Biomolecules

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. Further analysis of the protein primary structure, complementary analysis of N-glycosylation, protein modifications as well as other compendial methods are carried out in collaboration with trusted, audited and GMP-certified subcontractors or partners.

VelaLabs expertise covers the biomolecules as listed below. More detailed competitive intelligence based information about these biomolecules may be available upon request.

ANTIBODIES

ADALIMUMAB

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

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 (Mab) Campath® 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
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
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
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

Golimumab, (Simponi®), is a human monoclonal antibody that targets also TNF-α. Starting from 2009 the EMA has approved Golimumab for the treatment of Rheumatoid Arthritis, Psoriatic Arthritis and Ankylosing Spondylitis and the FDA as well as the EMA for the treatment of Ulcerative Colitis. The patents for Golimumab will expire in 2024 in the US as well as in the EU.

 

INFLIXIMAB
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. 149 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, by end of 2016 was still struggling at court with these.

 

NATALIZUMAB
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. The Natalizumab patents expired in 2015 in the EU as well as in the US.


NIVOLUMAB

Nivolumab, (Opdivo®), is a human IgG4 anti- programmed cell death protein -1 (PD-1) monoclonal 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. PD-L1 is expressed on 40–50% of melanomas and has limited expression otherwise in most visceral organs. If PD-L1 binds to PD-1, the T cell becomes inactive. Because PD-L1 inhibits T cells from attacking the tumor, blocking of PD-1/PD-L1 binding allows T cells to attack again tumor cells.

Nivolumab got its first approval in 2014 in the US and is currently marketed as a first or second line treatment for inoperable or metastatic melanoma, partly in combination with Ipilimumab.

 

OMALIZUMAB
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 was approved in 2014 in Europe, the US and about 10 other countries for treating patients 12 years and above with Chronic Spontaneous Urticaria (CSU) (also known as Chronic Idiopathic Urticaria), which cannot be treated with H1-antihistamines.

RANIBIZUMAB

Ranibizumab (Lucentis®, among others) 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
Rituximab (Rituxan®, MabThera®) is a chimeric IgG1/kappa monoclonal antibody against the protein 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. Rituximab patents expired in 2013 in the EU and in 2016 in the US.


TOCILIZUMAB
Tocilizumab (Actemra®) is an immunosuppressive agent and for the treatment of Rheumatoid Arthritis and Systemic Juvenile Idiopathic Arthritis, a severe form of Arthritis in children. It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin-6 (IL-6) is a cytokine that plays an important role in immune response. The FDA approved Tocilizumab in 2010 and the EU in 2014 for treatment of RA.

TRASTUZUMAB
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 Trastuzumab expired in the EU in 2014 and will expire in 2019 in the US.


USTEKINUMAB
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 Ustekinumab will be until 2022.



FUSION PROTEINS

ABATACEPT

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. Basic patents for Abatacept will expire in 2017 in the US as well as in the EU


ETANERCEPT
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 a homodimer made of two chains of 75 kDa each, binding to TNFα. 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 Etanecept 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.



HORMONES

FSH
Follicle Stimulating Hormone (FSH, Gonal F®, Puregon®) is a hormone found in humans and animals. It 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.


G-CSF
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.


HGH
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
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®.


pegG-CSF
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 the US (EU in 2017) and biosimilars are in development at companies such as Mylan, Biocon, and Coherus.


PTH
Parathyroid hormone (PTH, Natpara®, Preos®, Preotact®), parathormone or parathyrin is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids. Effective hormone-receptor interaction requires solely the 34-N-terminal amino acids (teriparatide). PTH increases the concentration of calcium in the blood by acting upon the parathyroid hormone 1 receptor in bone and kidney, and the parathyroid hormone 2 receptor in the central nervous system, pancreas, testis, and placenta. The first launches of PTH drugs were in 2006 and first biosimilars are already marketed or in development.