept competitively inhibits binding of TNF-α to TNFRs, rendering TNF-α biologically inactive. Etanercept also modulates indirectly different biological functions such as expression of adhesion molecule E-selectin, production of interleukin-6 (IL-6) and matrix metalloproteinase 3 (MMP-3), as well as IL-1. Etanercept is indicated for the treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis and plaque psoriasis. Enbrel® patents expired in 2012 in US and in 2015 in Europe.
Darbepoetin alfa (Aranesp®) contains in comparison to natural erythropoietin five amino acid changes (at N30, T32, V87, N88, T90) resulting into creation of two new sites for N-linked carbohydrate addition. It has a three-fold longer serum half-life as compared to epoetin alpha and epoetin beta. Darbepoetin alfa stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Aranesp® is indicated for the treatment of anemia due to chronic kidney disease, including patients on dialysis and patients not on dialysis. Aranesp® is also indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelo-suppressive chemotherapy. Patents on Aranesp® will expire in US in May 2024 and already expired in Europe in July 2016.
Epoetin alfa (Epogen® / Eprex® / Procrit®) contains 165 amino acids with the identical sequence of naturally occurring erythropoietin. Epoetin alfa and epoetin beta have differences in the glycosylation pattern. The mode of action of epoetin alpha is the same as of that of darbepoetin alpha. Epogen® is indicated for the treatment of anemia due to chronic kidney disease, anemia due to zidovudine in patients with HIV infection, treatment of patients with non-myeloid malignancies, and for reduction of the need for allogeneic red blood cell transfusions during elective, noncardiac, nonvascular surgery. The patents on Epogen® / Eprex® expired in US and Europe in 2013.
Follicle stimulating hormone (FSH) consists of two non-covalently linked glycoproteins designated as alpha- and beta-subunits, which consist of 92 and 111 amino acids, respectively. The molecular weight is 22.7 kDa. 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, and there are only differences in glycosylation patterns. FSH is synthesized and secreted by the gonadotrophs of the anterior pituitary gland. In general, it regulates the development, growth, pubertal maturation, and reproductive processes of the body including maturation of ovarian follicles and sperm cells. Follitropin is indicated for different complications in ovulation and pregnancy. Basic patents have already been expired.
Filgrastim (granulocyte colony stimulating factor, G-CSF, Neupogen®) consists of 175 amino acid residues (18.8 kDa) with two disulfide bridges. Filgrastim binds to the G-CSF receptor, stimulates the proliferation of progenitor cells and their maturation into neutrophils (white blood cells). Filgrastim also stimulates the release of neutrophils from bone marrow and increases their phagocytic activity. By stimulation of the production of more neutrophils, filgrastim treatment can thus be used to fight infection in patients undergoing chemotherapy for cancer treatment. Neupogen® is approved for five indications in the following patient populations: Chemotherapy -induced febrile neutropenia, acute myeloid leukemia, cancer patients receiving bone marrow transplant, peripheral blood progenitor cell collection and engraftment, and severe chronic neutropenia. Patents on Neupogen® expired in the US in December 2013 and in Europe in 2006.
Human growth hormone (HGH, Nutropin®, Humatrope®, Genotropin®, Norditropin®, Saizen®), also known as somatotropin, is a 191-amino acid, single-chain, non-glycosylated 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 indicated as replacement therapy in persons with growth hormone deficiency. There is off-label prescription and use of HGH for a variety of other applications. Human pituitary-derived hormone was available since the late 1950s and in 1981. Genetech developed the first recombinant product. Patents already expired and a variety of biosimilars are marketed or in development.
Animal sourced insulins are now rarely available in developed countries and even use of recombinant human insulin is declining in different markets whereas insulin analogues are dominating the market since years. Basal insulins are long acting, bolus insulins are fast acting. Insulin is indicated to treat high blood glucose including diabetes mellitus type 1 and 2, gestational diabetes, and complications of diabetes such as diabetic ketoacidosis and hyperosmolar hyperglycemic states. Insulin is also used with glucose to treat high blood potassium levels. Patent protection of recombinant human insulin has expired for more than 15 years and also patents for many analogues have been expired so far, e.g. for Lantus® and Humalog®.
Interferon-β1a (IFN-β1a, Avonex®) is a cytokine of the interferon family. It is a 166 amino acid glycoprotein with a single N-linked carbohydrate chain on Asn80 residue. Commercial IFN-β1a preparations have core-fucosylated glycoforms differing in sialylation and glycol-antennary degree. IFN-β1a is acting on a variety of processes and molecules within the immune system. For example, it balances the expression of anti-inflammatory and pro-inflammatory cytokines. Avonex® is indicated for treatment of relapsing forms of multiple sclerosis to slow accumulation of physical disability and to decrease frequency of clinical exacerbations in patients with first clinical episode and magnetic resonance imaging consistent with multiple sclerosis. Basic patents for Avonex® have expired in 2013.
Pegfilgrastim (pegylated granulocyte colony stimulating factor, pegG-CSF, Neulasta®) is a variant of G-CSF coupled to a polyethylene glycol (PEG) moiety at the N-terminus of human G-CSF. This pegylated form has a longer half-life, thus reducing the necessity of daily injections. The patents on Neulasta® expired in US in October 2015 and in Europe in August 2017.
Parathyroid hormone (PTH, Natpara®, Preos™, Preotact®) is a polypeptide containing 84 amino acids (9.4 kDa). Only the 34 N-terminal amino acids are required for the bioactive conformation. Teriparatide (Forteo®) consisting of these 34 amino acids has the same efficacy as PTH. PTH secreted by 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 levels. Thus, chronically elevated PTH will deplete bone stores. Teriparatide is indicated for treatment of osteoporosis in postmenopausal women and men at high risk for fracture and for glucocorticoid-induced osteoporosis in men and postmenopausal women. PTH is indicated as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism. The patents of Forteo® expired in US and Europe in August 2019.