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Amgen files ‘breakthrough’ leukaemia drug Blinatumomab (AMG103) in the US
Blinatumomab
Biotechnology giant Amgen has filed its investigational cancer immunotherapy blinatumomab in the US for the treatment of certain forms of acute lymphoblastic leukaemia (ALL).
Specifically, the Biologic License Application seeks approval to market the drug for patients with Philadelphia-negative (Ph-) relapsed/refractory B-precursor forms of the aggressive blood/bone marrow cancer.
Blinatumomab (AMG103) is a drug that has anti-cancer properties. It belongs to a new class of constructed monoclonal antibodies, bi-specific T-cell engagers (BiTEs), that exert action selectively and direct the human immune system to act against tumor cells. Blinatumomab specifically targets the CD19 antigen present on B cells.[1]
The drug was developed by a German-American company Micromet, Inc. in cooperation with Lonza; Micromet was later purchases byAmgen, which has furthered the drug’s clinical trials.
Structure and mechanism of action
Blinatumomab linking a T cell to a malignant B cell.
Blinatumomab enables a patient’s T cells to recognize malignant B cells. A molecule of blinatumomab combines two binding sites: a CD3 site for T cells and a CD19 site for the target B cells. CD3 is part of the T cell receptor. The drug works by linking these two cell types and activating the T cell to exert cytotoxic activity on the target cell.[2]
Therapeutic use
Clinical trials
In a phase 1 clinical study with blinatumomab, patients with non-Hodgkin’s lymphoma showed tumor regression, and in some cases completeremission.[3] There are ongoing phase 1 and phase 2 clinical trials of blinatumomab in patients with acute lymphoblastic leukemia (ALL),[4]lung or gastrointestinal cancers.[citation needed] One phase II trial for ALL reported good results in 2010 and another is starting.[5]
| Monoclonal antibody | |
|---|---|
| Type | Bi-specific T-cell engager |
| Source | Mouse |
| Target | CD19, CD3 |
| Clinical data | |
| Legal status |
?
|
| Identifiers | |
| CAS number | 853426-35-4  |
| ATC code | None |
| UNII | 4FR53SIF3A  |
| Chemical data | |
| Formula | C2367H3577N649O772S19 |
| Mol. mass | 54.1 kDa |
References
- Statement on a Nonproprietary Name adopted by the USAN Council: Blinatumomab
- Mølhøj, M; Crommer, S; Brischwein, K; Rau, D; Sriskandarajah, M; Hoffmann, P; Kufer, P; Hofmeister, R; Baeuerle, PA (March 2007). “CD19-/CD3-bispecific antibody of the BiTE class is far superior to tandem diabody with respect to redirected tumor cell lysis”. Mol Immunol 44 (8): 1935–43. doi:10.1016/j.molimm.2006.09.032. PMID 17083975.
- Bargou, R; et al. (2008). “Tumor regression in cancer patients by very low doses of a T cell-engaging antibody”. Science 321 (5891): 974–977. doi:10.1126/science.1158545.PMID 18703743.
- ClinicalTrials.gov NCT00560794 Phase II Study of the BiTE Blinatumomab (MT103) in Patients With Minimal Residual Disease of B-precursor Acute ALL
- “Micromet initiates MT103 phase 2 trial in adult ALL patients”. 20 Sep 2010.
External links
MAKE IN INDIA
http://makeinindia.com/
http://makeinindia.com/sector/pharmaceuticals/
Ibritumomab tiuxetan
Ibritumomab tiuxetan, sold under the trade name Zevalin, is a monoclonal antibody radioimmunotherapy treatment for relapsed or refractory, low grade or transformed B cell non-Hodgkin’s lymphoma, a lymphoproliferative disorder. The drug uses the monoclonal mouse IgG1 antibody ibritumomab (pronounced as <ih bri TYOO mo mab>)[1] in conjunction with the chelator tiuxetan, to which a radioactive isotope (either yttrium-90 or indium-111) is added. Tiuxetan is a modified version of DTPA whose carbon backbone contains an isothiocyanatobenzyl and a methyl group.[2][3]
Mechanism of action
The antibody binds to the CD20 antigen found on the surface of normal and malignant B cells (but not B cell precursors), allowing radiation from the attached isotope (mostly beta emission) to kill it and some nearby cells. In addition, the antibody itself may trigger cell death via antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis. Together, these actions eliminate B cells from the body, allowing a new population of healthy B cells to develop from lymphoid stem cells.
Zevalin (Ibritumomab tiuxetan) is a radio-labeled antibody. The antibody seeks and binds to cells that have a receptor called CD20 — present on both normal and malignant mature b-cells.
Once bound to the target cells, Zevalin delivers radiation, which enhances the killing effect of the antibody.
Because immature b-cells do not have the CD20 receptor, normal b-cells will recover in about nine months after treatment.
Rituxan (the naked antibody) is administered prior to Zevalin with the goal of clearing the majority of normal b-cells so that the therapeutic dose (the radio-labeled antibody) is more focused on tumor cells.
Preparation
Zevalin is supplied as a single dosage kit supplied by IDEC Pharmaceuticals Corp. It consists of Ibritumomab covalently conjugated to the metal chelator tiuxetan, which forms a stable complex with indium-111 for imaging and yttrium-90 for therapy.
The kit is supplied with four vials – a vial containing 3.2 mg of conjugated antibody in 2 ml saline, a vial containing 2 ml 50mM sodium acetate, a vial containing phosphate buffer, and a fourth empty reaction vial. Prior to labeling, a volume of sodium acetate buffer equivalent to 1.2 times the volume of the tracer solution is transferred to the reaction vial. Then 5.5 mCi (203.5 MBq) indium-111 or 40mCi (1.48 GBq) yttrium-90 is added to the reaction vial and mixed thoroughly without shaking. Next, 1.3 ml of conjugated antibody is added. The mixture is incubated for exactly 30min for indium-111 and for 5 min with yttrium-90 labeling, followed by the addition of enough phosphate buffer to make the final volume 10 ml. The labeling yield is determined by ITLC-SG with 0.9% saline as the mobile phase. Labeling efficiency should be greater than 95%.[4]
http://pubs.rsc.org/en/content/articlelanding/2006/cs/b514859f/unauth#!divAbstract
A cartoon depiction of the radiolabelled monoclonal antibody 90Y-ibritumomab tiuxetan 18.
Administration
In order to qualify for ibritumomab, a patient needs to have bone marrow involvement of < 25% and > 15% bone marrow cellularity. Since ibritumomab is known to cause cytopenia, platelet and neutrophil counts are also taken pretreatment. Refractory/relapsed patients should have platelet counts of 100,000 per cubic millimetre (100,000/cmm) or greater; consolidation patients should have counts of 150,000/cmm or greater. Since a murine antibody is used, the patient might also be tested for human anti mouse antibodies (HAMA). Having bulky disease does not disqualify a patient.
The ibritumomab regimen takes 7–9 days. An imaging dose of the drug is no longer required in the U.S. Rituxan 250 mg/sq.m is given day 1, then on day 7-9 the Rituxan dose is repeated and Zevalin given within four hours. The dose of Zevalin 0.4 mCi/kg (= 14.8MBq/kg) if platelet counts are above 150,000/cmm; 0.3 mCi/kg (= 11.1MBq/kg) if 100,000-150,000/cmm. The Zevalin dose never exceeds 32 mCi (= 1184MBq).[5]
Ibritumomab tiuxetan is administered by intravenous infusion which usually lasts around 10 minutes. Only acrylic shielding is needed, not lead. A trained nuclear medicine technologist performs the infusion and safely disposes of waste.
Efficacy
Treatment with ibritumomab showed higher response rates in clinical trials compared to treatment with only rituximab (similar to ibritumomab, but without the attached radioisotope), and showed very promising results for patients who no longer respond to rituximab.
In patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL, where no prior anti-CD20 therapy was allowed, the ORR was 83% / 55% and CR was 38% / 18%, comparing ibritumomab to rituximab. [6]
Recently, extended follow-up data for the ZEVALIN ([90Y]-ibritumomab tiuxetan) First-line Indolent (FIT) study presented at the American Society of Hematology (ASH) Annual Meeting demonstrated the continued improvement in progression-free survival (PFS) following ibritumomab consolidation therapy for patients with follicular B-cell non-Hodgkin’s lymphoma who achieved a response to first-line therapy over chemotherapy alone. Additionally, ibritumomab consolidation did not adversely affect the use of various effective second-line treatments including stem cell transplants in patients who relapsed.[7]
In a Phase II study on patients with relapsed and refractory mantle cell lymphoma, the OR was 42% and CR was 26%.[8]
A study demonstrated that rituximab followed by single agent ibritumomab in a front-line setting for patients with MALT lymphoma and low-grade follicular lymphoma that primarily involved the conjunctiva or orbit, produced a complete response rate of 83 percent.[9]
http://rd.springer.com/article/10.2165%2F00024669-200201050-00004#page-1
History
Developed by the IDEC Pharmaceuticals, which is now part of Biogen Idec, ibritumomab tiuxetan was the first radioimmunotherapy drug approved by the Food and Drug Administration (FDA) in 2002 to treat cancer. It was approved for the treatment of patients with relapsed or refractory, low‑grade or follicular B‑cell non‑Hodgkin’s lymphoma (NHL), including patients with rituximab refractory follicular NHL.
In December 2007, Cell Therapeutics Inc acquired the U.S. rights to sell, market, and distribute this radioimmunotherapy antibody from Biogen for approximately US$30 million, or the equivalent of about two years’ net sales revenue in the U.S. for the drug.[10] Outside of the U.S., Bayer Schering Pharma continues to have the rights to the drug.
In March 2009, Spectrum Pharmaceuticals acquired 100% control of RIT Oncology, LLC, to commercialize Zevalin in the US. Now Spectrum Pharmaceuticals is responsible for all activities relating to Zevalin in the US.
In September 2009, ibritumomab received approval from the FDA for an expanded label for the treatment of patients with previously untreated follicular non-Hodgkin’s Lymphoma (NHL), who achieve a partial or complete response to first-line chemotherapy.
Costs
Ibritumomab which is not available in a generic form because it is still under patent protection, is currently the most expensive drug available given in a single dose, costing over US$ 37,000 (€ 30,000) for the average dose. However, ibritumomab is essentially an entire course of lymphoma therapy which is delivered in 7–9 days, with one visit for pre-dosing Rituxan, and one visit a week later for the actual Zevalin therapeutic dose preceded by Rituxan. Compared to other monoclonal antibody treatments (many of which are well over US$ 40,000 for a course of therapy), this drug is priced in the middle for many of these therapies.
 |
|
| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Mouse |
| Target | CD20 |
| Clinical data | |
| Trade names | Zevalin |
| AHFS/Drugs.com | monograph |
| Licence data | US FDA:link |
| Legal status | |
| Routes | intravenous |
| Identifiers | |
| CAS number | 174722-31-7 |
| ATC code | V10XX02 (90Y) |
| DrugBank | DB00078 |
External links
- http://www.zevalin.com/ – Official Zevalin web site
- http://www.spectrumpharm.com/ – Spectrum Pharmaceuticals, Inc. web site
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/ibriide021902LB.pdf – Package Insert
http://www.fda.gov/ohrms/dockets/ac/01/slides/3782s2_02_idec/sld015.htm
References
- Ibritumomab: Pronunciation
- Milenic, Diane E.; Brady, Erik D.; Brechbiel, Martin W. (June 2004). “Antibody-targeted radiation cancer therapy”. Nat Rev Drug Discov 3 (6): 488–499. doi:10.1038/nrd1413. ISSN 1474-1776. PMID 15173838.
- WHO Drug Information
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/ibriide021902LB.pdf
- Ibritumomab: Indications
- Ibritumomab: Efficacy
- ZEVALIN Consolidation in First-Line Therapy in Patients with Non-Hodgkin’s Lymphoma Resulted in a Progression-Free Survival of Greater Than 67 Months
- Zevalin and mantle cell
- ZEVALIN(R) Produced 83 Percent Complete Response Rate in Mucosa-Associated Lymphoid Tissue (MALT) Orbital Lymphoma Study
- [1]
// // // // //
September 23, 2014
// CASI Signs China Licensing Deal With Spectrum For 3 Cancer Drugs…http://www.outsourcedpharma.com/doc/casi-signs-china-licensing-deal-with-spectrum-for-cancer-drugs-0001
// CASI Signs China Licensing Deal With Spectrum For 3 Cancer Drugs// // // // //
CASI Pharmaceuticals and Spectrum Pharmaceuticals (SPPI) announced the signing of a license agreement that gives CASI exclusive rights to develop three cancer drugs from Spectrum and market them in China, including Macau, Hong Kong, and Taiwan.
The agreement concerns the two approved cancer drugs Zevalin (ibritumomab tiuxetan) Injection non-Hodgkin’s lymphoma (NHL) and Marqibo (vinCRIStine sulfate LIPOSOME injection) for acute lymphoblastic leukemia (ALL) as well as the investigational Phase 3 drug Captisol-Enabled Melphalan (CE melphalan) being studied as a conditioning treatment before autologous stem cell transplant in patients with multiple myeloma. Spectrum recently reported that Melphalan met its primary endpoint in its pivotal safety and efficacy trial. In view of the results, Spectrum said it intends to file a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) for the drug in the second half of 2014.
// // // // //
Sun Pharma, Merck & Co Inc ink pact for Tildrakizumab
Sep 17, 2014,
Under terms of the agreement, Sun Pharma will acquire worldwide rights to tildrakizumab for use in all human indications from Merck in exchange for an upfront payment of USD 80 million.
Pharma major Sun Pharmaceutical Industries today entered into a licensing agreement with Merck & Co Inc for investigational therapeutic antibody candidate, tildrakizumab to be used for treatment of plaque psoriasis. Under terms of the agreement, Sun Pharma will acquire worldwide rights to tildrakizumab for use in all human indications from Merck in exchange for an upfront payment of USD 80 million, the companies said in a joint statement. Tildrakizumab is being evaluated in Phase III registration trials for the treatment of chronic plaque psoriasis, a skin ailment. “Merck will continue all clinical development and regulatory activities, which will be funded by Sun Pharma. Upon product approval, Sun Pharma will be responsible for regulatory activities, including subsequent submissions, pharmacovigilance, post approval studies, manufacturing and commercialisation of the approved product,” it added.
Sun Pharma managing director Dilip Shanghvi.
| Monoclonal antibody | |
|---|---|
| Source | Humanized (from mouse) |
| Target | IL23 |
| Clinical data | |
| Legal status |
?
|
| Identifiers | |
| CAS number | 1326244-10-3 |
| ATC code | None |
| Chemical data | |
| Formula | C6426H9918N1698O2000S46 |
| Mol. mass | 144.4 kDa |
Tildrakizumab is a monoclonal antibody designed for the treatment of immunologically mediated inflammatory disorders.[1]
Tildrakizumab was designed to block interleukin-23, a cytokine that plays an important role in managing the immune system andautoimmune disease. Originally developed by Schering-Plough, this drug is now part of Merck‘s clinical program, following that company’s acquisition of Schering-Plough.
As of March 2014, the drug was in phase III clinical trials for plaque psoriasis. The two trials will enroll a total of nearly 2000 patients, and preliminary results are expected in June, 2015. [2][3]
References
FDA approves Keytruda for advanced melanoma, First PD-1 blocking drug to receive agency approval
September 4, 2014
FDA Release
The U.S. Food and Drug Administration today granted accelerated approval to Keytruda (pembrolizumab) for treatment of patients with advanced or unresectable melanoma who are no longer responding to other drugs.
Melanoma, which accounts for approximately 5 percent of all new cancers in the United States, occurs when cancer cells form in skin cells that make the pigment responsible for color in the skin. According to the National Cancer Institute, an estimated 76,100 Americans will be diagnosed with melanoma and 9,710 will die from the disease this year.
Keytruda is the first approved drug that blocks a cellular pathway known as PD-1, which restricts the body’s immune system from attacking melanoma cells. Keytruda is intended for use following treatment with ipilimumab, a type of immunotherapy. For melanoma patients whose tumors express a gene mutation called BRAF V600, Keytruda is intended for use after treatment with ipilimumab and a BRAF inhibitor, a therapy that blocks activity of BRAF gene mutations.
“Keytruda is the sixth new melanoma treatment approved since 2011, a result of promising advances in melanoma research,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Many of these treatments have different mechanisms of action and bring new options to patients with melanoma.”
The five prior FDA approvals for melanoma include: ipilimumab (2011), peginterferon alfa-2b (2011), vemurafenib (2011), dabrafenib (2013), and trametinib (2013).
The FDA granted Keytruda breakthrough therapy designation because the sponsor demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies. It also received priority review and orphan product designation. Priority review is granted to drugs that have the potential, at the time the application was submitted, to be a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan product designation is given to drugs intended to treat rare diseases.
The FDA action was taken under the agency’s accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials. An improvement in survival or disease-related symptoms has not yet been established.
Keytruda’s efficacy was established in 173 clinical trial participants with advanced melanoma whose disease progressed after prior treatment. All participants were treated with Keytruda, either at the recommended dose of 2 milligrams per kilogram (mg/kg) or at a higher dose of 10 mg/kg. In the half of the participants who received Keytruda at the recommended dose of 2 mg/kg, approximately 24 percent had their tumors shrink. This effect lasted at least 1.4 to 8.5 months and continued beyond this period in most patients. A similar percentage of patients had their tumor shrink at the 10 mg/kg dose.
Keytruda’s safety was established in the trial population of 411 participants with advanced melanoma. The most common side effects of Keytruda were fatigue, cough, nausea, itchy skin (pruritus), rash, decreased appetite, constipation, joint pain (arthralgia) and diarrhea. Keytruda also has the potential for severe immune-mediated side effects. In the 411 participants with advanced melanoma, severe immune-mediated side effects involving healthy organs, including the lung, colon, hormone-producing glands and liver, occurred uncommonly.
Keytruda is marketed by Merck & Co., based in Whitehouse Station, New Jersey.
Pembrolizumab, Lambrolizumab, MK-3475
STRUCTURAL FORMULA
Heavy chain
QVQLVQSGVE VKKPGASVKV SCKASGYTFT NYYMYWVRQA PGQGLEWMGG 50
INPSNGGTNF NEKFKNRVTL TTDSSTTTAY MELKSLQFDD TAVYYCARRD 100
YRFDMGFDYW GQGTTVTVSS ASTKGPSVFP LAPCSRSTSE STAALGCLVK 150
DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTKT 200
YTCNVDHKPS NTKVDKRVES KYGPPCPPCP APEFLGGPSV FLFPPKPKDT 250
LMISRTPEVT CVVVDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNSTY 300
RVVSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYT 350
LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS 400
DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLGK 447
Light chain
EIVLTQSPAT LSLSPGERAT LSCRASKGVS TSGYSYLHWY QQKPGQAPRL 50′
LIYLASYLES GVPARFSGSG SGTDFTLTIS SLEPEDFAVY YCQHSRDLPL 100′
TFGGGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV 150′
QWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV 200′
THQGLSSPVT KSFNRGEC 218′
Disulfide bridges
22-96 22”-96” 23′-92′ 23”’-92”’ 134-218′ 134”-218”’ 138′-198′ 138”’-198”’
147-203 147”-203” 226-226” 229-229” 261-321 261”-321” 367-425 367”-425”
Glycosylation sites (N)
Asn-297 Asn-297”
lambrolizumab, or MK-3475
| C6504H10004N1716O2036S46 (peptide) | |
| MOL. MASS | 146.3 kDa (peptide) |
Pembrolizumab, Lambrolizumab (also known as MK-3475) is a drug in development by Merck that targets the PD-1 receptor. The drug is intended for use in treating metastatic melanoma.
http://www.ama-assn.org/resources/doc/usan/lambrolizumab.pdf structureof lambrolizumab, or MK-3475
https://download.ama-assn.org/resources/doc/usan/x-pub/pembrolizumab.pdf
Statement on a Nonproprietary Name Adopted by the USAN Council. November 27, 2013.
see above link for change in name
may 2, 2013,
An experimental drug from Merck that unleashes the body’s immune system significantly shrank tumors in 38 percent of patients with advanced melanoma, putting the company squarely in the race to bring to market one of what many experts view as the most promising class of drugs in years.
The drugs are attracting attention here at the annual meeting of the American Society of Clinical Oncology, even though they are still in the early stage of testing. Data from drugs developed by Bristol-Myers Squibb and by Roche had already been released.
The drugs work by disabling a brake that prevents the immune system from attacking cancer cells. The brake is a protein on immune system cells called programmed death 1 receptor, or PD-1.
Merck’s study, which was presented here Sunday and also published in the New England Journal of Medicine, involved 135 patients. While tumors shrank in 38 percent of the patients over all, the rate was 52 percent for patients who got the highest dose of the drug, which is called lambrolizumab, or MK-3475.
But that is what is disclosed tonight, as to pembrolizumab, or MK-3475. Wow. With over $44 billion in 2013 worldwide revenue, that disclosure implies (to seasoned SEC lawyers) that spending on this one drug (or, biologic, to be more technical about it — but remember 40 years ago, Merck had no protein chain biologics research & development programs in its pipe — only chemical drug compounds). . . is material, to that number. Normally that would, in turn, mean that the spending is approaching 5 per cent of revenue. So — Merck may be spending $2.2 billion over the next 12 rolling months, on MK-3475. That’s one BIGhairy science bet, given that Whitehouse Station likely already had over $2 billion invested in the program, at year end 2013.
About Pembrolizumab
Pembrolizumab (MK-3475) is an investigational selective, humanized monoclonal anti-PD-1 antibody designed to block the interaction of PD-1 on T-cells with its ligands, PD-L1 and PD-L2, to reactivate anti-tumor immunity. Pembrolizumab exerts dual ligand blockade of PD-1 pathway.
Today, pembrolizumab is being evaluated across more than 30 types of cancers, as monotherapy and in combination. It is anticipated that by the end of 2014, the pembrolizumab development program will grow to more than 24 clinical trials across 30 different tumor types, enrolling an estimated 6,000 patients at nearly 300 clinical trial sites worldwide, including new Phase 3 studies in head and neck and other cancers. For information about Merck’s oncology clinical studies, please click here.
The Biologics License Application (BLA) for pembrolizumab is under priority review with the U.S. Food and Drug Administration (FDA) for the proposed indication for the treatment of patients with advanced melanoma previously-treated with ipilimumab; the PDUFA date is October 28, 2014. Pembrolizumab has been granted FDA’s Breakthrough Therapy designation for advanced melanoma. If approved by the FDA, pembrolizumab has the potential to be the first PD-1 immune checkpoint modulator approved in this class. The company plans to file a Marketing Authorization Application in Europe for pembrolizumab for advanced melanoma in 2014.
About Head and Neck Cancer
Head and neck cancers are a related group of cancers that involve the oral cavity, pharynx and larynx. Most head and neck cancers are squamous cell carcinomas that begin in the flat, squamous cells that make up the thin surface layer (epithelium) of the head and neck (called the). The leading risk factors for head and neck cancer include tobacco and alcohol use. Infection with certain types of HPV, also called human papillomaviruses, is a risk factor for some types of head and neck cancer, specifically cancer of the oropharynx, which is the middle part of the throat including the soft palate, the base of the tongue, and the tonsils. Each year there are approximately 400,000 cases of cancer of the oral cavity and pharynx, with 160,000 cancers of the larynx, resulting in approximately 300,000 deaths.
About Merck Oncology: A Focus on Immuno-Oncology
At Merck Oncology, our goal is to translate breakthrough science into biomedical innovations to help people with cancer worldwide. Harnessing immune mechanisms to fight cancer is the priority focus of our oncology research and development program. The Company is advancing a pipeline of immunotherapy candidates and combination regimens. Cancer is one of the world’s most urgent unmet medical needs. Helping to empower people to fight cancer is our passion. For information about Merck’s commitment to Oncology visit the Oncology Information Center at http://www.mercknewsroom.com/oncology-infocenter.
About Merck
Today’s Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit http://www.merck.com and connect with us on Twitter, Facebook and YouTube.
Hamid, O; Robert, C; Daud, A; Hodi, F. S.; Hwu, W. J.; Kefford, R; Wolchok, J. D.; Hersey, P; Joseph, R. W.; Weber, J. S.; Dronca, R; Gangadhar, T. C.; Patnaik, A; Zarour, H; Joshua, A. M.; Gergich, K; Elassaiss-Schaap, J; Algazi, A; Mateus, C; Boasberg, P; Tumeh, P. C.; Chmielowski, B; Ebbinghaus, S. W.; Li, X. N.; Kang, S. P.; Ribas, A (2013). “Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma”. New England Journal of Medicine 369 (2): 134–44. doi:10.1056/NEJMoa1305133. PMID 23724846
key words
FDA, approved, Keytruda, advanced melanoma, PD-1 blocking drug, pembrolizumab, Lambrolizumab, MK-3475, Monoclonal antibody
Higher-Order Structure Comparability: Case Studies of Biosimilar Monoclonal Antibodies
Figure 1a: Diagram of the antibody array enzyme-linked immunosorbent assay (ELISA)
Figure 1b: ELISA format for the antibody array technology
Great successes for monoclonal antibody (MAb)–based biologics over the past decade have provided many valuable options for patients combating some of the most serious diseases in the world, including cancer and autoimmune diseases. MAbs and antibody–drug conjugates (ADCs) are among the fastest growing biologic segments in development, with hundreds of candidates currently under clinical study.
read at
http://www.bioprocessintl.com/manufacturing/biosimilars/higher-order-structure-comparability/
FDA approves Avastin to treat patients with aggressive and late-stage cervical cancer
August 14, 2014
The U.S. Food and Drug Administration today approved a new use for Avastin (bevacizumab) to treat patients with persistent, recurrent or late-stage (metastatic) cervical cancer.
Cervical cancer grows in the tissues of the lower part of the uterus known as the cervix. It commonly occurs when human papillomaviruses (HPV), a virus that spreads through sexual contact, cause cells to become cancerous. Although there are two licensed vaccines available to prevent many types of HPV that can cause cervical cancer, the National Cancer Institute estimates that 12,360 American women will be diagnosed with cervical cancer and 4,020 will die from the disease in 2014.
Avastin works by interfering with the blood vessels that fuel the development of cancerous cells. The new indication for cervical cancer is approved for use in combination with chemotherapy drugs paclitaxel and cisplatin or in combination with paclitaxel and topotecan.
“Avastin is the first drug approved for patients with late-stage cervical cancer since the 2006 approval of topotecan with cisplatin,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “It is also the first biologic agent approved for patients with late-stage cervical cancer and was approved in less than four months under the FDA’s priority review program, demonstrating the agency’s commitment to making promising therapies available to patients faster.”
The FDA reviewed Avastin for treatment of patients with cervical cancer under its priority review program because the drug demonstrated the potential to be a significant improvement in safety or effectiveness over available therapy in the treatment of a serious condition. Priority review provides an expedited review of a drug’s application.
The safety and effectiveness of Avastin for treatment of patients with cervical cancer was evaluated in a clinical study involving 452 participants with persistent, recurrent, or late-stage disease. Participants were randomly assigned to receive paclitaxel and cisplatin with or without Avastin or paclitaxel and topotecan with or without Avastin. Results showed an increase in overall survival to 16.8 months in participants who received chemotherapy in combination with Avastin as compared to 12.9 months for those receiving chemotherapy alone.
The most common side effects associated with use of Avastin in patients with cervical cancer include fatigue, decreased appetite, high blood pressure (hypertension), increased glucose in the blood (hyperglycemia), decreased magnesium in the blood (hypomagnesemia), urinary tract infection, headache and decreased weight. Perforations of the gastrointestinal tract and abnormal openings between the gastrointestinal tract and vagina (enterovaginal fistula) also were observed in Avastin-treated patients.
Avastin is marketed by South San Francisco, California-based Genentech, a member of the Roche Group.
| Country | Patent Number | Approved | Expires (estimated) |
|---|---|---|---|
| Canada | 2286330 | 2008-06-10 | 2018-04-03 |
| Canada | 2145985 | 2003-09-16 | 2012-10-28 |
| Property | Value | Source |
|---|---|---|
| melting point | 61 °C (FAB fragment), 71 °C (whole mAb) | Vermeer, A.W.P. & Norde, W., Biophys. J. 78:394-404 (2000) |
| Protein chemical formula | C6538H10034N1716O2033S44 |
|---|---|
| Protein average weight | 149 kDa |
A recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF). Bevacizumab contains human framework regions and the complementarity-determining regions of a murine antibody that binds to VEGF. Bevacizumab is produced in a Chinese Hamster Ovary mammalian cell expression system in a nutrient medium containing the antibiotic gentamicin and has a molecular weight of approximately 149 kilodaltons.
sequence
>"Bevacizumab light chain" DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>"Bevacizumab heavy chain" EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTY AADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEL LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Humanized (from mouse) |
| Target | VEGF-A |
| Clinical data | |
| Trade names | Avastin |
| AHFS/Drugs.com | monograph |
| Licence data | EMA:Link, US FDA:link |
| Pregnancy cat. | C (US) |
| Legal status | ℞ Prescription only |
| Routes | Intravenous |
| Pharmacokinetic data | |
| Bioavailability | 100% (IV only) |
| Half-life | 20 days (range: 11–50 days) |
| Identifiers | |
| CAS number | 216974-75-3 |
| ATC code | L01XC07 |
| DrugBank | DB00112 |
| UNII | 2S9ZZM9Q9V |
| KEGG | D06409 |
| ChEMBL | CHEMBL1201583 |
| Chemical data | |
| Formula | C6638H10160N1720O2108S44 |
| Mol. mass | approx. 149 kDa |
FDA grants breakthrough therapy designation to Boehringer’s Idarucizumab, BI 655075
- 1-225-Immunoglobulin G1, anti-(dabigatran) (human-Mus musculus γ1-chain) (225→219′)-disulfide with immunoglobulin G1, anti-(dabigatran) (human-Mus musculus κ-chain)Protein SequenceSequence Length: 444, 225, 219
BI 655075, Idarucizumab
- Idarucizumab [INN]
- UNII-97RWB5S1U6
CAS 1362509-93-0
Treatment of dabigatran associated haemorrhage
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for Boehringer Ingelheim Pharmaceuticals’ idarucizumab, an investigational fully humanised antibody fragment being studied as a specific antidote for Pradaxa.
Boehringer Ingelheim Pharmaceuticals Medicine & Regulatory Affairs senior vice-president Sabine Luik said: “We are committed to innovative research and to advancing care in patients taking Pradaxa.
http://apps.who.int/trialsearch/Trial.aspx?TrialID=EUCTR2013-004813-41-EE
- IDARUCIZUMAB (BI 655075)
- What is it? It is a humanized antibody fragment directed against dabigatran; generated from mouse monoclonal antibody against dabigatran; humanized and reduced to a FAb fragment.
- What anticoagulant drugs might it reverse? Dabigatran.
- Clinical trial status: (a) A phase 3 study of patients on dabigatran with major bleeding or needing emergency surgery is in the planning stages and will likely start in 2014. (b) A phase 1 study to determine the effect of idarucizumab on coagulation tests in dabigatran-treated healthy volunteers has been completed (NCT01688830), another two are ongoing (NCT01955720; NCT02028780).
June 26, 2014
Pradaxa Antidote, Idarucizumab Designated Breakthrough Therapy
Boehringer Ingelheim announced that the FDA has granted Breakthrough Therapy designation to idarucizumab, an investigational fully humanized antibody fragment (Fab), being evaluated as a specific antidote for Pradaxa (dabigatran etexilate mesylate).
Data from a Phase 1 trial demonstrated that idarucizumab was able to achieve immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy humans. The on-set of action of the antidote was detected immediately following a 5-minute infusion while thrombin time was reversed with idarucizumab. Reversal of the anticoagulation effect was complete and sustained in 7 of 9 subjects who received the 2g dose and in 8 out of 8 subjects who received the 4g dose. The 1g dose resulted in complete reversal of anticoagulation effect; however, after approximately 30 minutes there was some return of the anticoagulation effects of dabigatran.
RELATED: Anticoagulant Dosing Conversions
A global Phase 3 study, RE-VERSE AD, is underway in patients taking Pradaxa who have uncontrolled bleeding or require emergency surgery or procedures. Currently there are no specific antidotes for newer oral anticoagulants.
Pradaxa is approved to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation (AF). Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with parenteral anticoagulant for 5–10 days. To reduce risk of recurrent DVT/PE in patients who have been previously treated.
For more information call (800) 542-6257 or visit Boehringer-Ingelheim.com.
BI-836845 a fully human mAb targeting IGF-1 created using HuCAL technology from Morphosys, for the potential iv infusion treatment of cancer, including solid tumors and breast cancer.
BI-836845
Human monoclonal IgG1 lambda antibody against IGF-1 (insulin growth factor-1) and IGF-2
| IGF pathway modulator (iv, cancer), Boehringer Ingelheim; |
Phase 2 Clinical
Anticancer protein kinase inhibitor; Anticancer monoclonal antibody
WO-2008155387
Boehringer Ingelheim International Gmbh
Boehringer Ingelheim is developing BI-836845, a fully human mAb targeting IGF-1 created using HuCAL technology from Morphosys, for the potential iv infusion treatment of cancer, including solid tumors and breast cancer.
In April 2011, a phase I trial was initiated in the UK . In October 2011, another phase I trial was initiated in Taiwan. In February 2014, recruitment was ongoing. At that time, the trial was expected to be completed in March 2015 In June 2014, the drug was listed as being in phase I development for solid tumors in Japan and for breast cancer
In May 2014, an open-label, randomized, parallel-assigned, phase II trial (NCT02123823; 1280.4; 2013-001110-15) to evaluate the safety and efficacy of BI-836845 and everolimus in combination with exemestane in women with breast cancer (expected n = 198) was planned to be initiated in Belgium, France and the Netherlands. At that time, the trial was expected to complete in December 2017
In June 2014, an open-label, single-group assigned, phase I trial (NCT02145741; 1280.15) to evaluate BI-836845 in Japanese patients (expected n = 18) with advanced solid tumors was planned to be initiated in Japan. At that time, the trial was expected to complete in June 2015
In March 2011, a non-randomized, open-label, phase I study (NCT01317420; 1280.2; 2010-021714-29) was planned to begin later that month in patients with solid tumors (expected n = 70) in the UK, to assess the safety, efficacy, pharmacokinetics, pharmacodynamics and pharmacogenomics of BI-836845. The study began in April 2011; at that time, completion was expected in March 2013 .
In June 2012, preclinical data were presented at the 48th ASCO meeting in Chicago, IL. In the study, the combination of BI-836845 plus rapamycin was more effective than single agent therapy at inhibiting Ewing’s sarcoma cell proliferation in vitro and in a nude mouse xenograft model .
In November 2011, preclinical data were presented at the 23rd AACR-NCI-EORTC International Conference in San Francisco, CA. BI-836845 potently inhibited proliferation of the multiple myeloma cell line LP-1 with an EC50 of 0.4 nM.
BI-836845 is a human monoclonal IgG1 lambda antibody against IGF-1 (insulin growth factor-1) and IGF-2 (insulin growth factor-2). Phase II clinical trials are ongoing at Boehringer Ingelheim for the treatment of patients with breast cancer, and phase I clinical trials are ongoing with patients with advanced solid tumors.
Insulin-like growth factor-1 (IGF-1; a 70 amino-acid polypeptide) and insulin-like growth factor-2 (IGF-2; a 67 amino-acid polypeptide) are 7.5-kD soluble factors present in serum that can potently stimulate the growth of many mammalian cells (reviewed by Pollack et al., 2004). Although IGFs can be detectable in a number of tissues the main source of circulating IGFs is the liver which secretes the IGFs and IGF binding proteins (IGFBPs) in response to a complex signaling pathway that is initiated in the pituitary gland and transduced via growth hormone. On secretion into the bloodstream the IGFs form complexes with the IGFBPs which not only protects them from proteolytic degradation in the serum en route to their target tissues but also prevents their association with the IGF receptors. In addition to this endocrine source of IGFs they are also known to be secreted in an autocrine or paracrine manner in target tissues themselves. This is known to occur during normal fetal development where the IGFs play a key role in the growth of tissues, bone and organs. It is also seen in many cancer tissues where there is thought to be paracrine signaling between tumour cells and stromal cells or autocrine IGF production by the tumour cells themselves (reviewed by LeRoith D, 2003).
30 May 2014
MEDIA ALERT
ASCO 2014: Boehringer Ingelheim to present latest oncology research, including overall survival results
• Highly anticipated new overall survival data for Giotrif® (afatinib*) to be presented on June 2nd (3:00 – 6:00 PM, E Hall D2 [Abstract #8004 scheduled for 4:00 – 4:12 PM])
• 7 total abstracts accepted for Giotrif® (afatinib*), nintedanib** and BI 836845**: 1 for oral presentation and 6 posters
| BI 836845 (IGF ligand antibody)** | ||
| A Phase I dose escalation study of weekly BI 836845, a fully human, affinity-optimized, insulin-like growth factor (IGF) ligand neutralizing antibody, in patients with advanced solid cancers | Chia-Chi Lin, Kwang-Yu Chang, Dennis Chin-Lun Huang, Vicky Marriott, Ludy van Beijsterveldt, Li-Tzong Chen, Ann-Lii Cheng | Sunday, June 1 8:00 – 11:45 AM S Hall A2 (Abstract #2617 Poster #80) |
| Phase I dose escalation study of 3-weekly BI 836845, a fully human, affinity optimized, insulin-like growth factor (IGF) ligand neutralizing antibody, in patients with advanced solid tumours | Rihawi K, Ong M, Michalarea V, Bent L, Buschke S4, Bogenrieder T, Anthoney A, de Bono J, Twelves CJ | Sunday, June 1 8:00 – 11:45 AM S Hall A2 (Abstract #2622 Poster #85) |
The activity of the IGFs is thought to be regulated by a complex and relatively poorly understood interaction involving seven different IGFBPs and other serum proteins. Activation of the IGFs involves their release from this ternary complex after proteolytic release of the serum binding protein and IGFBPs, this is thought to occur in close proximity to cell surfaces where the IGFs are then free to bind to their receptors and transduce intracellular signals that ultimately leads to cellular proliferation and the inhibition of apoptosis. IGF-1 and IGF-2 are able to bind to the IGF-1 receptor (IGF-1R) expressed on many normal tissues, which functionally is a 460 kD heterotetramer consisting of a dimerised alpha- and beta-subunit, with similar affinities (Rubin et al., 1995). IGF-2 can also bind to the IGF-2 receptor (also know as the mannose-6-phosphate receptor) which does not have any known signaling function, rather it is thought to act as a sink for IGF-2 and prevent it from binding and signaling through the IGF-1R. In this respect the IGF-2R has been demonstrated to be a tumour suppressor protein. The IGF-1R is structurally similar to the insulin receptor which exists in two forms, IR-A and IR-B, which differ by an alternatively spliced 12 amino acid exon deletion in the extracellular domain of IR-A. IR-B is the predominant IR isoform expressed in most normal adult tissues where it acts to mediate the effects of insulin on metabolism. IR-A on the other hand is known to be highly expressed in developing fetal tissues but not in adult normal tissues. Recent studies have also shown that IR-A, but not IR-B, is highly expressed in some cancers. The exon deletion in IR-A has no impact on insulin binding but does cause a small conformational change that allows IGF-2 to bind with much higher affinity than for IR-B (Frasca et al., 1999; Pandini et al., 2002). Thus, because of it’s expression in cancer tissues and increase propensity for IGF-2 binding, IR-A may be as important as IGF1-R in mediating the mitogenic effects of IGF-2 in cancer.
Binding of the IGFs to IGF-1R triggers a complex intracellular signaling cascade which results in activation of proteins that stimulate growth and inhibit apoptosis (reviewed by Pollack et al., 2004). In terms of growth, upregulated translation is induced by the activation of p70 S6 kinase, which in turn phosphorylates the S6 ribosomal protein (Dufner and Thomas, 1999). Thus, IGF-stimulated cell growth can be measured by the rapid increase in phosphorylated S6 ribosomal protein.
Unlike the EGFR and Her2neu receptors there is no known amplification of the IGF1-R or IR-A receptors in cancers indicating that receptor activation is controlled by the presence of active ligand. There is a very large body of scientific, epidemiological and clinical literature implicating a role for the IGFs in the development, progression and metastasis of many different cancer types (reviewed by Jerome et al., 2003; and Pollack et al., 2004).
For example, in colorectal cancer the expression of IGF-2 mRNA and protein is elevated in clinical colorectal tumour specimens compared with adjacent normal tissue (Freier et al., 1999; Li et al., 2004). There is also a positive correlation of elevated IGF serum levels with proliferating cell index in patients with colorectal neoplasia (Zhao et al., 2005). In addition, elevated circulating levels of IGF-2 correlate with an increased risk of developing colorectal cancers and adenomas (Renehan et al., 2000a) and b); Hassan et al., 2000). Loss of parental imprinting (LOI) of the IGF-2 gene, an epigenetic alteration that results in elevated IGF-2 expression, is a heritable molecular trait that has recently been identified in patients with colorectal and other tumour types. Loss of IGF-2 imprinting has been shown to be associated with a five-fold risk of colorectal neoplasia (Cui et al., 2003; Cruz-Correa et al., 2004) and adenomas (Woodson et al., 2004). Antibodies targeting the alpha-subunit of the IGF-1R which block IGF binding and internalize the receptor have been shown to delay the growth of the xenografted colon cancer-derived cell lines such as COLO 205 (Burtrum et al., 2003).
Elevated levels of IGFs are associated with a poor prognosis in human pulmonary adenocarcinomas (Takanami et al., 1996) and IGFs are expressed and secreted by many SCLC— and NSCLC-derived cell lines (Quinn et al., 1996). Transgenic over-expression of IGF-2 induces spontaneous lung tumours in a murine model (Moorhead et al., 2003). In terms of hepatocellular carcinoma (HCC), human clinical specimens and animal models of HCC express higher levels of IGF mRNA and protein than corresponding normal tissues and this has been correlated with increased tumour growth (Wang et al., 2003; Ng et al., 1998). IGF-2 has also been shown to be a serological marker of HCC with elevated levels in the serum of HCC patients compared with controls (Tsai et al., 2005). An orthotopic xenograft tumour model of HCC was established using Hep 3B cells, and used to demonstrate that inhibition of IGF-2 expression using a methylated oligonucleotide enhances survival (Yao et al., 2003a) and b).
Many childhood solid tumours such as Ewing sarcoma and rhabdomyosarcoma appear to be particularly dependent on the IGF signaling pathway for their growth (Scotlandi et al., 1996). LOI of the IGF-2 gene has been implicated as a primary genetic event in the development for embryonal rhabdomyosarcoma (Fukuzawa et al., 1999). Autocrine IGF signaling is also thought to strongly influence the growth of Ewing sarcoma in cases where the type-1 EWS-FLI1 chimeric transcription factor is expressed through a chromosomal translocation resulting in elevated expression of target genes including the IGF ligands and IGF-1R, and reduced expression of IGFBP-3. Antibodies and small molecule compounds targeting the IGF-1R have been shown to reduce the growth of xenografted pediatric solid tumour derived cell lines (Kolb et al., 2008; Manara et al., 2007).
Using IGF ligand-specific antibodies it has been demonstrated that the growth of human prostate cancer cells in adult human bone implanted into SCID mice can be inhibited (Goya et al., 2004). In addition, it was demonstrated that the same IGF ligand antibodies could block the paracrine supply of IGF and suppress the liver metastasis of human colorectal cancer cells in a murine xenograft system (Miyamoto et al., 2005).
There is also considerable evidence suggesting that the IGF signaling system reduces the sensitivity of cancers to chemotherapeutic agents and radiation. One of the earliest findings in this respect was the demonstration that IGF-1R knock-out mouse embryos are refractory to transformation by viruses, oncogenes and over-expressed growth factor receptors (Sell et al., 1993; Sell et al., 1994) and that over-expression of IGF-1R protects cells from UV irradiation and gamma radiation-induced apoptosis (Kulik et al., 1997). Furthermore, using liver tumour cell lines that secrete large amounts of IGF-2, it was found that neutralization of IGF-2 significantly increased response to chemotherapeutic agents such as cisplatin and etoposide in vitro, especially at lower, cytostatic doses, suggesting that IGF-2 can reduce the susceptibility to chemotherapeutic agents (Lund et al., 2004). Consistent with these findings it has been demonstrated that antibodies targeting the IGF-1R increase the susceptibility of tumour xenografts to growth inhibition by chemotherapeutic drugs and radiation (Goetsch et al., 2005).
A number of antibodies that show cross-reactive binding to human IGF-1 and human IGF-2 have been reported. Antibody sm1. was raised against human IGF-1 and shows 40% cross-reactivity to human IGF-2 and was shown to inhibit the proliferation of a mouse fibroblast cell line BALB/c3T3 which was stimulated with 20 ng/ml human IGF-1 (Russell et al., 1984). In a study designed to functionally epitope map IGF-1 by raising monoclonal antibodies to whole IGF-1 protein and portions of the protein a number of antibodies where identified that cross reacted with IGF-2 (Manes et al., 1997). The percent cross-reactivity with IGF-2 ranged from 0 to 800% and several antibodies were identified which were equally IGF-1 and IGF-2 reactive. KM1486 is a rat monoclonal antibody that cross-reacts with human IGF-1 and IGF-2 and it was demonstrated that KM1486 can inhibit growth of human prostate cancer cells in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice (Goya et al., 2004). In addition, it was demonstrated that KM1486 suppresses the liver metastasis of human colorectal cancers (Miyamoto et al., 2005). KM1486 has also been described in WO 03/093317, JP 2003-310275, WO 2005/018671, WO 2005/028515, and WO 2005/027970.
For the treatment of human disease an antibody with a fully human sequence is highly desirable in order to minimize the risk of generating a human anti-antibody reaction and neutralizing antibodies that will rapidly eliminate the administered antibody from the body and thereby reduce the therapeutic effect. As such, and given the roles of IGF-1 and IGF-2 dependent signaling in the development and progression of cancers it would be desirable to obtain high affinity fully human antibodies that co-neutralise the mitogenic effects of both ligands.
In addition, to maximize the therapeutic potential of such an antibody, it is important to have a suitably long terminal half life (T1/2). Prior to terminal half life determination in human subjects, the most accurate estimation of an antibody’s human terminal half life can be obtained from administration to non-human primates such as cynomolgus monkeys. For example, bevacizumab, a registered humanized monoclonal antibody against vascular endothelial growth factor (VEGF) used for the treatment of several human cancers, has a terminal half-life in cynomolgus monkeys of 8.57±0.38 days (Lin et al., 1999), which translates to a terminal half life in humans of approximately 20 days allowing for a single administration once every two weeks (Lu et al., 2008).
It was a further object of the invention to obtain an antibody that does not affect binding of insulin to its receptor.
The clinical development of therapeutic agents is supported by pharmacodynamic biomarkers of drug activity. Clinical studies with antibodies targeting the IGF-1R have demonstrated that an increase in total serum IGF-1 levels may be a useful pharmacodynamic marker for these agents (Pollack et al., 2007). The reason for the increase in total serum IGF-1 levels is likely due to a feedback mechanism involving pituitary growth hormone (GH) secretion which releases both IGF-1 and IGFBPs from the liver. Indeed, in humans it has been demonstrated that free or bioactive IGF-1, which represents only around 1% of total IGF-1 levels, determines the feedback response (Chen et al., 2005). The inventors thus sought to confirm whether total serum IGF-1 levels are also a useful pharmacodynamic marker for the activity of a therapeutic anti-IGF antibody. In this case it would be desirable for such antibody to be cross-reactive with IGFs from a suitable animal species, e.g. mouse or rat, such that a pharmacodynamic effect can already be tested pre-clinically.
Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, Boehringer Ingelheim operates globally with 142 affiliates and a total of more than 47,400 employees. The focus of the family-owned company, founded in 1885, is researching, developing, manufacturing and marketing new medications of high therapeutic value for human and veterinary medicine.
Taking social responsibility is an important element of the corporate culture at Boehringer Ingelheim. This includes worldwide involvement in social projects, such as the initiative “Making more Health” and caring for the employees. Respect, equal opportunities and reconciling career and family form the foundation of the mutual cooperation. In everything it does, the company focuses on environmental protection and sustainability.
In 2013, Boehringer Ingelheim achieved net sales of about 14.1 billion euros. R&D expenditure corresponds to 19.5% of its net sales.
Fig.1 Production of MAb
| Adam, P.J.; Friedbichler, K.; Hofmann, M.H.; Bogenrieder, T.; Borges, E.; Adolf, G.R. BI 836845, a fully human IGF ligand neutralizing antibody, to improve the efficacy of rapamycin by blocking rapamycin-induced AKT activation 48th Annu Meet Am Soc Clin Oncol (ASCO) (June 1-5, Chicago) 2012, Abst 3092 |
| Lin, C.-C.; Chang, K.-Y.; Huang, D.C.; Marriott, V.; Van Beijsterveldt, L.; Chen, L.-T.; Cheng, A.-L. A phase I dose escalation study of weekly BI 836845, a fully human, affinity-optimized, insulin-like growth factor (IGF) ligand neutralizing antibody, in patients with advanced solid cancers 50th Annu Meet Am Soc Clin Oncol (ASCO) (May 30-June 3, Chicago) 2014, Abst 2617 |
Adam, P.J.; Ostermann, E.; Lamche, H.R.; Hofmann, M.H.; Kroez, M.; Borges, E.; Adolf, G.R.
Pharmacodynamic properties and anti-tumor efficacy of BI 836845, a fully human IGF ligand neutralizing antibody
AACR-NCI-EORTC Int Conf Mol Targets Cancer Ther (November 12-16, San Francisco) 2011, Abst A208
| Rihawi, K.; Ong, M.; Michalarea, V.; et al. Phase I dose escalation study of 3-weekly BI 836845, a fully human, affinity optimized, insulin-like growth factor (IGF) ligand neutralizing antibody, in patients with advanced solid tumors 50th Annu Meet Am Soc Clin Oncol (ASCO) (May 30-June 3, Chicago) 2014, Abst 2622 |
Glenmark Pharmaceuticals inaugurates new Antibody Manufacturing Facility in La Chaux-de-Fonds, Switzerland
Glenmark Pharmaceuticals inaugurates new Antibody Manufacturing Facility in La Chaux-de-Fonds, Switzerland
Glenmark opens a new cGMP-compliant monoclonal antibody manufacturing facility in La Chaux-de-Fonds, Switzerland
• State of the art manufacturing facility for supply of clinical trial material
• With the facility Glenmark has end-to-end capabilities for the development of novel, state-of-the-art monoclonal antibodies including bi-specific antibodies
La Chaux-de-Fonds, Switzerland, June 4, 2014 – Glenmark Pharmaceuticals S.A (GPSA), a wholly owned subsidiary of Glenmark Pharmaceuticals Limited, India (GPL), announced the opening of its new cGMP compliant monoclonal antibody manufacturing facility in La Chaux-de-Fonds, Switzerland. This manufacturing facility supplements Glenmark’s existing in-house discovery and development capabilities and will supply material for clinical development.
The manufacturing facility has been designed for use of single use bioreactor systems and also houses a suite for manufacturing cell banks. The facility is fully compliant with quality, environmental and safety standards for manufacturing clinical trial material.
http://www.moneycontrol.com/stocks/stock_market/corp_notices.php?autono=813829
4th-Jun-2014 10:33
Source: BSE
The company says the facility supplements existing in-house discovery and development capabilities and will supply material for clinical development. Glenmark Pharmaceuticals’ Swiss research centre is an integrated antibody discovery and development unit with in-house capabilities and infrastructure for conducting antibody discovery, cell line development, in vitro testing and characterisation of antibodies, process development and analytical research. The new manufacturing facility supplements the research and development capabilities and will enable production of clinical grade material.
Single-use bioreactor systems and a suite for manufacturing cell banks are included in the new facility, which is fully compliant with quality, environmental and safety standards for manufacturing clinical trial material. Michael Buschle, President – Biologics, at Glenmark Pharmaceuticals, said: ‘This state-of-the-art manufacturing facility is a testimony to Glenmark’s commitment to growing its R&D and manufacturing facility in the canton of Neuchâtel.
We have been doing cutting-edge work in the area of novel monoclonal antibodies and have several monoclonal antibody candidates and bispecific antibodies in the pipeline.
The manufacturing facility will help us bring these antibodies to the clinic faster.’ There are currently 69 staff at the research centre developing biologics for the treatment of pain, inflammatory, oncologic and respiratory conditions. In 10 years, the centre has filed several patents on novel biologic entities: GBR 500, its most advanced candidate, has been licensed to Sanofi and is currently in Phase II development; GBR 900, a molecule for the treatment of chronic pain, is currently in Phase I; and GBR 830, an anti OX-40 antagonist, is scheduled to enter the clinic later this year
La Chaux-de-Fonds, Switzerland ………city
EU approves Takeda’s bowel drug Entyvio
Hot on the heels of an approval in the US, regulators in Europe have now also given Takeda’s Entyvio (vedolizumab) the nod for two inflammatory bowel diseases. The European Commission has granted Marketing Authorisation for use of the gut-selective humanised monoclonal antibody to treat adults with moderately to severely active ulcerative colitis (UC) and adults with moderately to severely active Crohn’s disease (CD).
Read more at: http://www.pharmatimes.com/Article/14-05-27/EU_approves_Takeda_s_bowel_drug_Entyvio.aspx#ixzz334DL7xQJ
New Drug Approvals 
