InvestorsHub Logo
Followers 72
Posts 4827
Boards Moderated 0
Alias Born 01/24/2004

Re: None

Monday, 04/23/2007 8:59:27 AM

Monday, April 23, 2007 8:59:27 AM

Post# of 345554
Feb’07: TNT-based Trial Init. in Eur. by ‘Licensee’

Conjecture: the licensee is Merck-KGaA’s and the drug is “NHS-IL2-LT (EMD 521873)”, branded as SELECTIKINE, an immunocytokine that targets DNA of necrotic cells.

2-22-07 PR: TNT-BASED TRIALS INITIATED IN EUR. BY LICENSEE
“Peregrine's Licensee Initiates Phase I Clinical Trial in Europe With Novel Tumor Necrosis Therapy Cancer Agent”
http://www.peregrineinc.com/content.php?mi=MTc=&appAction=--PRINT&Id=OTY2MTg1
Feb. 22 2007: Peregrine… announced that one of its licensees [most likely: Merck KGaA – see below] has initiated European clinical trials of a novel anti-cancer agent developed with technology licensed from Peregrine. The investigational drug uses Peregrine's proprietary tumor necrosis therapy (TNT) technology… "We believe our TNT technology has considerable potential for targeting anti-cancer therapies, and we are very pleased that one of our licensees has now advanced another TNT anti-cancer agent into clinical trials," said Steven W. King, CEO of Peregrine. "The recent launch of a TNT lung cancer therapy by a local firm in China, our new clinical program in India assessing TNT-based Cotara for brain cancer and this clinical debut in Europe make this an exciting time for TNT-based anti-cancer programs."
The licensee initiating this new trial currently prefers to remain anonymous. Peregrine expects to receive a royalty on net sales of any TNT-targeted anti-cancer drugs eventually marketed by this licensee. Further terms of the agreement were not disclosed.
…PR end.

###FACTS THAT SUGGEST THAT THE ‘LICENSEE’ IS, IN FACT, MERCK KGAA, AND THE DRUG IS THE TNT-BASED IMMUNOCYTOKINE NHS-IL2-LT (EMD 521873), BRANDED BY MERCK-KGAA AS “SELECTIKINE”:

= = = = = = = = = = = = = = =
I. MERCK KGAA’S 4TH QTR 2006 REPORT DATED 3-1-07:
Under Oncology (pg.26), this is listed:
NHS-IL2-LT (EMD 521873), immunocytokine that targets DNA of necrotic cells, in phase I trials.
Also, on Pg. 30:
Merck Serono (Serono Acquisition – Merck Serono Div. launched 1-7-2007)
Oncology:
5. Erbitux… CRC/Japan submitted.
6. Stimuvax… Phase III.
7. Tucotuzumab… Phase II.
8. NHS-IL2-LT enters phase I.
http://www.merck.de/servlet/PB/show/1647260/AR2006_Merck_KGaA_presentation_en.pdf
[Serono is a biotechnology company headquartered in Geneva, Switzerland. Serono was sold to Merck KGaA in Sept.2006 for 10.6bb Euros. The new entity, which merges Serono with Merck's Ethicals division, will be called Merck-Serono.]
http://www.merckserono.net/index.html

= = = = = = = = = = = = = = =
II. ONCOLOGY INST. OF SO. SWITZERLAND, EMD521873/SELECTIKINE TRIAL:
STUDY: Investigation of Safety, Tolerability, Pharmacokinetics, Biological and Clinical Activity of EMD 521873 Alone and in Combination with Fixed Low Doses of Cyclophosphamide in Patients with Solid Tumors or B-Cell Non-Hodgkins Lymphoma
AGENT: Selectikine
Eligible patients: Solid Tumors or B-Cell Non-Hodgkins Lymphoma
Activation date: Dec. 2006
Oncology Institute of So. Switzerland, Ospedale San Giovanni, CH-6500 Bellinzona
http://www.eoc.ch/allegati/studi_unità_linfomi.pdf
NOTE: Cyclophosphamide (the generic name for Cytoxan, Neosar) is a nitrogen mustard alkylating agent, used to treat various types of cancer and some autoimmune disorders. It is a "prodrug"; it is converted in the liver to active forms that have chemotherapeutic activity. The main use of cyclophosphamide is together with other chemotherapy agents in the treatment of lymphomas, some forms of leukemia and some solid tumors. It is a chemotherapy drug that works by slowing or stopping cell growth. It also works by decreasing the immune system's response to various diseases.

= = = = = = = = = = = = = = =
III. “NHS-IL2-LT (EMD 521873), immunocytokine that targets DNA of necrotic cells” (from Merck-KgaA’s 10K) seems to equate to this TNT/IL-2 cytokine fusion protein presented at AACR 2004 and PR’D by Peregrine:
3-30-2004 PR:
“Peregrine Announces Pub. of Data Related to its TNT Tech. Platform - Pre-clinical Data Presented at AACR 2004”
Mar.30 2004: Peregrine announced today that data related to its Tumor Necrosis Therapy (TNT) technology platform was presented at the AACR annual meeting. The presented research describes the expression and testing of Peregrine's human TNT monoclonal antibody (NHS76) linked to the human cytokine Interleukin-2 (IL-2). The expressed fusion protein retained functional activity of IL-2 and had a very low toxicity profile in animal studies. TNT directed cytokines are currently under development by Merck KGaA of Darmstadt, Germany, under a licensing agreement with Peregrine.
The presentation, "Engineering of an IL-2 immunocytokine with very low toxicity that retains potent anti-tumor activity in immune competent and immune deficient mouse tumor models," detailed a new TNT-based immunocytokine under evaluation at Merck KGaA. The immunocytokine consisted of the NHS76 targeting antibody linked to a mutant version of the cytokine IL-2 known as D2OT, which has an improved safety profile compared with native IL-2. Presented were studies in several mouse tumor models demonstrating that NHS- IL-2(D20T) is extremely well tolerated and retains most of its anti-tumor activity against established metastases. The immunocytokine also retains significant anti-tumor activity, although somewhat higher doses are required to achieve equivalent effects. The studies also showed that "small metastatic tumors can be targeted using an immunocytokine with specificity for a necrotic marker such as DNA."… The combination of a targeting monoclonal antibody linked to a cytokine is known as an immunocytokine. In the newly published article, an immunocytokine was constructed using a TNT antibody linked to the cytokine IL-2. The TNT antibody guides IL-2 to the tumor where the cytokine can help boost the body's ability to fight the cancer. Immunocytokines are expected to have lower side effects than conventional chemotherapy and thus represent an attractive alternative to standard tumor therapy…
http://www.peregrineinc.com/content.php?mi=MTc=&appAction=--PRINT&Id=NTA5ODM4
= = = = = = = AACR 2004 Abstract #654:
“Engineering of an IL-2 Immunocytokine with Very Low Toxicity That Retains Potent Anti-Tumor Activity in Immune Competent and Immune Deficient Mouse Tumor Models”
Stephen D. Gillies… Kin-Ming Lo, EMD-Lexigen Research Center [subsidiary of Merck KGaA]
The use of IL-2 for cancer therapy has been limited by its side effect profile that primarily includes effects in the vascular compartment such as vascular leak syndrome and hypotension. Many theories have been proposed to explain the mechanism of IL-2 toxicity including direct binding to endothelial cells as well as over-stimulation of intermediate affinity IL-2 receptor (IL-2R) bearing cells (e.g. NK cells) in the bloodstream. In our studies of IL-2 toxicity we have identified a specific IL-2 mutant, D20T, which has little selectivity for high over intermediate affinity IL-2 receptors as a free IL-2 molecule but which has profound selectivity when it is fused to the carboxyl terminus of an antibody to form an immunocytokine. Measurements in vitro show it to have near normal biological activity using T cell lines expressing the high affinity IL-2R but little or no activity using lines expressing only the intermediate IL-2R. This mutation also removes a sequence motif proposed earlier to resemble a binding site for endothelial cells found in many bacterial exotoxins. Surprisingly, this mutation within IL-2 had a detrimental effect on the circulating half-life of the immunocytokine that could only be reversed by removing the N-linked glycosylation site within the IgG constant region (CH2 domain). The final molecule was engineered using the V regions from a human antibody, NHS76, with high affinity for the necrotic core of solid tumors, thus allowing for selective targeting of this modified IL-2 to virtually any tumor with necrosis. Our in vitro studies with this molecule show that the binding to necrotic tissue is mediated through its high affinity for single or double-stranded DNA, despite original reports that the NHS76 antibody recognized DNA-histone complexes. Studies in several mouse tumor models demonstrate that this immunocytokine, NHS-IL2 (D20T), is extremely well tolerated in immune competent mice and retains most of its anti-tumor activity against established metastases. It also retains significant anti-tumor activity in immune deficient SCID mice lacking functional T cells, although somewhat higher doses are required to achieve equivalent effects. These results suggest additional effector cells expressing high-affinity IL-2R, besides T cells, are functioning in these tumor models. They also show that small metastatic tumors can be targeted using an immunocytokine with specificity for a necrotic marker such as DNA.
http://www.aacrmeetingabstracts.org/cgi/content/abstract/2004/1/151-c?maxtoshow=&HITS=10&hit...

= = = = = = = = = = = = = = =
IV. 10-2000 MERCK KGAA (GERMANY) TNT-BASED “CYTOKINE FUSION PROTEINS” LICENSING AGREEMENT
$400k upfront plus future milestone payments and royalties on net sales…
4-30-2001 10K:
TUMOR NECROSIS THERAPY (COTARA)
During Oct.2000, the Company entered into a licensing agreement with Merck KGaA to license a segment of its TNT technology for use in the application of cytokine fusion proteins. Under the terms of the licensing agreement, the Company will receive up-front payments of up to $400,000 upon the satisfaction of certain conditions set forth in the agreement, of which, the Company received $50,000 in Nov.1999. The Company will also receive a royalty on net sales, as defined in the agreement, upon the commencement of commercial sales.
MERCK KGAA NEWS RELEASE – 10-24-2000:
“Techniclone Corporation and Merck KGaA Sign Agreement On Use of Tumor Necrosis Therapy Technology”
Oct.24, 2000: Techniclone Corp. today announced that the Company has completed an agreement for a segment of its Tumor Necrosis Therapy (TNT) technology with Merck KGaA of Darmstadt, Germany [ http://www.merck.de ]. Under the agreement, Techniclone will grant Merck the right to use its proprietary TNT antibodies for producing immunocytokines - novel antibody-cytokine fusion proteins used in the treatment of various diseases. Within Merck, the international team of its affiliate Lexigen [ http://www.emdlexigen.com ], based in Lexington, MA, will develop these novel immunocytokines using Techniclone's TNT technology. The agreement involves an undisclosed upfront payment and a royalty upon commencement of commercial sales… "This license agreement will allow us the opportunity to explore some promising new therapeutic constructs based on immunocytokines. I am very excited about working with their scientific team to bring these compounds to commercialization" stated Dr. Alan Epstein. Dr. John Bonfiglio, Techniclone's President, stated, "This licensing agreement with Merck KGaA allows Techniclone to leverage its proprietary technology in an area we are not currently pursuing and would not be able to pursue without the permission of Merck KGaA. The deal is structured so that Lexigen/Merck will provide all scientific, preclinical, clinical and commercialization resources as well as their know-how in the use of antibodies linked to cytokines. Techniclone will provide antibodies and the genes encoding them for use in the genetic engineering of immunocytokines. In return, we will receive a royalty for all products developed under this deal. The deal is also further verification of the potential utility of this TNT antibody targeting technology in the field of cancer therapeutics."… Merck's operating activities come under the umbrella of Merck KGaA, in which the Merck family holds a 73% interest and free shareholders own the remaining 27%. The former U.S. subsidiary, Merck & Co., has been completely independent of the Merck Group since 1917…
http://me.merck.de/EMD/UK/uknews2.nsf/d4c60a303233fb87c1256fc500368312/e1f7d9c611a723c2c1256fc5003a7...
Alt link: http://www.virtualtrials.com/news3.cfm?item=339&showtext=y

= = = = = = = = = = = = = = =
V. PPHM’s 4-30-06 10K:
“During October 2000, we entered into a licensing agreement with Merck KGaA to out-license a segment of our TNT technology for use in the application of cytokine fusion proteins. During January 2003, we entered into an amendment to the license agreement, whereby we received an extension to the royalty period from 6 years to 10 years from the date of the first commercial sale. Under the terms of the agreement, we will receive a royalty on net sales if a product is approved under the agreement. Merck KGaA has not publicly disclosed the development status of its program.”
“Vasopermeation Enhancements Agents (“VEAs”) - During fiscal year 2006, VEA program expenses decreased $211,000 from $567,000 in fiscal year 2005 to $356,000 in fiscal year 2006. The decrease in VEA program expenses is primarily due to a decrease in sponsored research fees and technology license fees combined with a decrease in antibody development fees regarding expenses incurred in the prior year. In Jan.2005, we entered into an agreement with Merck KGaA of Darmstadt, Germany, that gave us access to Merck's technology and expertise in protein expression to advance the development of our VEA technology and other platform technologies. We are currently developing a clinical candidate under our VEA technology utilizing Merck’s expertise in protein expression.”
PPHM’s 10-31-05 10Q: “In Jan.2005, we entered into an agreement with Merck KGaA of Darmstadt, Germany, that will give us access to Merck's technology and expertise in protein expression to advance the development of our VEA technology and other platform technologies. Merck KGaA is presently working on a clinical candidate under the VEA technology platform.”

VI. MERCK KGAA’s WEBSITE:
Immunocytokines – Providing Local Stimulation of the Immune System
http://www.merck.de/servlet/PB/menu/1207070/index.html
EMD LEXIGEN is a subsidiary of Merck KGaA, Darmstadt, Germany
Helping people lead better, healthier lives. At the EMD Lexigen Research Center, that’s our unwavering commitment. We are a research-driven company focused on developing new generations of therapies for cancer and other serious and life-threatening diseases.
http://www.emdlexigen.com
Scientific Programs:
Immunocytokines
• Fusion Proteins
• Aids Therapy
Immunocytokines are fusion proteins consisting of an antibody attached to a cytokine. These molecules combine the specificity of an antibody with the powerful immune-stimulating features of cytokines.
http://www.emdlexigen.com/immuno.htm
The immunocytokine technology platform allows various combinations of different antibodies and cytokines. Hence, researchers at Merck and Lexigen continue to develop further immunocytokines for the future.
HTTP://www.immunocytokines.com => http://www.merck-media.de/oncology/immustart.html
EMD Pharmaceuticals, Inc., a sister company founded in 1999 to expand Merck KGaA’s commercial pharmaceutical operations in the United States. EMD Pharmaceuticals is active in the clinical development, manufacture and sale of Merck KGaA’s products in the U.S., with operations in Durham, N.C., and Lexington and Billerica, MA.

= = = = = = = = = =
Eur. Trials search: http://www.controlled-trials.com

Volume:
Day Range:
Bid:
Ask:
Last Trade Time:
Total Trades:
  • 1D
  • 1M
  • 3M
  • 6M
  • 1Y
  • 5Y
Recent CDMO News