EP3380520A2 - Anti-alpha-v integrin antibody for the treatment of fibrosis and/or fibrotic disorders - Google Patents
Anti-alpha-v integrin antibody for the treatment of fibrosis and/or fibrotic disordersInfo
- Publication number
- EP3380520A2 EP3380520A2 EP16808567.8A EP16808567A EP3380520A2 EP 3380520 A2 EP3380520 A2 EP 3380520A2 EP 16808567 A EP16808567 A EP 16808567A EP 3380520 A2 EP3380520 A2 EP 3380520A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- di17e6
- antibody
- modification
- fibrosis
- ssc
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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Definitions
- the invention is directed to the treatment of fibrosis and/or fibrotic diseases by means of antibodies.
- the invention is furthermore directed to the prophylaxis of fibrosis and/or fibrotic diseases by antibodies. Above all, the invention relates to the
- an anti-alpha-v integrin (receptor) antibody to patients suffering from fibrosis and/or fibrotic diseases, including but not limited to systemic sclerosis (SSc). More specifically, the instant invention relates to the treatment of fibrotic diseases of the skin, lung, heart, liver and/or kidney by means of said antibody, and/or the prophylaxis thereof. Even more specifically, the instant invention relates to the administration of a recombinant, de-immunized monoclonal antibody targeting av- integrins patients suffering from systemic sclerosis, including, but not limited to systemic sclerosis of the skin, lung, heart and/or kidney.
- SSc systemic sclerosis
- the invention relates to the therapy of said patients by means of the anti-alpha-v integrin antibody DI17E6 (Abituzumab) and structural mutants or modifications thereof.
- One important target of said therapy is to slow, halt and/or revert said fibrosis and/or fibrotic diseases in patients, thus preferably to generally improve the status of a patient suffering from fibrosis and/or fibrotic disease.
- One further important target of said therapy is to slow, halt and/or revert systemic sclerosis in patients, thus preferably to generally improve the status and quality of life of the patient suffering from said systemic sclerosis.
- Another prefrerred aspect of the invention relates to the prophylaxis against fibrosis and/or fibrotic disorders in subjects, preferably human subjects, which are likely to develop fibrosis and/or fibrotic disorders, by administering the anti-alpha-v integrin antibody DI17E6 (Abituzumab) and/or structural mutants or modifications thereof.
- subjects preferably human subjects, which are likely to develop fibrosis and/or fibrotic disorders
- Fibrosis is preferably defined as the formation of excess fibrous tissue, preferably fibrous connective tissue, in an organ or tissue, preferably in a reparative or reactive process. This can preferably qualified as a reactive, benign, or pathological state. In response to injury, this is preferably called scarring, and if fibrosis arises from a single cell line, this is preferably called a fibroma. Physiologically, fibrosis typically acts to deposit connective tissue, which can obliterate the architecture and function of the underlying organ or tissue. Fibrosis can preferably be used to describe the pathological state of excess deposition of fibrous tissue, as well as the process of connective tissue deposition in healing.
- fibrosis is preferably used to describe the pathological state of excess deposition of fibrous tissue. Fibrosis in the pathological sense is similar to the process of scarring, in that both involve stimulated cells laying down connective tissue, including collagen and glycosaminoglycans. Immune cells called macrophages, as well as any damaged tissue between surfaces called interstitium, typically release TGF- ⁇ . There are numerous reasons for this, including inflammation of the nearby tissue, or a generalized inflammatory state, with increased circulating mediators. TGF- ⁇
- Fibrosis can occur in many tissues of many organs within the body, typically as a result of inflammation or damage, and examples include: Fibrosis of the lung, e.g. pulmonary fibrosis, cystic fibrosis and/or idiopathic
- Fibrosis of the liver e.g. liver cirrhosis;
- Fibrosis of the heart e.g. atrial fibrosis, endomyocardial fibrosis and/or as the consequential damage of a previous myocardial infarction.
- fibrosis and especially pathological fibrosis, preferably includes
- arthrofibrosis predominantly of the knee and shoulder, but also occurring in a variety of other joints
- Crohn's Disease intestines
- Dupuytren's contracture predominantly in the hands and/or fingers
- Keloid predominantly affecting the skin
- Mediastinal fibrosis predominantly relating to the soft tissue of the mediastinum
- Myelofibrosis predominantly affecting the bone marrow
- Peyronie's disease penis
- Nephrogenic systemic fibrosis predominantly affecting the skin
- progressive massive fibrosis e.g.
- fibrosis pathological fibrosis and fibrotic diseases or fibrotic disorders are known and understood in the art.
- all pathological forms of fibrosis i.e. forms that are not directly related to acute damage and/or normal wound healing, are also referred to in the context of the present invention as fibrotic disorders.
- fibrotic disorders are preferably those states of fibrosis which exceed the level of fibrosis that is normally found in desired, correct wound healing processes.
- Systemic sclerosis (SSc, ICD-10 classification M34) is an especially preferred fibrotic disorder to be treated according to the instant invention.
- Systemic sclerosis is often also referred to as systemic scleroderma and sometimes as progressive systemic sclerosis.
- Systemic sclerosis is a clinically heterogeneous multi-organ connective tissue disease with a characteristic but variable spectrum of clinical and laboratory presentations with features of autoimmunity, vascular injury and progressive fibrosis, leading to pain, disability, progressive dysfunction and ultimately failure of vital organs such as lung, heart, or kidney.
- SSc can be differentiated from a group of diseases termed localized scleroderma, that preferably include conditions such as morphea, linear scleroderma and scleroderma en-coup-de-sabre, and preferably also other disorders that mimic one or more signs of scleroderma.
- localized scleroderma preferably include conditions such as morphea, linear scleroderma and scleroderma en-coup-de-sabre, and preferably also other disorders that mimic one or more signs of scleroderma.
- Organ involvement in SSc can lead to decline of its function and precocious mortality when vital organs such as lung, liver, kidney and heart are affected.
- the skin is almost always involved.
- SSc is classified into diffuse cutaneous (dc) SSc and localized cutaneous (lc) SSc.
- IcSSc skin involvement typically extends from the distal extremities to the knees and elbows; in dcSSc the skin involvement typically extends proximally, involving the trunk upper arms and/or thighs. More details on preferred subsets and disease classifications can be found in the sections "Classification" and "Diagnosis and Symptoms".
- SSc can have overlapping features with other connective tissue diseases (CTD) such as systemic lupus erythematosus, polymyositis, rheumatoid arthritis or Sjogren's syndrome.
- CTD connective tissue diseases
- SSc vascular abnormalities The characteristic pathologic finding in SSc vascular abnormalities is a noninflammatory proliferative/obliterative vasculopathy involving small arteries and arterioles in multiple vascular beds. Although in long-standing SSc these lesions generally occur in the absence of inflammation, in early stage disease, inflammatory cell infiltrates are prominent in many organs. Histopathologic evidence of vascular damage is present before fibrosis can be detected in involved and non-involved skin, indicating a generalized process. Manifestations, such as Raynaud's phenomenon, generally precede other disease manifestations.
- SSc vasculopathy Additional clinical signs include cutaneous telangiectasia, nail-fold capillary alterations, pulmonary arterial hypertension (PAH), digital pit formation, gastric antral vascular ectasia, and scleroderma renal crisis.
- PAH pulmonary arterial hypertension
- the initial vascular insult is apparently endothelial cell injury.
- Secondarily platelets may become activated and release mediators that may contribute to vasoconstriction, fibroblast activation and myofibroblast transdifferentiation.
- Endothelial dysfunction may lead to abnormal vascular dilation/constriction resulting in impaired blood flow responses and episodes of ischemia-reperfusion with oxidative stress that amplifies vascular injury.
- Endothelin-1 the most potent vasoconstrictor known, is reported to be elevated in patients with SSc, with higher levels in dcSSc than IcSSc.
- Obstructive vasculopathy of small blood vessels leads to tissue hypoxia and the described tissue remodelling.
- Vasculogenesis may be impaired in SSc and contribute to the
- Fibrosis is characterized by accumulation of excessive amounts of type I collagen and other fibrillar collagens, fibronectin, elastin, proteoglycans, and other connective tissue molecules in the extracellular matrix (ECM).
- ECM extracellular matrix
- the process causes disruption of tissue architecture.
- interstitial and vascular fibrosis in the skin and internal organs contributes directly to their progressive dysfunction and eventual failure.
- Most prominently affected are the lungs, gastro-intestinal tract, heart, tendon sheath, and perifascicular tissue surrounding skeletal muscle.
- Fibrosis in the skin causes marked expansion of the dermis. The process obliterates the hair follicles, sweat glands, and other skin appendages.
- Collagen fiber accumulation is most prominent in the deep dermis, and gradually invades the subadjacent adipose layer with entrapment of fat cells.
- the proportion of a-smooth muscle actin-positive myofibroblasts that are intermediates between fibroblasts and contractile smooth muscle cells and play a major role in fibrogenesis, is increased in the lesional skin.
- patchy infiltration of the alveolar walls with lymphocytes, plasma cells, macrophages, and eosinophils is seen.
- interstitial lung fibrosis and vascular damage predominate, often coexisting within the same lesions.
- Intimal thickening of the pulmonary arteries underlies PAH, and at autopsy is often
- pneumonitis a form of interstitial lung disease characterized by mild-to-moderate interstitial inflammation, type II pneumocyte hyperplasia, and uniform distribution of fibrosis.
- SSc is associated with the usual interstitial pneumonia pattern, which is characterized by scattered fibroblastic foci and patchy distribution of fibrosis. Progressive thickening of the alveolar septa ultimately results in obliteration of the airspaces and honeycoombing, and consequent loss of pulmonary blood vessels. This process impairs gas exchange and contributes to increasing pulmonary arterial tension.
- the prevalence of interstitial lung disease in patients with dcSSc is reported to be about 53% and about 35% in patients with IcSSc.
- SSc kidneys vascular changes in SSc kidneys are most prominent in the small interlobular and arcuate arteries, which show reduplication of elastic lamina, marked intimai proliferation, and accumulation of ground substance. These changes can also be found in SSc patients who do not have renal crisis. Fibrinoid necrosis of the arteriolar walls may be seen. Intimai thickening leads to severe narrowing and total obliteration of the lumen, often with microangiopathic hemolysis.
- fibroblasts normally residing in the connective tissue or pericytes residing around blood vessels may become activated by growth factors such as TGF- ⁇ resulting in proliferation and increased collagen synthesis.
- TGF- ⁇ growth factors
- Tissue injury, mechanical tension and TGF- ⁇ induce activation of fibroblast-like cells and a phenotypic change, resulting in the transformation of these cells into
- myofibroblasts a process designated fibroblast-myofibroblast-transformation (FMT).
- FMT fibroblast-myofibroblast-transformation
- Myofibroblasts are characterized by increased motility, expression of a smooth muscle actin, increased collagen synthesis, tissue inhibitors of metalloproteinases, and other ECM components.
- Myofibroblasts are a major source of TGF- ⁇ activation during the fibrotic response and are responsible for contraction of early granulation tissue. In pathologic fibrogenesis, myofibroblasts persist, resulting in excessively contracted ECM characteristic of chronic scars.
- Immune dysfunction :
- the innate and adaptive arms of the immune system seem to be activated in early SSc, and autoimmunity is prominent; however, the role of cellular and humoral autoimmune effector pathways in the pathogenesis is uncertain.
- activated CD4 and CD8 lymphocytes and monocytes and macrophages and less commonly B cells, eosinophils, mast cells, and natural killer cells, are observed in perivascular regions in the lesional skin, lungs, and other affected organs.
- Mononuclear cell infiltrates in skin are predominantly CD3CD4 positive T cells and express markers of activation. Circulating autoantibodies with multiple antigenic specificities can be detected in virtually all patients with SSc.
- PBC primary biliary cirrhosis
- PM/DM polymyositis/dermatomyositis
- SDV severe digital vasculopathy
- SRC scleroderma renal crisis.
- SSc is typically associated with one or more of the following clinical characteristics:
- the clinical manifestations of SSc are protean, reflecting its complex underlying pathology.
- the frequency of various clinical features differs according to the stage and subset of the disease.
- the course and the severity of organ involvement are unpredictable in individual patients.
- the severity and activity of each complication needs to be considered in making treatment decisions. Fatigue and lethargy are common throughout the illness, although usually more pronounced in its early phases. Reactive depression is a frequent accompaniment to this often relentless and disfiguring disorder.
- the prevalence of major organ manifestations reported in textbooks is given in table 2.
- Telangectasias are dilated small blood vessels in the skin forming red spots.
- Telangiectasias in SSc are typically oval or rectangular in shape.
- Mouth perioral tight skin, reduced oral aperture, dental caries, xerostomia.
- Esophagus dysmotility, reflux; complications: strictures, hiatal hernia, Barrett's
- metaplasia replacement of physiologic squamous epithelium by columnar epithelium with goblet cells, precancerous condition.
- Stomach gastroparesis with bloating and vomiting, gastric antral vascular ectasia with intermittent bleeding (can cause anemia).
- Fibrotic process in tendons, ligaments and joint capsules can contribute together with skin fibrosis to joint contractures.
- ILD interstitial lung disease
- HRCT computer tomography
- FVC Forced Vital Capacity
- TLC Total Lung Capacity
- PAH pulmonary arterial hypertension
- PAH pulmonary arterial hypertension
- PAH pulmonary arterial hypertension
- PAH chronic hypoxia
- PAH chronic thromboembolism
- PAH usually does not manifest with dyspnea until quiet advanced stages. Reduced exercise capacity is a typical finding.
- PAH can be characterized by abnormal echocardiographic, pulmonary function and/or electrocardiographic findings, although right heart catheterization remains the gold standard and is required to confirm the diagnosis of PAH. Definitive diagnosis requires exclusion of thromboembolic disease, >25 mm Hg of the mean pulmonary arterial pressure at rest or >30 mm Hg with exercise. The prognosis of PAH associated with SSc is worse than idiopathic pulmonary arterial hypertension.
- Myocardial enzyme elevation including abnormalities of cardiac rate and rhythm, diastolic or global dysfunction as a consequence of myocardial ischemia, fibrosis, and/or myocarditis.
- scleroderma renal crisis characterized by severe arterial hypertension, that can cause heart failure, stroke or encephalopathy with generalized seizures, flash pulmonary edema, and progressive or acute renal failure with increased creatinine serum levels, proteinuria, microscopic hematuria, and sometimes microangiopathic haemolytic anemia and thrombocytopenia, can evolve into end stage renal disease requiring long-term dialysis or renal transplantation, early mortality in approximately 10%.
- SSc The hallmark of SSc is induration and thickening of the skin ("scleroderma"), but also many internal organs can be involved in SSc.
- the two major clinical subsets are differentiated by the pattern of cutaneous involvement and additional associated clinical and laboratory features (Table 4).
- the CREST syndrome (acronym derived from calcinosis cutis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) has been individualized based on a combination of clinical features but may be classified as IcSSC.
- SSc can have features of other connective tissue diseases or fulfil their criteria.
- SSc without skin involvement (“scleroderma sine scleroderma”) is rare and usually diagnosed late in the course due to absent skin signs. SSc in childhood and adolescence is extremely rare. Further classifications can be found in the section titled "Diagnosis and Symptoms”.
- dcSSc Diffuse cutaneous systemic sclerosis
- Proximal skin thickening involving the trunk, upper arms and thighs, in addition to symmetrical involvement of the fingers, hands, arms, face/neck.
- IcSSc cutaneous systemic sclerosis
- the diagnosis of SSc is usually made based on clinical manifestations, in particular the pattern of skin involvement.
- the American College of Rheumatology (ACR) has proposed diagnostic criteria to classify patients. Either one major criterion (i.e.
- proximal scleroderma or two or more of the minor criteria (i.e. [1] sclerodactyly, [2] digital pitting scars of fingertips or loss of substance of the distal finger pad, [3] bilateral basilar pulmonary fibrosis) are required to classify patients as SSc.
- a tissue biopsy is preferably not required for the diagnosis of SSc.
- Table 5 The ACR-EULAR Criteria for the classification of Systemic Sclerosis
- SSc Typical symptoms of SSc are given below in tabulated form (Table 6). Table 6. Symptoms of SSc (clinical signs and other clinical features see Tables 2 and 3)
- Skin sclerosis sensation of swollen hands or fingers, sometimes pain, sometimes pruritus, impaired manual dexterity/disability in daily private and professional life due to joint contractures and pain, impaired movement in other than finger and hand joints, decreased skin sensitivity due nerve compression, dry skin from loss of skin appendices.
- Esophagus retrosternal discomfort or pain, dysphagia, burning pain/heartburn,
- cough typically dry
- pain from pleuritis multiple symptoms due to oxygen therapy and lung transplantation.
- the average survival time from diagnosis of all SSc patients is reported to be approximately 13 years, whereas the 5-year survival rate of patients with SSc-ILD is reported to be 40-60%, showing the higher mortality rate in patients with SSc-ILD compared to overall SSc.
- SSc-organ involvement -53%
- cancer ⁇ 15%)
- atherosclerosis Death from SSc-organ involvement is more common in patients with diffuse skin involvement, older age at onset, and males.
- SSc-related myocardial disease death was 14% with most causes being related to arrhythmias. Renal causes of death only accounted for 4%, all of which were related to scleroderma renal crisis. Three percent of patients died from gastrointestinal-related causes. With respect to the non-SSc-related deaths, causes were as follows: infections (13% of all deaths), neoplasia (13%), and cardiovascular disease (12%). Patients with non-SSc-related deaths were then analyzed for SSc-related comorbidities. A significant number of patients who died from pneumonia also had presence of gastroesophageal reflux with or without documented aspiration.
- gastroesphageal reflux with aspiration due to esophageal dysmotility, arthritis, obesity, anemia and deconditioning due to physical inactivity may also contribute.
- Dyspnea is a very important and independent predictor of function and health-related quality of life (HRQoL). FVC and pulmonary artery systolic pressure were significant independent predictors of dyspnea.
- the disability index (Dl) of the modified Health Assessment Questionnaire (HAQ) correlates with scleroderma heart, kidney disease, tendon friction rubs, hand contractures, and proximal muscle strength.
- HAQ-DI is predictive of mortality and correlates with reduced fist closure, reduced hand spread, and presence of tender joints.
- Disability in SSc worsens over time, with dyspnea and disease type being the strongest predictor of disability.
- Patients with digital ulcers have significantly higher global disability, hand disability, and anxiety. Most patients with SSc have limitation in daily activities and have an increased need for help at home.
- Skin involvement assessed by the modified Rodnan Skin Score (mRSS) is strongly associated with disability and pain.
- SSc is associated with a high prevalence of depression and anxiety.
- Depression is associated with ILD. Health related quality of life is reduced in SSc patients and similar to rheumatoid arthritis patients. Raynaud's phenomenon has impact on disability (overall, grip, eating dressing), pain, and mood. Pain and depressive symptoms are significant determinants of physical functioning and social adjustment.
- the known monoclonal anti-alpha v antibody DI17E6 (designated also as DI-17E, DI17e6, Abituzumab, abituzumab, EMR62242 or EMD 525797) is highly effective in interfering with cell signalling processes relevant for the development, occurance and/or manifestation of fibrosis and especially of fibrotic disorders.
- said anti-alpha v antibody DI17E6 is highly effective in interfering with cell signalling processes relevant for the development, occurrence and/or manifestation of systemic sclerosis.
- Evidence therefore is shown in the Experimental Section given herein and as discussed above and below.
- a subject of the instant invention is the monoclonal anti-alpha av antibody DI17E6 and/or a biologically active variant or modification thereof, for use in the treatment of fibrosis and/or fibrotic disorders.
- a preferred subject of the instant invention is the monoclonal anti-alpha av antibody DI17E6 and/or a biologically active variant or modification thereof, for use in the treatment of systemic sclerosis.
- a further subject of the instant invention is thus the use of the monoclonal anti-alpha av.
- antibody DI17E6 and/or a biologically active variant or modification thereof for the manufacture of a medicament for the treatment of fibrosis and/or fibrotic disorders, and especially for the treatment of systemic sclerosis, and/or a method for the treatment of fibrosis and/or fibrotic disorders, and especially for the treatment of systemic sclerosis, comprising administering to a patient the monoclonal anti-alpha av antibody DI17E6 and/or a biologically active variant or modification thereof. Due to its favorable safety profile, the monoclonal anti-alpha av antibody DI17E6 and/or a biologically active variant or modification thereof are deemed suitable also for the prophylaxis of said disorders.
- Figure 1 Abituzumab Blocks Abituzumab Blocks Elevated aSMA
- Figure 12 COMP expression by IPAH (PPH), IPF, SSc-PAH, SSc-
- Figure 20 Signature Score of 19-gene SSc fibrosis signature mild
- NAFLD Non-alcoholic fatty liver
- Non-alcoholic fatty liver disease Non-alcoholic fatty liver disease
- PSC Primary sclerosing cholangitis
- PBC primary biliary cholangitis
- NAFLD Non-alcoholic fatty liver disease
- the known monoclonal anti-alpha v antibody DI17E6 (designated herein also as Abituzumab, abituzumab, EMR62242 or EMD 525797) is found to be highly effective in interfering with cell signalling processes relevant for the development, occurance and/or manifestation of fibrosis and especially of fibrotic disorders.
- Fibrotic diseases represent one of the largest groups of diseases for which there is no effective therapy to date.
- the fibrotic processes are regulated by complex set of interactions within a network of profibrotic and antifibrotic mediators.
- TGF- ⁇ i.e. Tranforming Groth Factor beta, often also referred to as TGFb, TGF b, TGFB, TGF B, TGF-b, TGF-B, TGFbeta, TGF beta or TGF-beta
- TGF- ⁇ i.e. Tranforming Groth Factor beta
- FMT myofibroblast transition
- TGF- ⁇ isoforms are synthesized as latent precursers complexed with latent TGF- ⁇ binding proteins, which contains a Latency Associated Peptide (LAP) region.
- LAP Latency Associated Peptide
- the LAP of TGF- ⁇ contains an RGD motif which interacts with the integrins ⁇ 1 , ⁇ 3, ⁇ , ⁇ and ⁇ resulting in activation of TGF- ⁇ .
- Abituzumab is a pan-av integrin antibody that was found to allosterically to the ligand- binding av subunit and thus prevents ligand from binding to all ⁇ heterodimers and therefore inhibits av integrin-dependent activation of latent TGF- ⁇ and thus blocks acquisition of the myofibroblast phenotype by fibroblasts and other precursors.
- the obtained data demonstrate that the monoclonal anti-alpha av antibody DI17E6 and/or a biologically active variant or modification thereof is capable of blocking multiple functions of av integrins, including binding to RGD containing sequences in av-integrin ligands, such as vitronectin, fibronection and the latency associated protein of TGF-P1 ( ⁇ _ ⁇ - ⁇ 1).
- cytokine TGF- ⁇ is the main regulator of physiologic fibrogenesis and pathologic fibrosis, including SSc as described herein, and that the anti- ⁇ integrin antibody DI17E6, or a biologically active variant or modification thereof, is able to control the activation of TGF- ⁇ in a manner that appears to be advantageous for the treatment of fibrosis, fibrotic diseases and/or systemic sclerosis.
- TGF- ⁇ has many other functions in tissue repair, angiogenesis, immunoregulation, and cell proliferation and differentiation. TGF- ⁇ can be secreted by platelets, monocytes/macrophages, T cells, and fibroblasts. Its signalling and cell regulation is highly complex.
- TGF- ⁇ producing cells generate it as a biologically inactive precursor molecule that resides as a latent complex in the ECM reservoir and is unable to interact with its receptors.
- the conversion of latent TGF- ⁇ to its active form capable of binding its cell surface receptors is mediated by molecules such as thrombospondin-1 , certain ⁇ integrin heterodimers (figure 1), and various proteases, and is tightly regulated.
- TGF- ⁇ Activated TGF- ⁇ binds to the type II TGF- ⁇ receptor, triggering of an intracellular signal transduction cascade that leads to induction of target genes. So far there is evidence for ⁇ 3, ⁇ 3, ⁇ and ⁇ can control the activation of TGF- ⁇ . This is described and discussed in more detail above and/or below.
- the cytokine TGF- ⁇ is considered to be the main regulator of physiologic fibrogenesis and pathologic fibrosis, including SSc (see also the section relating to
- TGF- ⁇ "Histopathological and pathophysiological characteristics"). The numerous cellular effects of TGF- ⁇ are described herein, and some of the most pertinent roles of TGF- ⁇ , including its connection and/or its association with integrins, are given in Table 7 (below). Table 7. Fibrogenic activities of TGF- ⁇ recruits monocytes
- CTGF fibrogenic cytokine production
- IFN- ⁇ interferon-gamma
- EMT epithelial-to mesenchymal transition
- a preferred subject of the instant invention relates to the anti-av integrin antibody DI17E6, or a biologically active variant or modification thereof, for use in the treatment of patients suffering from fibrotic diseases and especially systemic sclerosis (SSc).
- fibrotic diseases and/or “systemic sclerosis” have the meaning and characteristics as is known in the art. More preferably, the terms fibrotic diseases", and/or “systemic sclerosis” have the meanings and characteristics as described above and/or below.
- a preferred subject of the instant invention relates to the anti-av integrin antibody DI17E6, or a biologically active variant or modification thereof, for use in systemic sclerosis, wherein the systemic sclerosis comprises systemic sclerosis of the lung, liver, kidney, cardiovascular system and/or or skin. More preferably, the disease to be treated according to the invention is selected from systemic sclerosis of the lung, the liver and the kidney. Especially preferably, the disease to be treated according to the invention is the systemic sclerosis of the lung or comprises the systemic sclerosis of the lung.
- the anti-av integrin antibody DI17E6, or a biologically active variant or modification thereof for use in systemic sclerosis, preferably for use in systemic sclerosis as described above and/or below in more detail, preferably wherein the systemic sclerosis affects one or more organs selected from the group consisting of lung, liver, kidney, heart and skin, more preferably lung, liver, kidney and/or heart, and especially lung or heart.
- the anti- ⁇ integrin antibody DI17E6, or a biologically active variant or modification thereof for use in the treatment of systemic sclerosis, preferably for use in the treatment of systemic sclerosis as described above and/or below in more detail, wherein the systemic sclerosis affects the cardiovascular system, the blood vessels and/or the blood.
- the disease to be treated according to the invention is preferably selected from diastolic dysfunction and myelofibrosis.
- the anti-av integrin antibody DI17E6, or a biologically active variant or modification thereof for use, preferably for use as described in more detail above and/or below, wherein the systemic sclerosis comprises one or more indications selected from the group consisting of idiopathic pulmonary fibrosis, primary sclerosing cholangitis, non-alcoholic steatohepatitis (NASH), primary focal glomerulosclerosis, primary segmental glomerulosclerosis, diabetic nephropathy, diastolic dysfunction and myelofibrosis.
- NASH non-alcoholic steatohepatitis
- the anti-av integrin antibody DI17E6, or a biologically active variant or modification thereof for use, preferably for use as described in more detail above and/or below, wherein the systemic sclerosis comprises an indication or disease, wherein one or more of the clinical pictures or manifestations of both focal glomerulosclerosis, or primary focal glomerulosclerosis, and segmental
- glomerulosclerosis or primary focal glomerulosclerosis
- the anti-av integrin antibody DI17E6, or a biologically active variant or modification thereof for use, preferably for use as described in more detail above and/or below, in the treatment of focal segmental glomerulosclerosis (FSGS).
- FSGS focal segmental glomerulosclerosis
- the anti-av integrin antibody DI17E6, or a biologically active variant or modification thereof for use, preferably for use as described in more detail above and/or below, wherein said treatment comprises patients suffering from pulmonary fibrosis and/or alveolitis (interstitial lung disease, ILD).
- the anti-av integrin antibody DI17E6, or a biologically active variant or modification thereof, for use according to claim 1 wherein the disease to be treated is systemic sclerosis of the skin.
- the systemic sclerosis of the skin is selected from the group consisting of diffuse cutaneous systemic sclerosis (dcSSc) and limited cutaneous systemic sclerosis (IcSSc).
- Especially preferred subjects of the invention include: The anti-av integrin antibody DI17E6 or a biologically active variant or modification thereof, preferably the anti-av integrin antibody DI17E6, for use in the treatment of pulmonary fibrosis, alveolitis (interstitial lung disease, ILD), and/or scleroderma! interstitial lung disease (SSc-ILD).
- ILD interstitial lung disease
- SSc-ILD scleroderma! interstitial lung disease
- the administration of said dose is repeated several times every 4 weeks or every month, respectively.
- said administration of said dose every 4 weeks or every month, respectively, is repeated at least 4 times, more preferably at least 8 times, even more preferably at least 16 times and especially at least 24 times.
- said administration of said dose every 4 weeks or every month is repeated for about one year, for about one and a half year, for about 2 years, or for about two and a half or for about three years.
- said administration of said dose every 4 weeks or every month, respectively, is preferably repeated not more than about 36 times, more preferably not more than about 28 times, even more preferably not more than about 24 times and especially not more than about 16 times or about 12 times.
- preferred ranges for the duration of said repeated administrations are 4 to 36 months, 8 to 36 months, 12 to 36 months, 8 to 28 months, 12 to 28 months, or 16 to 28 months.
- repeated administration at least temporarily, after about half a year, after about one year, after about one and a half year, after about 2 years or after about two and a half years, e.g. in order to see how the patient's state evolved and to decide wether or not a new repeated administration shall be started.
- the above discribed repeated administration is especially preferred with regard to Abituzumab.
- the anti-av integrin antibody DI17E6 or a biologically active variant or modification thereof preferably the anti-av integrin antibody DI17E6, for use in the treatment as described above and/or below, and preferably for use as described in the paragraph directly above wherein the dose, preferably the effective dose, is administered in a single dose.
- the DI17E6 antibody for use as described above and/or below, and especially as described in the paragraph directly above, comprising one or more modifications within the heavy chain framework regions
- FR3 KATMTADTSSSTAYMQLSGLTSEDSAVYYCAS (SEQ ID No. 18)
- FR4 WGQGTSVTVSS (SEQ ID No. 19),
- a method of treating fibrotic diseases preferably systemic sclerosis and especially systemic sclerosis as described above and/or below, comprising administering to a patient the DI17E6 antibody and/or a biologically active variant or modification thereof, wherein the biologically active variant or modification comprises the CDR regions and heavy and light chain variable regions, which are 80% - 95% identical in amino acid sequence compared to the variable regions of DI17E6.
- DI17E6 Immunologically triggered antibodies directed against DI17E6 can be detected in some (16%) patients; however, no impact on PKs or safety could be found.
- single-agent EMD 525797 given as single and multiple doses is shown to be well tolerated in patients. No safety concern can be identified and there is preliminary evidence of clinical benefit in numerous patients. Due to its target and safety profile, DI17E6 (EMD 525797) is a promising agent for single agent and/or combination therapy.
- DI17E6 antibody as described above and/or below for use in the treatment of disorders as described above and/or below, wherein the antibody is administered in a monotherapy setting without additional cotherapeutic agents.
- the DI17E6 antibody as described above and/or below for use in the treatment of disorders as described above and/or below, wherein the antibody is administered in an combination therapy setting in combination with MMF (Mycophenolat or Mycophenolate).
- MMF Mycophenolat or Mycophenolate
- MMF Mycophenolat or Mycophenlate
- MMF Mycophenolat or Mycophenolate
- the DI17E6 antibody as described above and/or below for use in the treatment of patients with SSc-ILD, wherein the antibody is administered in an amount of about 1.500 mg per month, preferably in an amount of about 1.500 mg as a single administration once a month, in an combination therapy setting in combination with MMF (Mycophenolat or Mycophenolate).
- MMF Mycophenolat or Mycophenolate
- DI17E6 antibody as described above and/or below for use in the treatment of fibrosis, preferably excessive and/or pathological fibrosis, preferably in a manner as described above and/or below.
- DI17E6 antibody as described above and/or below for use in the treatment of fibrotic disorders, preferably fibrotic disorders as described above and/or below, preferably in a manner as described above and/or below.
- DI17E6 antibody as described above and/or below for use in the treatment of systemic sclerosis (SSc), preferably in a manner as described above and/or below.
- systemic sclerosis comprises systemic sclerosis of the lung, liver, kidney, cardiovascular system and/or skin.
- systemic sclerosis SSc
- systemic sclerosis affects one or more organs selected from the group consisting of lung, liver, kidney, heart and skin.
- DI17E6 antibody as described above and/or below for use in the treatment of systemic sclerosis (SSc), wherein the systemic sclerosis affects the
- cardiovascular system the blood vessels and/or the blood.
- DI17E6 antibody as described above and/or below for use in the treatment of systemic sclerosis (SSc), wherein said systemic sclerosis affects the lung and/or the skin.
- DI17E6 antibody as described above and/or below foruse in the treatment of systemic sclerosis (SSc), wherein said systemic sclerosis affects the lung.
- SSc systemic sclerosis
- DI17E6 antibody as described above and/or below for use in the treatment of systemic sclerosis (SSc), wherein said systemic sclerosis affects the skin.
- DI17E6 antibody as described above and/or below for use in the treatment of systemic sclerosis (SSc), wherein said systemic sclerosis affects the liver.
- systemic sclerosis comprising one or more indications selected from the group consisting of idiopathic pulmonary fibrosis, primary sclerosing cholangitis, non-alcoholic steatohepatitis (NASH), primary focal glomerulosclerosis, primary segmental glomerulosclerosis, diabetic nephropathy, diastolic dysfunction and myelofibrosis.
- SSc systemic sclerosis
- NASH non-alcoholic steatohepatitis
- primary focal glomerulosclerosis primary segmental glomerulosclerosis
- diabetic nephropathy diastolic dysfunction
- myelofibrosis myelofibrosis
- DI17E6 antibody as described above and/or below for use in the treatment of systemic sclerosis (SSc), wherein said systemic sclerosis comprises pulmonary fibrosis and/or alveolitis (interstitial lung disease, ILD).
- SSc systemic sclerosis
- ILD interstitial lung disease
- DI17E6 antibody as described above and/or below for use in the treatment of pulmonary fibrosis and/or alveolitis (interstitial lung disease, ILD).
- DI17E6 antibody as described above and/or below for use in the treatment of SSc-ILD or scleroderma-ILD.
- DI17E6 antibody as described above and/or below for use in the treatment of patients suffering from SSc-ILD.
- DI17E6 antibody as described above and/or below for use in the treatment of patients suffering from scleroderma-ILD.
- DI17E6 antibody as described above and/or below for use in the treatment of cutaneous systemic sclerosis (dcSSc) or limited cutaneous systemic sclerosis (IcSSc).
- DI17E6 antibody as described above and/or below for use in the treatment of subjects, preferably human subjects, with systemic sclerosis-associated interstitial lung disease (SSc-ILD).
- SSc-ILD systemic sclerosis-associated interstitial lung disease
- Abituzumab for use in the treatment of subjects, preferably human subjects, with systemic sclerosis-associated interstitial lung disease (SSc-ILD).
- SSc-ILD systemic sclerosis-associated interstitial lung disease
- the DI17E6 antibody as described above and/or below for use in the treatment of subjects, preferably human subjects, with SSc-ILD who already receive mycophenolate.
- DI17E6 antibody as described above and/or below for use in the treatment of subjects, preferably human subjects, with SSc-ILD who already receive mycophenolate, preferably constant doses of mycophenolate.
- Abituzumab for use in the treatment of subjects, preferably human subjects, with SSc-ILD who already receive mycophenolate.
- the biologically active variant or modification of said anti-av integrin antibody DI17E6 as described above and/or below for use in the treatment of fibrosis and/or fibrotic disorders wherein said biological active variant or modification comprises the CDR regions and heavy and light chain variable regions of DI17E6, which are at least 80% identical, at least 90% identical, at least 95% identical, at least 98% identical or at least 99% identical in amino acid sequence compared to the variable regions of DI17E6.
- the biologically active variant or modification of said anti-av integrin antibody DI17E6 as described above and/or below for use in the treatment of fibrosis and/or fibrotic disorders wherein said biological active variant or modification comprises the heavy and/or light chain variable regions of DI17E6, which are at least 90% identical, at least 95% identical, at least 98% identical, at least 99% identical, or at least 99.5% identical in amino acid sequence compared to the respective heavy and/or light chain variable regions of DI17E6.
- the biologically active variant or modification of said anti-av integrin antibody DI17E6 as described above and/or below for use in the treatment of fibrosis and/or fibrotic disorders wherein said biological active variant or modification comprises the heavy and/or light chain CDR regions of DI17E6, which are at least 90% identical, at least 92% identical, at least 94% identical, at least 96% identical, at least 98% or at least 99% identical in amino acid sequence compared to the respective heavy and/or light chain CDR regions of of DI17E6.
- FR3 KATMTADTSSSTAYMQLSGLTSEDSAVYYCAS (SEQ ID No. 18)
- FR4 WGQGTSVTVSS (SEQ ID No. 19),
- systemic sclerosis comprises systemic sclerosis of the lung, liver, kidney, cardiovascular system and/or skin.
- systemic sclerosis SSc
- said systemic sclerosis affects one or more organs selected from the group consisting of lung, liver, kidney, heart and skin.
- indications selected from the group consisting of idiophathic pulmonary fibrosis, primary sclerosing cholangitis, non-alcoholic steatohepatitis (NASH or Nash), primary focal glomerulosclerosis, primary segmental glomerulosclerosis, diabetic nephropathy, diastolic dysfunction and myelofibrosis.
- NASH or Nash non-alcoholic steatohepatitis
- a method of treating fibrosis and/or fibrotic diseases in a subject by:
- NM_000093 IGFBP2 (NM_000597), NM_005576, MOXD1 (NM_015529), ADRA2A (NM_000681), COL5A2 (NM_000393), MMP10 (NM_002425),
- TNFRSF21 (NM_014452), ITGA7 (NM_002206), TGF- 3 (NM_003239),
- MMP11 (NM_005940), SPP1 (NM_000582), CCL2 (NM_002982), and TNC (NM_002160), in particular the 9-gene signature based on the genes COL15A1 (NM_001855), COL1A1 (NM_000088), COMP (NM_000095), COL10A1
- TUAD signature (NM_000493), COL5A1 (NM_000093), COL5A2 (NM_000393), ITGA7 (NM_002206), MMP11 (NM_005940), and TNC (NM_002160) hereafter also referred to as TUAD signature.
- a method of monitoring the severity of fibrosis in fibrotic diseases and/or the emergence of fibrosis in diseases with potential to develop fibrosis in a subject by tracking the changes of a score calculated from a multi-gene signature comprising 2 or more, preferably 5 or more, more preferably 9 or more, even more preferably 15 or more and especially 16, 17, 18 or 19 genes, selected from the group consisting of the genes COL15A1 (NM_001855), COL1A1
- NM_000493 COL5A1 (NM_000093), IGFBP2 (NM_000597), NM_005576, MOXD1 (NM_015529), ADRA2A (NM_000681), COL5A2 (NM_000393), MMP10 (NM_002425), TNFRSF21 (NM_014452), ITGA7 (NM_ 002206), TGF ⁇ 3
- NM_002982 and TNC (NM_002160), in particular the 9-gene signature based on the genes COL15A1 (NM_001855), COL1A1 (NM_000088), COMP
- TUAD signature (NM_002160) hereafter also referred to as TUAD signature.
- a method of treating fibrosis and/or fibrotic diseases in a subject by:
- a gene signature comprising 2 or more, preferably 5 or more, more preferably 10 or more, even more preferably 15 or more and especially 16, 17, 18 or 19 genes, selected from the group consisting of the genes COL15A1 (NM_001855), COL1A1 (NM_000088), COMP (NM_000095), RGS5 (NM_003617), COL10A1 (NM_000493), COL5A1 (NM_000093), IGFBP2 (NM_000597), NM_005576, MOXD1 (NM_015529), ADRA2A (NM_000681), COL5A2 (NM_000393), MMP10 (NM_002425), TNFRSF21 (NM_014452), ITGA7 (NM_002206), TGF- 3
- NM_002982 and TNC (NM_002160), in particular the 9-gene signature based on the genes COL15A1 (NM_001855), COL1A1 (NM_000088), COMP
- TUAD signature (NM_002160) hereafter also referred to as TUAD signature.
- DI17E6 or a biologically active variant or modification thereof, preferably a biologically active variant or modification thereof according as described herein, and especially abituzumab, for the manufacture of a medicament for the prophylaxis and/or treatment of fibrosis and/or fibrotic disorders.
- DI17E6 or a biologically active variant or modification thereof, preferably a biologically active variant or modification thereof according as described herein, and especially abituzumab, for the manufacture of a medicament for the prophylaxis and/or treatment of fibrosis and/or fibrotic disorders as described herein, and especially the prophylaxis and/or treatment of one or more indications selected from the group consisting of idiophathic pulmonary fibrosis, primary sclerosing cholangitis, non-alcoholic steatohepatitis (NASH), primary focal glomerulosclerosis, primary segmental
- abituzumab for the manufacture of a medicament for the prophylaxis and/or treatment of fibrosis and/or fibrotic disorders as described herein, and especially the prophylaxis and/or treatment of one or more indications selected from the group consisting of idiophathic pulmonary fibrosis, primary sclerosing cholangitis, non-alcoholic steatohepatitis (NASH), primary focal
- nephropathy nephropathy, diastolic dysfunction and myelofibrosis.
- abituzumab for the manufacture of a medicament for the prophylaxis and/or treatment of systemic sclerosis, preferably comprising pulmonary fibrosis, alveolitis (interstitial lung disease, ILD), and/or scleroderma! interstitial lung disease (SSc-ILD).
- ILD interstitial lung disease
- SSc-ILD scleroderma! interstitial lung disease
- abituzumab for the manufacture of a medicament for the prophylaxis and/or treatment of focal segmental glomerulosclerosis (FSGS).
- FSGS focal segmental glomerulosclerosis
- DI17E6 or a biologically active variant or modification thereof, preferably a biologically active variant or modification thereof according as described herein, and especially abituzumab, for the manufacture of a medicament for the prophylaxis and/or treatment of fibrosis and/or fibrotic disorders as described herein, wherein the treatment additionally comprises the administration of one or more active ingredients, selected from the group consisting of mycophenolic acid, mycophenolate, mycophenolate mofetil, mycophenolate sodium, methotrexate, amethopterin and prednisone.
- active ingredients selected from the group consisting of mycophenolic acid, mycophenolate, mycophenolate mofetil, mycophenolate sodium, methotrexate, amethopterin and prednisone.
- abituzumab for the manufacture of a medicament for the prophylaxis and/or treatment of fibrosis and/or fibrotic disorders as described herein, wherein the treatment additionally comprises the administration of
- mycophenolic acid mycophenolate, mycophenolate mofetil and/or
- abituzumab for the manufacture of a medicament for the prophylaxis and/or treatment of fibrosis and/or fibrotic disorders as described herein, wherein the treatment additionally comprises the administration of
- methotrexate and/or amethopterin are methotrexate and/or amethopterin.
- abituzumab for the manufacture of a medicament for the prophylaxis and/or treatment of fibrosis and/or fibrotic disorders as described herein, wherein the treatment additionally comprises the administration of prednisone.
- DI17E6 Due to its uniquely different mode of action, DI17E6, or a biologically active variant or modification thereof, preferably a biologically active variant or modification thereof according as described herein, and especially abituzumab, is deemed to be applicable in combination with basically all treatment options applied in the
- prophylaxis and/or treatment of fibrosis and/or fibrotic disorders especially fibrosis and/or fibrotic disorders as described herein.
- DI17E6, or a biologically active variant or modification thereof, preferably a biologically active variant or modification thereof according as described herein, and especially abituzumab, to treatment regimen that include the
- a typical standard medicament in the treatment of fibrosis and/or fibrotic disorders including, but not limited to one or more active ingredients, selected from the group consisting of mycophenolic acid, mycophenolate, mycophenolate mofetil, mycophenolate sodium, methotrexate, amethopterin and prednisone.
- anti-av integrin antibody DI17E6 or the biologically active variant or modification thereof, for use as described above and/or below, preferably as described above, wherein said antibody, or said modification thereof, is the antibody with the registered International Non-proprietary Name (INN)
- Abituzumab is a method as described above and/or below, preferably as described above, wherein said antibody, or said modification thereof, is the antibody with the registered International Non-proprietary Name (INN) Abituzumab.
- the use of the anti-av integrin antibody DI17E6, or the biologically active variant or modification thereof, for the manufacture of a medicament for the prophylaxis and/or treatment of fibrosis and/or fibrotic disorders preferably as described above and/or below, and especially preferably as described above, wherein said antibody, or said modification thereof, is the antibody with the registered International Non-proprietary Name (INN) Abituzumab.
- the anti-av integrin antibody DI17E6 preferably also referred to herein as Abituzumab or abituzumab
- Abituzumab or abituzumab is an engineered specifically tailored lgG2 hybrid monoclonal antibody directed to alpha-v integrin (receptor).
- This antibody is described in detail in WO 2009/010290, the disclosure of which is incorporated herein in its entirety.
- mouse mAb 17E6 Its hypervariable regions (CDRs) derive from murine mAb 17E6 (EMD 73034).
- This parent mouse lgG1 antibody is described, for example by Mitjans et al. (1995; J. Cell Sci. 108, 2825) and patents US 5,985,278 and EP 719 859.
- Mouse mAb 17E6 is produced by hybridoma cell line 272-17E6 and deposited under accession number DSM ACC2160.
- the anti-av integrin antibody DI17E6 as used according to the invention comprises:
- anti-av integrin antibody 17E6 optionally comprising one or more mutations of amino acids at specific positions, and
- lgG2 hinge region was replaced by the human lgG1 hinge domain, and;
- DI17E6 (designated as “DI17E6Y2h(N297Q)" or “EMD 525797”) as used for the treatment as claimed and in the clinical trials as described above and below, has the following amino acid sequence:
- variable and constant light chain sequences SEQ ID No. 1
- variable and constant heavy chain sequences SEQ ID No. 2
- DI17E6 variants of DI17E6 can be used according to the teaching of this invention.
- DI17E6 variants comprising one or more modifications within the heavy chain framework regions
- FR3 KATMTADTSSSTAYMQLSG LTS E DSAVYYCAS (SEQ ID No. 18)
- FR4 WGQGTSVTVSS (SEQ ID No. 19),
- position heavy chain framework region is mutated at one, more or all of the following positions can be mutated: A9, E13, M20, K38, R40, A72, S76, Q82, G85, T87, S91 and S113.
- the invention as described includes also modifications and variants of the DI17E6 antibody that are functionally and / or pharmaceutically identical or similar to unmodified DI17E6, and wherein the CDR regions and heavy and light chain variable regions are at least 80%, at least 85%, at least 90%,at least 95%, at least 98%, or at least 99% identical in their amino acid sequence compared to the respective variable regions of DI17E6.
- the invention also includes modifications and variants of the DI17E6 antibody that are functionally and / or pharmaceutically identical or similar to unmodified DI17E6, and wherein the constant regions are at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 98%, or at least 99%, identical in their amino acid sequence compared to the respective constant regions of DI17E6. Changes in the constant regions of the IgG chains of the antibody may improve specific properties like immunogenicity, ADCC, and so on.
- the invention as described includes also modifications and variants of the DI17E6 antibody that are functionally and / or pharmaceutically identical or similar to (unmodified) DI17E6 or abituzumab, and wherein the heavy and light chain variable regions are at least 95%, at least 98%, at least 99% or at least 99.5% identical in their amino acid sequence compared to the respective heavy and light chain variable regions of DI17E6.
- the invention also includes modifications and variants of the DI17E6 antibody that are functionally and / or pharmaceutically identical or similar to unmodified DI17E6, preferably as described above in this paragraph, wherein the constant regions are at least 90%, or at least 95%, or at least 99%, or at least 99.5%, or at least 99.9%, identical in their amino acid sequence compared to the respective constant regions of DI17E6. Changes in the constant regions of the IgG chains of the antibody may improve specific properties like immunogenicity, ADCC, and so on.
- the invention as described includes also modifications and variants of the DI17E6 antibody that are functionally and / or pharmaceutically identical or similar to (unmodified) DI17E6 or abituzumab, and wherein the CDR regions on the variable heavy and/or light chain are at least 90%, at least 92%, at least 94%, at least 96% or at least 98% identical in their amino acid sequence compared to the respective CDR regions on the variable heavy and/or light chain regions of DI17E6.
- the invention also includes modifications and variants of the DI17E6 antibody that are functionally and / or pharmaceutically identical or similar to unmodified DI17E6, preferably as described above in this paragraph, wherein the constant regions are at least 90%, or at least 95%, or at least 99%, or at least 99.5%, or at least 99.9%, identical in their amino acid sequence compared to the respective constant regions of DI17E6.
- the invention as described includes also modifications and variants of the DI17E6 antibody that are functionally and / or pharmaceutically identical or similar to (unmodified) DI17E6 or abituzumab, wherein the heavy and light chain CDR regions are 100% identical to (unmodified) DI17E6 or abituzumab, but wherein the heavy and light chain variable regions other than said CDR regions are at least 95%, at least 98%, at least 99% or at least 99.5% identical in their amino acid sequence compared to the respective heavy and light chain variable regions of DI17E6.
- the invention preferably also includes modifications and variants of the DI17E6 antibody that are functionally and / or pharmaceutically identical or similar to unmodified DI17E6, preferably as described above in this paragraph, wherein the constant regions are at least 90%, or at least 95%, or at least 99%, or at least 99.5%, or at least 99.9%, identical in their amino acid sequence compared to the respective constant regions of DI17E6.
- the invention as described includes also modifications and variants of the DI17E6 antibody that are functionally and / or pharmaceutically identical or similar to (unmodified) DI17E6 or abituzumab, wherein the CDR regions on the variable heavy and/or light chain are at least 90%, at least 92%, at least 94%, at least 96% or at least 98% identical in their amino acid sequence compared to the respective CDR regions on the variable heavy and/or light chain regions of DI17E6, and wherein the heavy and light chain variable regions other than said CDR regions are at least 95%, at least 98%, at least 99% or at least 99.5% identical in their amino acid sequence compared to the respective heavy and light chain variable regions of DI17E6.
- the invention preferably also includes modifications and variants of the DI17E6 antibody that are functionally and / or pharmaceutically identical or similar to unmodified DI17E6, preferably as described above in this paragraph, wherein the constant regions are at least 90%, or at least 95%, or at least 99%, or at least 99.5%, or at least 99.9%, identical in their amino acid sequence compared to the respective constant regions of DI17E6.
- the DI17E6 antibody or abituzumab is a recombinant, de- immunized monoclonal antibody of the lgG2 subclass as described above and below which targets and inhibits ligand binding to human av-integrins.
- the carbohydrate structures normally present in the Fc region of said DI17E6 antibody or abituzumab have been removed by genetically altering the amino acid residue that normally serves as the point of attachment rendering the molecule aglycosylated.
- the antibody is especially preferably composed of 4 polypeptide chains, 2 identical heavy chains consisting of 447 amino acids each and 2 identical light chains consisting of 214 amino acids each. Typically, the 4 chains are held together by a combination of covalent (disulfide) and non-covalent bonds.
- the approximate molecular weight of the molecule is 145 kDa.
- DI17E6 antibody as described herein and especially
- abituzumab or EMD 525797 is characterized as a high affinity pan-av-integrin inhibitor, which has been shown in vitro to inhibit integrin-dependent activation of latent TGF- ⁇ , to inhibit FMT, to prevent upregulation of integrins on myofibroblasts, and to block contraction of myofibroblasts.
- it specifically binds to a unique epitope that is specific for the human av-integrin chain.
- it does not crossreact with other integrins such as the ⁇ 4 ⁇ 1 and the platelet fibrinogen receptor allbp3 and preferably does not trigger ADCC and CDC.
- DI17E6 is believed to be highly effective in patients suffering from fibrotic diseases, more preferably systemic sclerosis and especially in one or more of the indications of systemic sclerosis described herein. More
- abituzumabis believed to be highly effective in patients suffering from fibrotic diseases, more preferably systemic sclerosis and especially in one or more of the indications of systemic sclerosis described herein.
- DI17E6 as described herein, and especially
- abituzumab is suitable to provide a more effective and/or safer therapy od fibrotic diseases as described herein, will be better tolerated and can provoke better immune response than seen with the therapies previously known.
- treatment with abituzumab is believed to be more effective, safer, will be better tolerated and can provoke better immune responses in the treatment of patients with SSc-ILD, preferably also patients who already receive constant doses of mycophenolate.
- TGF- ⁇ is shown to be the master mediator of tissue fibrosis.
- the TGF- ⁇ signalling pathways are activated, and that some of the ⁇ integrins heterodimers control the activation of TGF- ⁇ , the anti-av integrin antibody DI17E6, or a biologically active variant or modification thereof, is believed to have a beneficial effect in SSc due to its shown interference with TGF- ⁇ activation, and additionally due its TGF- independent functions on av integrins that are found to be involved in fibrosis.
- EMD 525797 may be beneficial in patients with SSc through multiple modes of action. This is described in more detail above and/or below.
- DI17E6 cannot be directly tested in rodent models of fibrosis because of lacking cross-reactivity (see section A3.1.3 Mode of action). Preclinical models of fibrosis in nonhuman primates for SSc or SSc-ILD are deemed difficult, if not unfeasible.
- Osteopontin is reported to be one of the cytokines produced by activated macrophages and mediates various functions, including cell attachment and migration, by interacting with av integrin.
- Transforming growth factor beta is an important driver of pulmonary fibrosis and therapeutic strategies to inhibit its actions are sought.
- TGF- ⁇ has other homeostatic roles that could make therapeutic inhibition problematic.
- Horan et al. Am J Respir Crit Care Med Vol 177. pp 56-65, 2008
- Inhibition of the integrin avb6, a key activator of TGF- ⁇ in lung using a monoclonal pSmad2/3 primary antibody that blocks avb6-mediated TGF- ⁇ activation, in murine bleomycin-induced lung fibrosis model.
- BAL bronchoalveolar lavage
- TGF- ⁇ activation of TGF- ⁇ by ⁇ probably requires more than simply binding to LAP, as we have identified cytoplasmic mutants that bind LAP but do not activate TGF- ⁇ . Furthermore, the ⁇ 1 and ⁇ 8 ⁇ 1 integrins are both able to bind LAP but do not activate TGF- ⁇ .
- the PARI -mediated enhancement of ⁇ -dependent TGF- ⁇ activation found in these in vitro experiments might be interpreted as one mechanism by which activation of the coagulation cascade contributes to the development of acute lung injury.
- TGF Transforming growth factor
- TGF- ⁇ (but not TGF ⁇ 2) could be activated by two members of the integrin family, ⁇ 6 and ⁇ 8, which both were found to be expressed on said airway epithelial cells.
- wounding of the cell layer induced activation of TGF- ⁇ through effects of both integrins but the chosen mouse monoclonal antibody against human ⁇ (37E1) enhanced the degree of wound closure, whereas the chosen mouse monoclonal antibodies against human ⁇ (anti-HEL-AB MSB0011523H-1 , 10D5) did not.
- Transforming growth factor-b1(TGF ⁇ 1) is a potent mediator of the differentiation of fibroblasts into myofibroblasts.which is characterized by the appearance of the cytoskeletal protein a-smooth muscle actin. Lygoe et al. (Wound Rep. Reg.
- av integrins in the differentiation of human fibroblasts from the mouth, skin, and kidney into myofibroblasts and suggest that there might be a common differentiation pathway.
- av integrins might also participate in the optimal function of the angiogenesis through interaction with various growth factors such as Platelet Derived Growth Factor
- PDGF Vascular Endothelial Growth Factor
- FGF Fibroblast Growth Factor
- EMT Epithelial-to-mesenchymal transition
- TGF- ⁇ and ⁇ integrins are believed to be involved in this transdifferentiation process and that blocking of the function of these integrins by the anti-av integrin antibody DI17E6, or a biologically active variant or modification thereof downregulates EMT and thus become beneficial in fibrosis, fibrotic disorders and/or fibrosing lung disorders.
- Oxidative stress is believed to play a role in fibrotic diseases.
- ⁇ integrins are found to be overexpressed in SSc-ILD and other forms of lung fibrosis, and the respiratory epithelium in lung biopsies from patients with SSc-ILD and IPF expresses increased levels of ⁇ 6 by immunohistochemistry. Increased numbers of ⁇ 3, ⁇ 5 and ⁇ 6 expressing T cells are found in the bronchoalveolar lavage fluid from patients with SSc compared to normal controls (Luzina et al., Am J Respir Crit Care Med Vol 177. pp 56-65, 2008.
- ⁇ 6 integrin knockout mice develop lung inflammation, but do not proceed to develop pulmonary fibrosis, after bleomycin exposure (Luzina et al., ARTHRITIS & RHEUMATISM, Vol. 48, No. 8, August 2003, pp 2262-2274).
- Dermal fibroblasts from patients with SSc display enhanced expression of ⁇ 3 and ⁇ 5, and elevated TGF- ⁇ activation, which is inhibited by blocking antibody P1 F6 directed against ⁇ 5 (Asano et al., ARTHRITIS & RHEUMATISM Vol. 52, No. 9, September 2005, pp 2897-2905; Journal of Immunology, 2005, 175: 7708-7718;
- Cartilage oligomeric protein is an extracellular matrix (ECM) protein that resides in cartilage, tendon, and other connective tissue. COMP is overexpressed in skin biopsies from patients with SSc. In SSc, serum COMP levels are elevated, predict mortality, and correlate with lung function decline and skin fibrosis as
- mRSS Rodnan Skin Score
- COMP is also one of the four signature RNAs in SSc skin that predict severity of skin involvement.
- Yang et al. describe that Periostin facilitates skin sclerosis via PI3K/Akt dependent mechanism in a mouse model of scleroderma (Yang L, Serada S, Fujimoto M, Terao M, Kotobuki Y, et al. (2012) PLoS ONE 7(7): e41994 doi:10.1371/journal.pone.0041994).
- OPN-deficient mice developed less dermal fibrosis compared with wild-type (WT) mice in said fibrosis model. Finally, they found TGF- ⁇ production by OPN-deficient macrophages to be reduced
- OPN levels are reported to be increased in SSc patients, and the data obtained are deemed to suggest that OPN might play an important role in the development of dermal fibrosis in mice, and that OPN thus might be a therapeutic target in SSc.
- Plasma of a total of 70 patients with SSc was analysed by Lorenzen et al.
- EMD 525797 in various cancer indications is expected to be similar in fibrotic diseases, including SSc and especially including SSc-ILD. Together with the expected benefit of EMD 52579, the benefit /risk ratio of EMD 525797 in SSc-ILD should be positive in SSc-ILD and greater than for CYC. EMD 525797 is thus believed to be also beneficial on other manifestations of SSc.
- cytokine is a generic term for proteins released by one cell population which act on another cell as intercellular mediators.
- cytokines are lymphokines, monokines, and traditional polypeptide hormones. Included among the cytokines are growth hormone such as human growth hormone, N-methionyl human growth hormone, and bovine growth hormone; parathyroid hormone;
- thyroxine insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); hepatic growth factor; fibroblast growth factor; prolactin; placental lactogen; mouse gonadotropin-associated peptide; inhibin; activin; vascular
- VEGF endothelial growth factor
- TPO thrombopoietin
- nerve growth factors such as NGF ; platelet-growth factor; transforming growth factors (TGFs) such as TGF-a and TGF- ⁇ ; erythropoietin (EPO); interferons such as IFNa, IFNp, and IFNy; colony stimulating factors such as M-CSF, GM-CSF and G-CSF; interleukins such as IL-1 , IL-1a, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11 , IL-12; and TNFa or TNFp.
- Preferred cytokines according to the invention are interferons and TNFa.
- an "anti-angiogenic agent” refers to a natural or synthetic compound which blocks, or interferes with to some degree, the development of blood vessels.
- the anti- angiogenic molecule may, for instance, be a biological molecule that binds to and blocks an angiogenic growth factor or growth factor receptor.
- the preferred anti- angiogenic molecule herein binds to a receptor, preferably to an integrin receptor or to VEGF receptor.
- the term includes according to the invention also integrin (receptor) inhibitors.
- integrin inhibitors or "integrin receptor inhibitors” refers to a natural or synthetic molecule that blocks and inhibit an integrin receptor.
- the term includes antagonists directed to the ligands of said integrin receptors (such as for v &3: vitronectin, fibrin, fibrinogen, von Willebrand's factor, thrombospondin, laminin; for ⁇ ⁇ ⁇ : vitronectin; for ⁇ ⁇ ⁇ : fibronectin and vitronectin; for ⁇ ⁇ : fibronectin).
- Antagonists directed to the integrin receptors are preferred according to the invention.
- Integrin (receptor) antagonists may be natural or synthetic peptides, non-peptides, peptidomimetica, immunoglobulins, such as antibodies or functional fragments thereof, or immunoconjugates (fusion proteins).
- Preferred integrin inhibitors of the invention are directed to receptor of a v integrins (e.g. ⁇ ⁇ ⁇ 3) ⁇ ⁇ ⁇ 5, ⁇ ⁇ ⁇ 6 and subclasses).
- Preferred integrin inhibitors are a v antagonists, and in particular ⁇ ⁇ ⁇
- Preferred a v antagonists according to the invention are RGD peptides, peptidomimetic (non-peptide) antagonists and anti-integrin receptor antibodies such as antibodies blocking a v receptors.
- RGD peptides RGD peptides
- peptidomimetic (non-peptide) antagonists RGD peptides
- anti-integrin receptor antibodies such as antibodies blocking a v receptors.
- Exemplary, non-immunological ⁇ ⁇ ⁇ 3 antagonists are described in the teachings of US 5,753,230 and US 5,766,591.
- Preferred antagonists are linear and cyclic RGD-containing peptides. Cyclic peptides are, as a rule, more stable and elicit an enhanced serum half-life.
- a preferred further integrin antagonist of the invention is, however, cyclo-(Arg-Gly-Asp-DPhe-NMeVal) (EMD 121974, Cilengitide ® , Merck KGaA, Germany; EP 0770 622) which is efficacious in blocking the integrin receptors ⁇ ⁇ ⁇ 3 and ⁇ ⁇ ⁇ 5, and to a lesser extend ⁇ ⁇ ⁇ , ⁇ ⁇ , ⁇ ⁇ , ⁇ 3-
- a combination therapy of DI17E6 together with Cilengitide in fibrotic disease patients can be effective according to the invention.
- DI17E6 is administered usually by intravenous injection, however other administration forms convenient in the art for antibody / protein drugs are applicable. All standard infusion solutions and formulation are applicable, such as described in
- WO 2005/077414 or WO 2003/053465 including liposomal formulations. It is, in addition, favorable to provide human serum albumin nanoparticles loaded with
- DI17E6 and optionally (to increase cytotoxicity) chemotherapeutic drugs (Biomaterials 2010, 8, 2388-98; Wagner et al.).
- the anti-av integrin antibody DI17E6, or DI17E6, according to the instant invention is the antibody with the registered International Non-Proprietary Name (INN) Abituzumab.
- Abituzumab is a recombinant, de-immunized monoclonal antibody of the lgG2 subclass that targets and blocks ligand binding to the human av-integrins.
- the carbohydrate structures normally present in the Fc region have been removed by genetically altering the amino acid residue that normally serves as the point of attachment rendering the molecule aglycosylated.
- the antibody Abituzumab is preferably composed of four polypeptide chains, two preferably identical heavy chains consisting of 447 amino acids each and two preferably identical light chains consisting of 214 amino acids each. The four chains are held together by a combination of covalent (disulfide) and non-covalent bonds.
- the approximate molecular weight of the molecule is 145 kDa.
- the antibody Abituzumab can be produced by mammalian cell culture in a serum-free growth medium.
- the antibody be purified by affinity and ion-exchange
- Abituzumab e.g. in the concentration of 250 mg / 10 mL can be used as the final drug product as a sterile solution intended for intravenous (i.v.) administration.
- Abituzumab drug product can be supplied in a 30 R type I glass vial, e.g. closed with a grey butyl rubber stopper and for example sealed with an aluminum/red polypropylene flip-off seal.
- Such vials can be used as single-use vial contains, e.g. containing 250 mg of Abituzumab as a 25 mg/mL preservative-free citrate buffered saline solution, for example containing polysorbate 80 (Tween® 80) as stabilizer.
- Such vials may contain a sufficient overage to remove a 10 mL volume of Abituzumab final drug product.
- EP European Pharmacopeia
- USP United States Pharmacopeia
- Abituzumab is a humanized lgG2 antibody that is genetically modified not to induce antibody-dependent cell cytotoxicity (ADCC) or complement- dependent cytotoxicity (CDC).
- Said Abituzumab antibody binds to the human av- integrin receptor subunit with high specificity, thereby inhibiting ligand binding to the av heterodimers ( ⁇ 1 , ⁇ 3, ⁇ , ⁇ 6, ⁇ ). It specifically inhibits ⁇ -integrins and blocks av-integrin-mediated cell attachment and migration. It does not cross-react with other integrins, including the platelet fibrinogen receptor ⁇ 3, and recognizes only human and monkey av-integrins.
- Abituzumab recognizes an epitope on the av- integrin receptor subunit that is not located in or close to the ligand pocket. Therefore, its mechanism of action differs from that described for pure ligand-competing antagonists such as cyclic RGD peptides.
- the integrins ⁇ 3 and ⁇ are selectively expressed on activated endothelial cells (EC), on resting platelets, smooth muscle cells, in the thyroid, on some kidney endothelia and epithelia, on the fallopian tube endothelium, and on osteoclasts.
- av-integrins are expressed to a variable extent on malignant cells from different tumor entities, including those from colorectal cancer and prostate cancer. Accordingly, the binding of Abituzumab to its target preferably functionally blocks the integrin receptor and thus inhibits its binding to the corresponding extracellular matrix (ECM) ligand (i.e. vitronectin).
- ECM extracellular matrix
- Abituzumab binds only to human and cynomolgus monkey ⁇ -integrins, with comparable cross-reactivity between human and monkey tissues.
- Abituzumab has been shown in vitro to interfere with several aspects involved in tumor angiogenesis, such as EC attachment to ECM, destabilization of focal contacts, EC migration, transmission of angiogenic growth factor signaling (VEGF-induced ERK phosphorylation) and EC viability.
- VEGF-induced ERK phosphorylation angiogenic growth factor signaling
- VEGF-induced ERK phosphorylation angiogenic growth factor signaling
- VEGF-induced ERK phosphorylation angiogenic growth factor signaling
- Abituzumab In vivo, the anti-tumor effect of Abituzumab was evaluated using different av-integrin expressing tumor cell lines for tumor xenograft models (e.g., melanoma, NSCLC, CRC, prostate cancer).
- av-integrin expressing tumor cell lines for tumor xenograft models e.g., melanoma, NSCLC, CRC, prostate cancer.
- Abituzumab is specific for human and monkey av- integrins, its anti-angiogenic activity cannot be studied in conventional rodent xenograft tumor models. Therefore, the xenograft tumor experiments in mice demonstrated solely the potential anti-tumor activity of Abituzumab.
- Abituzumab was able to inhibit the growth in in vivo tumor experiments using cancer cell lines or primary explants of different indications (e.g., melanoma, NSCLC, prostate cancer and CRC).
- Abituzumab The anti-angiogenic mechanism of action of Abituzumab was evaluated in a human skin xenog raft/tumor cell line experiment in the absence of the target av-integrins on the malignant cells.
- Abituzumab inhibited the growth of human av-integrin-deficient melanoma cells injected into human skin that had been transplanted onto SCID mice. Because of the absence of the target on the tumor cells themselves, Abituzumab can target only the human endothelial cells, and tumor growth reduction is most likely caused by inhibition of tumor angiogenesis.
- Systemic administration of Abituzumab in cynomolgus monkeys blocked the induction of angiogenesis in subcutaneously implanted Matrigel plugs containing angiogenic growth factors to stimulate
- Especially preferred according to the invention are subjects as described herein, wherein the characteristics of two or more preferred, more preferred and/or especially preferred embodiments, aspects and/or subjects are combined into one embodiment, aspect and/or subject.
- preferred subjects or embodiments can be combined with other preferred subjects or embodiments; more preferred subjects or embodiments can be combined with other less preferred or even more preferred subjects or embodiments; especially preferred subjects or embodiments can be combined with other just preferred or just even more preferred subjects or embodiments, and the like.
- fibrotic disorder(s) and “fibrotic disease(s)” as used herein are also well-known and understood in the art.
- they are preferably used as synonyms and thus are preferably interchangeable, if the context they are used herein does not strongly implicate otherweise.
- the terms “week'V'a week”, “monthVa month” and/or “year'V'a year” can used with slight deviations from the definitions of the gregorian calendar.
- a month is often referred to as 28 days
- a year is often referred to 48 weeks.
- the term “week” or “a week” preferably refers to a period of time of about 5, about 6 or about 7 days, more preferably about 7 days.
- the term “month” or “a month” preferably refers to a period of time of about 28, about 29, about 30 or about 31 days, more preferably about 28, about 30 or about 31 days.
- year or “a year” preferably refers to a period of time of about 12 months or to a period of time of about 48, about 50, or about 52 weeks, more preferably12 months, or about 48 or about 52 weeks.
- aSMA Alpha Smooth Muscle Actin
- BSA Bovine Serum Albumin
- FGM Fibroblast Growth Medium
- FMT Fibroblast to Myofibroblast Transition
- IXM Image Xpress Micro Screening System
- NHLF Normal Human Lung Fibroblasts
- PBS Phosphate-Buffered Saline
- TGF- ⁇ Transforming Growth Factor-Beta 1
- FBS Fetal Bovine Serum
- TGF- ⁇ is a potent mediator of fibroblast to myofibroblast transition (FMT) which contributes to increased extracellular matrix deposition and is main driver of fibrotic diseases.
- FMT myofibroblast transition
- TGF- ⁇ is secreted in a latent form which contains a Latency Associated Peptide (LAP) region.
- LAP Latency Associated Peptide
- the LAP of TGF- ⁇ contains an RGD motif which interacts with the integrins ⁇ 1 , ⁇ 3, ⁇ 5, ⁇ and ⁇ resulting in activation of TGF- ⁇ .
- Abituzumab is a human antibody specific for av and therefore inhibits ⁇ 1 , ⁇ 3, ⁇ , ⁇ 6 and ⁇ .
- abituzumab The ability of abituzumab to block FMT was examined using an epithelial cell/fibroblast co-culture, mimicking the potential interaction of epithelial cells and fibroblasts in tissues undergoing fibrosis.
- Co-culture of NCI-H358 or Calu3 cells with fibroblasts resulted in induction of aSMA and multiple mRNA transcripts that are markers for FMT and also increased IL-6 production. In this system these markers were reduced by abituzumab treatment, demonstrating that av integrins play a role in FMT.
- Fibrotic diseases are characterized by excessive scarring due to production, deposition and contraction of extracellular matrix and is believed to be driven by myofibroblast proliferation and activation. Fibrotic diseases represent one of the largest groups of diseases for which there is no effective therapy. The fibrotic processes is regulated by complex set of interactions within a network of profibrotic and antifibrotic mediators. TGF- ⁇ signaling is believed to play an important role in fibroblast to myofibroblast transition (FMT) which contributes to increased
- TGF- ⁇ isoforms are synthesized as latent precursers complexed with latent TGF- ⁇ binding proteins, which contains a Latency Associated Peptide (LAP) region.
- LAP Latency Associated Peptide
- the LAP of TGF- ⁇ contains an RGD motif which interacts with the integrins ⁇ 1 , ⁇ 3, ⁇ , ⁇ and ⁇ resulting in activation of TGF- ⁇ .
- Abituzumab is a pan-av integrin antibody that binds allosterically to the ligand-binding av subunit and thus prevents ligand from binding to all ⁇ heterodimers and therefore inhibits av integrin-dependent activation of latent TGF- ⁇ and thus blocks acquisition of the myofibroblast phenotype by fibroblasts and other precursors.
- the purpose of the present study was to determine the ability of abituzumab to block TGF- ⁇ activation and FMT in vitro and thus showing its potential as a therapeutic agent for fibrotic diseases.
- test system is epithelial cell/fibroblast co-culture, mimicking the potential interaction of epithelial cells and fibroblasts in tissues undergoing fibrosis.
- Normal human lung fibroblast (NHLF) or Normal human dermal fibroblast (NHDF) from healthy donors were cocultured with NCI-H358 or Calu 3 cell line.
- Fibroblast culture media FGM with 2% FBS: FGMTM -2 BulletKitTM (CC-3132) contains one 500 ml bottle of Fibroblast Cell Basal Medium (CC-3131) and Fibroblast Bullet Kit (CC-4126) with the following growth supplements: 0.5ml hFGF-B (CC- 4065J); 0.5ml Insulin (CC-4021J); 10ml FBS (CC-4101J); 0.5ml GA-1000 (CC- 4081 J).
- FGMTM -2 BulletKitTM CC-3132 contains one 500 ml bottle of Fibroblast Cell Basal Medium (CC-3131) and Fibroblast Bullet Kit (CC-4126) with the following growth supplements: 0.5ml hFGF-B (CC- 4065J); 0.5ml Insulin (CC-4021J); 10ml FBS (CC-4101J); 0.5ml GA-1000 (CC- 4081 J).
- Fibroblast culture media for FMT assays FGM with 0.1% FBS: FGMTM -2 BulletKitTM (CC-3132) contains one 500 ml bottle of Fibroblast Cell Basal Medium (CC-3131) and Fibroblast Bullet Kit (CC-4126) with the following growth supplements :0.5ml hFGF-B (CC-4065J); 0.5ml Insulin (CC-4021J); 0.5ml FBS (CC-4101J); 0.5ml GA-1000 (CC- 4081J).
- FGMTM -2 BulletKitTM CC-3132 contains one 500 ml bottle of Fibroblast Cell Basal Medium (CC-3131) and Fibroblast Bullet Kit (CC-4126) with the following growth supplements :0.5ml hFGF-B (CC-4065J); 0.5ml Insulin (CC-4021J); 0.5ml FBS (CC-4101J); 0.5ml GA-1000 (CC- 4081J).
- NCI-H358 medium 500ml RPMI with 55ml of heat inactivated FBS + 5ml of sodium pyruvate
- NHLF and NHDF were grown in T 50 tissue culture flasks in FGM with 2% FBS until they were 70-80% confluent on the day of the assay.
- the cells were rinsed with 6ml HEPES buffered saline solution (Lonza Cat# CC-5022), trypsinized with 6ml trypsin/EDTA (Lonza Cat# CC-5012) for 5min at room temperature.
- the trypsin was inactivated with 6ml trypsin neutralizing solution (Lonza Cat# CC-5002), spun down at 400g for 4 min and washed once with FGM with 2% FBS.
- fibroblasts (NHLF or NHDF) were seeded at 10,000 cells/well in Collagen 1 Cellware 96-well Black/Clear Plate. Cells were cultured for 8 hours in FGM with 2% FBS. Media were aspirated and cells were starved overnight in FGM containing 0.1% FBS. Media were aspirated and 100ul of FGM with 0.1%FBS containing abituzumab or anti-HEL IgG at a cone of 20ng/ml were added and incubated for 30min. For coculture: NCI-H358 or Calu-3 were plated into the wells containing fibroblast at a density of 2,000 cells in 100ul of NCI-H358 or Calu-3 media. 5 days later, media were collected and stored at -80C for IL-6 detection. Cells were fixed and stained according to the alpha smooth muscle actin (aSMA) staining procedure.
- aSMA alpha smooth muscle actin
- fibroblasts (NHLF or NHDF) were seeded at
- RNA isolation and RT-PCR were stored at -80C until ready for RNA isolation and RT-PCR.
- aSMA immunofluorescence staining Cells were washed 2 times with PBS (200ul in 96 well plates), and then fixed with Fixation/Permeabilization Solution for 45mins at room temperature (50uL in 96 well plate). Cell were then washed 3 times with 5 min incubation using 1X BD perm wash buffer (diluted in distilled water at 1 :10 dilution). The cells were blocked with Odyssey block buffer (50ul in 96 well plates) for 60min at room temperature. The plates were washed 2 times with 5 min incubation between each wash using 1X BD perm wash buffer (200ul in 96 well plates).
- Anti-SMA antibody were added at 1 :100 dilution in wash buffer and incubated for 3 h at room temperature. Plates were then washed 2 times with 1X BD perm wash buffer (200ul in 96 well plate). Secondary Ab Goat Anti-mouse IgG conjugated with Alexa Fluor 488 were used at 1 :200 dilution in perm wash buffer in a final volume of 100ul and incubated for 1 h at room temperature. Cells were washed 2 times using 200ul 1X BD perm wash buffer with 5 minutes incubation between each washes.
- RNA were extracted according to the "RNeasy 96 Protocol for Isolation of Cytoplasmic RNA from Animal Cells-using Vaccum
- RNA Synthesis was done using the RT2 First Strand Kit and Real-Time PCR for RT2 profiler PCR arrays with cycling conditions for Applied Biosystems cyclers according to the procedures described in the RT2 Profiler PCR Array Handbook (Qiagen).
- Image Xpress Micro (IXM) machine and the MetaXpress software program were used for image acquisition and analysis.
- IXM Image Xpress Micro
- plate acquisition imaging protocol "2014-YW-SMA488-DAPI-10x”were used.
- multi wavelength cell scoring analysis parameter protocol “2014-5-7-YW- SMA488-DAPI-4x-2 para a" were used to quantify the amount of SMA fiber induction due to FMT. Images of individual well were downloaded as BMP files.
- IL-6 levels were determined using a commercial IL-6 ELISA assay (Human Duoset IL-6, R & D Systems) following the manufacturer's instructions. Optical density reading (OD) at 450nm are performed using Spectramax M5e reader (Molecular Devices) and IL-6 concentration for each sample extrapolated from a four-parameter logistic curve fit calculated using OD reading from the internal IL-6 standard.
- C T Threshold cycle The C T IS the cycle number at which the fluorescence generated within a reaction crosses the threshold line. Cj values are logarithmic and are used either directly for quantitative analyses.
- AACT AC T test sample(treatment) - ACT calibrator sample(without treatment)
- the amount of target, normalized to an endogenous reference (e.g. GAPDH) and relative to a calibrator (before treatment or control), is given by: 2 - ⁇ ⁇
- Tumor epithelial cell/fibroblast co- culture systems were used to mimick the potential interaction of epithelial cells and fibroblasts in tissues undergoing fibrosis. After 7 days of coculture basal level of aSMA were low in lung fibroblast or dermal fibroblast mono-cultures. NCI-H358 and Calu-3 induced aSMA expression the the fibroblast layer ( Figure 1).
- Lygoe KA Wall I, Stephens P, Lewis MP. Role of vitronectin and fibronectin receptors in oral mucosal and dermal myofibroblast differentiation. Biol Cell. 2007. 99:601-614 Lygoe KA, Norman JT, Marshall JF, Lewis MP. AlphaV integrins play an important role in myofibroblast differentiation. Wound Repair Regen. 2004. 12:461-470. Gardner H, Strehlow D, Bradley L, Widom R, Farina A, de Fougerolles A, Peyman J, Koteliansky V, Korn JH. Global expression analysis of the fibroblast transcriptional response to TGF- ⁇ . Clin Exp Rheumatol. 2004. 22(Suppl 33):S47-57
- TGF- ⁇ Increases aSMA, IL-6 and other Myofibroblast Marker Gene
- BSA Bovine Serum Albumin
- FGM Fibroblast Growth Medium
- FMT Fibroblast to Myofibroblast Transition
- IXM Image Xpress Micro Screening System
- NHLF Normal Human Lung Fibroblasts
- PBS Phosphate-Buffered Saline
- TGF- ⁇ Transforming Growth Factor-Beta 1
- TGF- ⁇ is shown here to be a potent mediator of fibroblast to myofibroblast transition (FMT) which contributes to increased extracellular matrix deposition and is main driver of fibrotic diseases. Furthermore, there is substantial evidence shown for crosstalk between aV integrins and TGF- ⁇ during these processes. TGF- ⁇ is secreted in a latent form which contains a Latency Associated Peptide (LAP) region. The LAP of TGF- ⁇ contains an RGD motif which interacts with the integrins ⁇ , 8 ⁇ 3, ⁇ , 8 ⁇ 6 and avp8 resulting in activation of TGF- ⁇ .
- LAP Latency Associated Peptide
- Abituzumab is a human antibody specific for aV and therefore inhibits ⁇ ⁇ 1 , 8 ⁇ 3, ⁇ , avp6 and ⁇ . This study shows and determines the effect of TGF- ⁇ on the aV integrin and fibrotic gene expression and that abituzumab can block TGF- ⁇ induced gene expression in vitro.
- TGF ⁇ -induced FMT caused increased in the expression of ITGB5 and to a lesser extent ITGB1 and ITGB3.
- TGF- ⁇ treatment increased myofibroblast marker genes in lung fibroblasts and
- Fibrotic diseases are characterized by excessive scarring due to production, deposition and contraction of extracellular matrix and is believed to be driven by myofibroblast proliferation and activation. Fibrotic diseases represent one of the largest groups of diseases for which there is no effective therapy. The fibrotic processes is regulated by complex set of interactions within a network of profibrotic and antifibrotic mediators. TGF- ⁇ signaling is believed to play an important role in fibroblast to myofibroblast transition (FMT) which contributes to increased
- TGF- ⁇ isoforms are synthesized as latent precursers complexed with latent TGF- ⁇ binding proteins, which contains a Latency Associated Peptide (LAP) region.
- LAP Latency Associated Peptide
- Abituzumab is a pan-av integrin antibody that binds allosterically to the ligand-binding aV subunit and thus prevents ligand from binding to all ⁇ heterodimers and therefore inhibits ccv integrin-dependent activation of latent TGF- ⁇ and thus blocks acquisition of the myofibroblast phenotype by fibroblasts and other precursors.
- the present study provided strong evidance of the effect of TGF- ⁇ on the aV integrin and fibrotic gene expression and that abituzumab blocks TGF- ⁇ induced gene expression in normal human lung fibroblasts (NHLF).
- the test system is the NHLF from healthy donors stimulated with TGF- ⁇ with or without Latent TGF- ⁇ .
- Primary NHLF upregulate alpha smooth muscle actin (primary readout) after TGF- ⁇ stimulation.
- NHLF culture media FGM with 2% FBS: FGMTM -2 BulletKitTM (CC-3132) contains one 500 ml bottle of Fibroblast Cell Basal Medium (CC-3131) and Fibroblast Bullet Kit (CC-4126) with the following growth supplements: 0.5ml hFGF-B (CC-4065J); 0.5ml Insulin (CC-4021J); 10ml FBS (CC-4101J); 0.5ml GA-1000 (CC-4081J).
- NHLF culture media for FMT assays FGM with 0.1% FBS: FGMTM -2 BulletKitTM (CC-3132) contains one 500 ml bottle of Fibroblast Cell Basal Medium (CC-3131) and Fibroblast Bullet Kit (CC-4126) with the following growth supplements :0.5ml hFGF-B (CC-4065J); 0.5ml Insulin (CC-4021J); 0.5ml FBS (CC-4101J); 0.5ml GA-1000 (CC- 4081J).
- FGMTM -2 BulletKitTM CC-3132 contains one 500 ml bottle of Fibroblast Cell Basal Medium (CC-3131) and Fibroblast Bullet Kit (CC-4126) with the following growth supplements :0.5ml hFGF-B (CC-4065J); 0.5ml Insulin (CC-4021J); 0.5ml FBS (CC-4101J); 0.5ml GA-1000 (CC- 4081J).
- NHLF were grown in T150 tissue culture flasks in FGM with 2% FBS until they were 70-80% confluent on the day of the assay.
- the cells were rinsed with 6ml HEPES buffered saline solution (Lonza Cat# CC-5022), trypsinized with 6ml trypsin/EDTA (Lonza Cat# CC-5012) for 5min at room temperature.
- the trypsin was inactivated with 6ml trypsin neutralizing solution (Lonza Cat# CC-5002), spun down at 400g for 4 min and washed once with FGM with2% FBS.
- cells were seeded at 7500 cells/well in Collagen 1 Cellware 96-well Black/Clear Plate. For gene
- cells were seeded at 50,000cells/well in 24 wells culture plates. Cells were cultured for 8 hours in FGM with 2% FBS. Media were aspirated and cells were starved overnight in FGM containing 0.1% FBS.
- aSMA and gene expression Media were aspirated and 100ul of FGM containing 0.1% FBS were added, TGF- ⁇ were added at 2X (20ng/ml) of desired concentration in 100ul of FGM containing 0.1%FBS. 72 hours later, media were collected and stored at -80C for IL-6 detection.
- NHLF TGF- ⁇ induced fibroblast myofibroblast transition
- aSMA expression studies using immunofluorescence cells were fixed and stained according to the alpha smooth muscle actin (aSMA) and aV Integrin staining procedure.
- aSMA alpha smooth muscle actin
- FMT related gene expression analysis cells were stored at - 80C until ready for RNA isolation and RT-PCR.
- Fixation/Permeabilization Solution for 45mins at room temperature (50uL in 96 well plate). Cell were then washed 3 times with 5 min incubation using 1X BD perm wash buffer (diluted in distilled water at 1 :10 dilution). The cells were blocked with Odyssey block buffer (50ul in 96 well plates) for 60min at room temperature. The plates were washed 2 times with 5 min incubation between each wash using 1X BD perm wash buffer (200ul in 96 well plates). Anti-SMA antibody were added at 1 :100 dilution in wash buffer. Anti-lntegrin Ab were used at 1ug/ml in perm buffer as final
- RNA were extracted according to the "RNeasy 96 Protocol for Isolation of Cytoplasmic RNA from Animal Cells-using Vaccum
- RNA Synthesis was done using the RT2 First Strand Kit and Real-Time PCR for RT2 profiler PCR arrays with cycling conditions for Applied Biosystems cyclers according to the procedures decribed in the RT2 Profiler PCR Array Handbook (Qiagen).
- Image Xpress Micro (IXM) machine and the MetaXpress software program were used for image acquisition and analysis.
- 3 color staining DAPI, FITC, and Cy5
- plate acquisition imaging protocol "2014-YW-SMA-lnt-DAPI-647-10x” were used.
- DAPI and FITC staining plate acquisition imaging protocol: "20 4-YW- SMA488-DAPI-10x” were used.
- multi wavelength cell scoring analysis parameter protocol "2014-5-7-YW-SMA488-DAPI-4x-2 para a" were used to quantify the amount of SMA fiber induction due to FMT. Images of individual well were downloaded as BMP files.
- IL-6 ELISA Levels of human IL-6 were determined using a commercial IL-6 ELISA assay (Human Duoset IL-6, R & D Systems) following the manufacturer's instructions. Optical density reading (OD) at 450nm are performed using Spectramax M5e reader (Molecular Devices) and IL-6 concentration for each sample extrapolated from a four-parameter logistic curve fit calculated using OD reading from the internal IL-6 standard.
- C T Threshold cycle The C T ⁇ s the cycle number at which the fluorescence generated within a reaction crosses the threshold line. C T values are logarithmic and are used either directly for quantitative analyses. For relative gene expression (basal level):
- AAC T AC T test sample(treatment) - ACj calibrator sample(without treatment)
- the amount of target, normalized to an endogenous reference (e.g. GAPDH) and relative to a calibrator (before treatment or control), is given by: 2 - ⁇
- TGF- ⁇ Increases Integrins Expression in Human Lung Fibroblast (see also Figure 3)
- TGF- ⁇ Increases aSMA, IL-6 and other Myofibroblast Marker Gene Expression in Lung Fibroblast (see also Figure 4)
- TGF- ⁇ treatment increased IL6 production and alpha smooth muscle expression as detected by immunoflurescence and RT-PCR.
- TGF- ⁇ treatment increased
- myofibroblast marker gene such as alpha smooth muscle, collagen, fibronectin, SERPINE1 , SNAI1 , periostin, N-Caherin expression in lung fibroblasts (see figure 4: TGF- ⁇ Increases aSMA, IL-6 and other Myofibroblast Marker Gene Expression in Lung Fibroblast).
- TGF- ⁇ increase expression of Integrins
- NHLF suboptimal dose of active TGF- ⁇ to increase expression of integrin together with hight dose of Latent form TGF- ⁇ .
- Combination of Latent and active TGF- ⁇ induced higher number of cells that expressed aSMA compared to Latent or active form alone.
- Abituzumab treatment reduced the expression of aSMA, production of IL-6 and FMT gene expression caused by TGF- ⁇ activation (see figure 5: Abituzumab Treatment of Fibroblast Cultures Reduces the TGF ⁇ -induced
- TGF- ⁇ increases aV integrins, aSMA, and other FMT genes such as collagen, fibronectin, SERPINE1 , SNAI1 , periostin, N-Caherin expression in human lung fibroblast.
- Abituzumab treatment of fibroblast cultures reduces the TGF ⁇ -induced increases in aSMA, IL6, CTGF, SERPINE, PLOD.
- Abituzumab is been shown to block av integrin-dependent activation of latent TGF- ⁇ at sites of extracellular matrix overproduction.
- abituzumab blocks fibroblast myofibroblast transition.
- TGF- ⁇ upregulates aV integrins, blocking av Integrin - dependent activation of latent TGF- ⁇ , blocks local upregulation of integrins on myofibroblast cell membranes, and thus is able to break the vicious cycle of TGF- ⁇ activation and myofibroblast accumulation.
- TGF- ⁇ transforming growth factor beta
- LAP latency associated peptide
- LTBP latent TGF- ⁇ binding protein
- TGF- ⁇ Transforming Growth Factor-Beta 1
- IL Interleukin Summary ⁇ 3, ⁇ 3, ⁇ 6 and ⁇ can control the activation of TGF- ⁇
- TGF- ⁇ is a major pro-fibrotic cytokine that plays an important part in the
- TGF- ⁇ contributes to fibrosis by promoting the differentiation of tissue fibroblasts into myofibroblasts.
- Myofibroblasts can produce extracellular matrix (ECM) proteins, and are the main drivers for ECM expansion and contraction during fibrosis.
- ECM extracellular matrix
- TGF- ⁇ is secreted in a latent complex, which in addition to TGF- ⁇ , also contains a latency associated peptide (LAP) and latent TGF- ⁇ binding protein (LTBP).
- LAP latency associated peptide
- LTBP latent TGF- ⁇ binding protein
- the complex can adopt an open conformation to release active TGF- ⁇ when LTBP is anchored to ECM and LAP binds one of the av integrins, namely ⁇ 1 , ⁇ 3, ⁇ , ⁇ 6 and ⁇ , on the ⁇ subunit.
- Abituzumab is a human antibody specific for the ligand-binding av subunit of av integrins. Upon binding to the av subunit, abituzumab can prevent av integrins from binding to its ligands such as LAP. The goal of this study was to evaluate the ability of abituzumab to block binding of LAP to ⁇ .
- abituzumab was able to block the binding of ⁇ to LAP precoated to ELISA plates in a dose-dependent manner.
- the finding clearly demonstrate the ability of abituzumab to block binding of av integrins to LAP, a key step in the activation of TGF- ⁇ . This forms part of the scientific basis for developing abituzumab for treating fibrotic diseases.
- TGF- ⁇ a major pro-fibrotic cytokine, plays an important part in the development of tissue fibrosis in various organs.
- TGF- ⁇ contributes to fibrosis by promoting the differentiation of tissue fibroblasts into myofibroblasts.
- Myofibroblasts can produce extracellular matrix (ECM) proteins and contract. They are the main drivers for ECM expansion and contraction during fibrosis.
- ECM extracellular matrix
- TGF- ⁇ is secreted in a latent complex which in addition to TGF- ⁇ , also contains a latency associated peptide (LAP) and latent TGF- ⁇ binding protein (LTBP).
- LAP latency associated peptide
- LTBP latent TGF- ⁇ binding protein
- the complex can adopt an open conformation to release active TGF- ⁇ when LTBP is anchored to ECM and LAP binds one of the av integrins, namely ⁇ 1 , ⁇ 3, ⁇ , ⁇ and ⁇ 8, on the ⁇ subunit.
- the purpose of the present study was to evaluate the ability of abituzumab to block binding of LAP to ⁇ 6.
- the test system is a competitive binding assay in which a plate is coated with recombinant human LAP and then incubated with recombinant human ⁇ 6 in the presence or absence of abituzumab also termed DI17E6.
- the amount of ⁇ 6 bound to LAP is detected by ELISA using a rabbit anti ⁇ 6 antibody (capture antibody) and a goat anti-rabbit IgG (detecting antibody) conjugated with horse radish paraoxide (HRP).
- Blocking buffer in double distilled water:
- Anti-HEL (MSB0011523H-1) is an antibody specific for the non-mammalian protein Hevein-like preproprotein from Arabidopsis, and was used as a negative control antibody for MSB0011521H-1.
- 17E6 is the original non-deimmunized mouse pan anti- av antibody from which abituzumab or DI17E6 was derived. These antibodies were added at the same concentrations as abituzumab or DI 7E6.
- the plate was incubated for 60 min at 37 °C with ⁇ , and abituzumab or its control antibodies. The plates were then washed for addition of secondary antibodies. Addition HRP-conjugated goat anti-rabbit IgG to plates, color development and reading. The plate was added HRP-conjugated goat anti-rabbit IgG and incubated for 90 min at 37 °C. The plate was then added R&D substrate reagent (Pack DY999) and incubated for 20 min to develop the color before the reaction was stopped with the addition of R&D stop solution DY994. The plate was then read at 450 nm on the Tecan ELISA Reader lnfiniteM200.
- Binding of ⁇ 6 to LAP measured by using ELISA.
- the amount of ⁇ bound to LAP was determined by using the procedures described above in Study Design.
- Binding of ⁇ to precoated LAP was detected by a specific anti ⁇ antibody- based ELISA. The binding was blocked in a concentration-dependent manner by DI17E6 when it was co-incubated with ⁇ in a plate precoated with LAP.
- the anti- ⁇ antibodies MSB0011521 H-1 and 10D5 also inhibited the binding.
- MSB0011523H-1 displayed any inhibitory effects. Also the ⁇ 3 integrin specific inhibitory antibody LM609 did not inhibit ⁇ 6 binding to LAP. The findings indicate that DI17E6 specifically inhibit the binding of ⁇ to LAP. Binding of ⁇ 6 to LAP measured by using ELISA. The amount of ⁇ 6 bound to LAP was determined by using the procedures described above in Study Design.
- Abituzumab Inhibits Binding of ⁇ 6 to LAP
- Binding of ⁇ to precoated LAP was detected by a specific anti ⁇ antibody- based ELISA. The binding was blocked in a concentration-dependent manner by DI17E6 when it was co-incubated with ⁇ 6 in a plate precoated with LAP.
- the anti- ⁇ antibodies MSB0011521 H-1 and 10D5 also inhibited the binding.
- MSB0011523H-1 displayed any inhibitory effects. Also the ⁇ 3 integrin specific inhibitory antibody LM609 did not inhibit ⁇ binding to LAP. The findings indicate that DI17E6 specifically inhibit the binding of ⁇ to LAP.
- SSc systemic sclerosis
- pre-final candidate gene list was filtered on two public genome- scale gene expression data sets for their association with pulmonary fibrosis.
- TUAD signature TGF ⁇ -up/Abituzumab-down signature
- TUAD signature another signature of genes that are up-regulated by TGF- ⁇ , thus representing a TGF- ⁇ dependent gene subgroup of the 19 gene signature.
- Gene expression is obtained by averaging probe set intensities per gene.
- GSE9285 (Milano et al., 2008) contains 75 samples in total. Skin biopsies were taken from the forearm and back of 17 patients with diffuse SSc (dSSc), 7 with limited SSc (ISSc), 3 patients with morphea and 6 healthy controls.
- dSSc diffuse SSc
- ISSc limited SSc
- Data set GSE32413 (Pendergrass et al., 2012) consists of 89 skin biopsy samples in total. Gene expression was measured of 22 patients with SSc and 9 healthy controls. 13 of the SSc patients were treated with rituximab, 9 were untreated. We use the baseline/pre-treatment samples for the assessment of differential expression between SSc skin and normal skin and exclude the biopsies taken 6 and 36 months after treatment.
- GSE45485 (Hincliff et al., 2013) contains 83 skin biopsies in total from 12 SSc patients treated with mycophenolate motefil (MMF) and 10 healthy controls. Only baseline (pre-treatment) samples from SSc patients were included in the analysis, samples taken 6 and 12 months after MMF treatment were excluded.
- GSE24206 (Meltzer et al., 201 ) 17 lung samples from 11 patients with
- Idiopathic Pulmonary Fibrosis IPF. 6 patients provided a pair of samples from upper and lower lobes, 5 patients contributed singleton samples). 6 control specimens were obtained from routine lung volume reduction of healthy donor lungs at the time of lung transplantation.
- Data set GSE48149 (unpublished) contains 53 lung samples in total. 8 patients with Idiopathic Pulmonary Arterial Hypertension (IPAH), 13 patients with IPF, 10 patients with Pulmonary Arterial Hypertension due to SSc (SSc-PAH) and 13 patients with Pulmonary Fibrosis due to SSc (SSc-PF) are included as well as 9 healthy controls.
- GSE21369 comprises 29 lung tissue samples of 23 subjects. Data of 11 patients diagnosed with Usual Interstitial Pneumonia/ldiopathic Pulmonary Fibrosis (UIP/IPF) and 6 controls were used, samples of patients with non-specific interstitial pneumonia were excluded.
- UIPF Usual Interstitial Pneumonia/ldiopathic Pulmonary Fibrosis
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Applications Claiming Priority (3)
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US201562258626P | 2015-11-23 | 2015-11-23 | |
EP16164879 | 2016-04-12 | ||
PCT/EP2016/001970 WO2017088974A2 (en) | 2015-11-23 | 2016-11-22 | Anti-alpha-v integrin antibody for the treatment of fibrosis and/or fibrotic disorders |
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EP3380520A2 true EP3380520A2 (en) | 2018-10-03 |
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EP16808567.8A Pending EP3380520A2 (en) | 2015-11-23 | 2016-11-22 | Anti-alpha-v integrin antibody for the treatment of fibrosis and/or fibrotic disorders |
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EP (1) | EP3380520A2 (zh) |
KR (1) | KR20180081617A (zh) |
CN (1) | CN108473582A (zh) |
AU (1) | AU2016360661B2 (zh) |
BR (1) | BR112018010337A2 (zh) |
CA (1) | CA3005764A1 (zh) |
EA (1) | EA201891204A1 (zh) |
MX (1) | MX2018006269A (zh) |
SG (1) | SG11201804243QA (zh) |
TW (1) | TW201720843A (zh) |
WO (1) | WO2017088974A2 (zh) |
Families Citing this family (5)
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WO2020074937A1 (en) * | 2018-10-09 | 2020-04-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of alpha-v-integrin (cd51) inhibitors for the treatment of cardiac fibrosis |
US20220091135A1 (en) * | 2019-01-04 | 2022-03-24 | Kyoto University | Test method for ulcerative colitis and primary sclerosing cholangitis |
US20220370545A1 (en) * | 2019-09-20 | 2022-11-24 | North Carolina State University | Integrin receptor alpha v beta 3 and its ligand involved in chronic itch |
AU2022259467A1 (en) * | 2021-04-12 | 2023-10-05 | Syddansk Universitet | Mfap4 and treatment of fibrosis |
CN116955967B (zh) * | 2023-09-20 | 2023-12-08 | 成都无糖信息技术有限公司 | 一种在网络靶场中模拟侦查调证的系统和方法 |
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CN102875681A (zh) * | 2005-07-08 | 2013-01-16 | 拜奥根Idec马萨诸塞公司 | 抗-αvβ6抗体及其用途 |
CA2693863C (en) * | 2007-07-17 | 2017-10-03 | Merck Patent Gmbh | Engineered anti-alpha v- integrin hybrid antibodies |
WO2010008543A2 (en) * | 2008-07-15 | 2010-01-21 | Trustees Of Dartmouth College | Molecular signatures for diagnosing scleroderma |
KR101972533B1 (ko) * | 2011-02-11 | 2019-08-26 | 메르크 파텐트 게엠베하 | 전립선암 치료용 항-알파-v 인테그린 항체 |
KR102577578B1 (ko) * | 2011-06-03 | 2023-09-11 | 조마 테크놀로지 리미티드 | Tgf-베타에 특이적인 항체 |
WO2013148232A1 (en) * | 2012-03-27 | 2013-10-03 | Genentech, Inc. | Methods of prognosing, diagnosing and treating idiopathic pulmonary fibrosis |
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2016
- 2016-11-22 CN CN201680077086.5A patent/CN108473582A/zh active Pending
- 2016-11-22 SG SG11201804243QA patent/SG11201804243QA/en unknown
- 2016-11-22 EA EA201891204A patent/EA201891204A1/ru unknown
- 2016-11-22 TW TW105138308A patent/TW201720843A/zh unknown
- 2016-11-22 EP EP16808567.8A patent/EP3380520A2/en active Pending
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- 2016-11-22 BR BR112018010337A patent/BR112018010337A2/pt not_active Application Discontinuation
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CA3005764A1 (en) | 2017-06-01 |
WO2017088974A3 (en) | 2017-07-13 |
CN108473582A (zh) | 2018-08-31 |
SG11201804243QA (en) | 2018-06-28 |
KR20180081617A (ko) | 2018-07-16 |
MX2018006269A (es) | 2018-09-05 |
EA201891204A1 (ru) | 2019-03-29 |
TW201720843A (zh) | 2017-06-16 |
BR112018010337A2 (pt) | 2018-12-04 |
AU2016360661B2 (en) | 2023-12-14 |
WO2017088974A2 (en) | 2017-06-01 |
AU2016360661A1 (en) | 2018-07-05 |
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