<< Back To Prostate Cancer News
  Patent Application Titled "Anti-Alpha-V Integrin Antibody for the Treatment of Prostate Cancer" Published Online  

Biotech Week (Published: Wednesday, April 16, 2014, Received: Wednesday, April 9, 2014, 11:49:12 PM CDT)
Merck Patent GmbH
Word Count: 3841

By a News Reporter-Staff News Editor at Biotech Week -- According to news reporting originating from Washington, D.C., by NewsRx journalists, a patent application by the inventors Hoffmann, Axel (Wehrheim, DE); Lannert, Heinrich (Schwetzingen, DE); Brischwein, Klaus (Muenchen, DE); Pipp, Frederic Christian (Gruendau, DE); Reindl, Juergen (Rossdorf, DE); Groll, Karib (Muehltal, DE); Zuehlsdorf, Michael (Darmstadt, DE); Pfaff, Otmar (Frankfurt am Main, DE); Raab, Sabine (Rosbach, DE); Dau, Ulrike (Darmstadt, DE); Destenaves, Benoit (Peron, FR), filed on February 7, 2012, was made available online on April 3, 2014 (see also Merck Patent GmbH).

The assignee for this patent application is Merck Patent GmbH.

Reporters obtained the following quote from the background information supplied by the inventors: "Prostate cancer is the most commonly occurring cancer aside skin cancer in the US, and is the second most common cause of male cancer deaths.

"Prostate cancer is classified in four stages: Stage I prostate cancer is found in the prostate only and cannot be felt during a digital rectal exam nor is it visible by imaging. In stage II prostate cancer, the tumor has grown inside the prostate but has not extended beyond it, whereas in stage III, the cancer has spread outside the prostate, but to a minimal extent only. Often, prostate cancer in stage III will have spread only to nearby tissues, such as the seminal vesicles. Finally, in stage IV, the cancer has spread outside the prostate to other tissues, such as the lymph nodes, bones, liver, and/or lungs or brain.

"The spectrum of prostate cancers that are progressing despite castrate levels of testosterone includes tumors that have shown varying degrees and durations of response to primary hormone treatment, and clinical manifestations that range from a rising prostate-specific antigen (PSA) alone, a rising PSA with osseous and/or soft-tissue spread, or a predominantly visceral disease pattern.

"Currently approved treatment of prostrate cancer includes surgical castration, chemical castration, or a combination of surgical and chemical castration. Removal of the testes, the primary testosterone producing organ, reduces the levels of circulating androgens, to less than 5% of normal levels. This reduction in androgen levels inhibits prostate tumor growth. Although the anti-tumor effects of surgical castration are direct, the anti-tumor effects can be temporary. Surgical castration often leads to clonal selection of androgen-independent prostate tumor cells. This results in re-growth of the prostate tumor in a form that proliferates without testosterone or DHT Stimulation. Chemical castration (also called medical castration) is often substituted for surgical castration, as an initial treatment. Despite its high prevalence, treatment options for men having prostate cancer remain relatively limited and typically depend on the stage of the cancer.

"Treatment options include surgical treatments such as radical prostatectomy, in which the prostate is completely removed and radiation, applied through an external beam that directs the dose to the prostate from outside the body or via low-dose radioactive seeds that are implanted within the prostate to kill cancer cells locally. Anti-androgen hormone therapy also is used in the treatment of prostate cancer, either alone or in conjunction with surgery or radiation. Hormone therapy typically aims at blocking the pituitary from producing hormones that stimulate testosterone production by use of castration or administration of hormone analogs and requires that patients have injections of these hormone analogs for protracted periods. Finally, chemotherapeutic approaches have been used to treat advanced prostate cancer, usually as a last resort when other approaches have failed. Since a couple of years, the combination of docetaxel and prednisone was established as the new standard of care for patients who have progressed on androgen deprivation.

"None of the treatments described above are curative and prostate cancer being androgen dependent at first, often will progress despite surgical and hormonal-based therapies, and become resistant over time, leading to a cancer type which is called 'hormone refractory cancer' or 'castration resistant cancer' (CRPC).

"Clinical disease manifestations of CRPC are commonly related to bone metastases and may include pain, pathologic fractures, and spinal cord compression, with local recurrences that may be associated with pelvic discomfort, renal dysfunction due to ureteral compression, bladder outlet obstruction, and sexual dysfunction. Further, while bone cancer is the predominant result of CRPC, patients may develop soft-tissue metastases (lymph node(s)) and visceral metastasis in liver, lung, brain, and other organs. Patients with CRPC are minimally responsive to chemotherapy and the majority of patients die due to progressive prostate cancer within 20 months of initiating treatment. Bisphosphonates are commonly used in patients with castrate-resistant prostate cancer who have bone metastases.

"It has been shown that prostate tumors remain dormant and clinically undetectable until they begin to secrete angiogenic factors and down-regulate the expression of angiogenic inhibitors. In general, it can be stated that angiogenesis is critical to the genesis of prostate tumors. Therefore, it was not completely surprising that anti-angiogenic agents inhibit prostate cancer cell growth.

"In prostate cancer, tumor cells express an abnormal integrin repertoire and are surrounded by a markedly aberrant extracellular matrix (ECM). These changes have profound consequences, given the ability of each integrin to regulate specific cell functions. Expression of .beta.3 and .beta.1 subunits activates specific signaling pathways and support distinct cancer cell functions. .beta.3 is uniquely required in cancer cells for increasing cdc2 levels as well as cdc2 kinase activity. These effects are specific for .beta.3 and are not observed for .beta.6. Up-regulation of .beta.3 and .beta.6 integrin variants has been described. Zheng et al. (Cancer Research 1999; 59, 1655-1664) used human prostate cancer cells isolated from sixteen surgical specimens, to show that these cells express .alpha.v.beta.3, whereas normal prostate epithelial cells do not. Similarly, .alpha.v.beta.6 was found to be expressed in adenocarcinoma (Li et al.; Molecular and Cellular Biology 2007; 27, 4444).

"The use of integrin inhibitors is likely to affect both cancer cell survival and angiogenesis since integrins are expressed by tumor cells as well as by endothelial cells. Although it is hard to discriminate between an effect on tumor growth and an effect on angiogenesis, a maximal response of these inhibitors can be predicted when the targeted integrin is expressed by both tumor and endothelial cells.

"Bone is the most frequent metastatic site for prostate cancer. Bisanz et al. (Molecular Therapy 2005; 12, 634-643) illustrate a positive role for alpha-v integrins on prostate tumor survival in the bone. Analysis of human prostate cancer bone xenografts shows that intratumoral administration of liposome encapsulated human alpha-v siRNAs significantly inhibits the growth of PC3 tumors in bone and increases apoptosis of prostate tumor cells. Further studies (McCabe et al., Oncogene 2007; 26, 6238-6243) demonstrate that .alpha.v.beta.3 integrin activation on tumor cells is essential for the recognition of key bone specific matrix proteins. These data suggest that the .alpha.v.beta.3 integrin modulates prostate cancer growth in distant metastasis.

"Since integrins mediate the interactions between tumor cells and bone microenvironment and facilitate growth in bone, a potential application of the use of integrin inhibitors is to prevent prostate cancer bone lesions. These lesions are osteoblastic and/or osteolytic and are frequently detected in prostate cancer patients (over 80% of prostate cancer patients have established bone metastasis at autopsy).

"A recent study has shown that the .alpha.v.beta.3 integrin promotes bone gain mediated by prostate cancer cells that metastasize to the bone and point to .alpha.v.beta.3 as a potential therapeutic target to block prostate cancer osteoblastic lesions. Immunohistochemical analysis has demonstrated the presence of .alpha.v integrin in a large proportion of human prostate cancer tissues samples.

"These and other results suggest that anti-integrin agents may have both direct and indirect antitumor activity. But there are only few clinical trials reporting that peptide or non-peptide integrin inhibitors are effective agents in prostate cancer therapy.

"Therefore, there is a need to provide a potent anti-integrin agent for use in the therapy of prostate cancer, especially castration-resistant prostate cancer developing bone metastases."

In addition to obtaining background information on this patent application, NewsRx editors also obtained the inventors' summary information for this patent application: "It has been found by the inventors that the known monoclonal anti-alpha v antibody DI-17E6 (designated herein also as EMR62242 or EMD 525797) is highly effective in (i) a monotherapy based clinical setting and (ii) in a combinatorial clinical setting together with hormonal agents and/or chemotherapeutic agents and/or tyrosine kinase inhibitors or other angiogenesis inhibitors in the treatment of prostate cancer.

"In a first aspect of the invention, it was shown in clinical trials that the known specifically engineered hybrid monoclonal anti-alpha-v antibody DI17E6 is well tolerated in prostate tumor patients without significant side effects at doses of at least 500 mg mAb each two weeks administered by infusion during a treatment period of at least four months (FIG. 3, Table 3).

"In a second aspect of the invention it was shown, when administering DI17E6 with doses of at least 500 mg each two weeks is effective in the treatment of prostate cancer, preferably castrate-resistant prostate cancer (CRPC). As a result, the number of prostate derived circulating tumor cells (CTC) in the blood of these patients can be significantly reduced within the treatment period, above all if this number was originally (at the beginning of the treatment) very high (FIG. 1).

"In a third aspect of the invention it was shown that the value of prostate specific antigen (PSA) can be significantly reduced in CRPC patients. The effect is dependent on the duration of the treatment and the disease status of the patient. In general after five or more months of treatment a PSA value can be obtained, which corresponds in less progressive cases to PSA values of healthy males, in other more severe cases, where the PSA value was dramatically high at the beginning of the antibody treatment, the PSA value after treatment can be reduced more than 10-fold (FIGS. 4, 5)

"In a fourth aspect of the invention it could be demonstrated that by the administration of DI17E6 in a dose of at least 500 mg each two weeks the metastatic affection of bone and lymph nodes can be significantly reduced.

"In a further aspect of the invention, it could be shown that DI17E6 reveals a dose-dependent response in prostate cancer patients, preferably castrate-resistant prostate cancer (CRPC) patients, with increasing efficacy at higher doses, wherein a dose of about 500 mg and higher each two weeks is effective, whereas a dose of about 250 mg DI17E6 or less is not effective in prostate cancer, preferably CRPC patients (FIG. 3, 5).

"It should be noted that DI17E6 is effective preferably in a monotherapy setting, wherein no further cytotoxic drug (such as cabazitaxel, docetaxel, doxorubicin, irinotecan etc.) was administered. This is the first time, where an engineered monoclonal antibody is effective in a tumor therapeutic approach without the necessity of the administration of a chemotherapeutic agent.

"It should be further noted that according to the first results in said clinical trials DI17E6 seems to be the more effective the more progressive the disease is. Thus, DI17E6 elicits a stronger effect on PSA values, circulating tumor cells and metastases in patients after ineffective hormone- and/or chemotherapy and even after surgery impacts such as prostatectomy as compared to patients in a less progressive disease state without such surgery or even without pretreatment with chemotherapeutics and/or hormones. In summary, DI17E6 is very promising in the treatment of CRPC above all in patients with a progressive or end-stage disease status after chemotherapy treatment.

"A further result is that DI17E6 is able to induce tumor shrinkage and tumor lesion (FIG. 6), especially in solid prostate tumors or tumor metastases deriving thereof, which are resistant to chemotherapy and/or radiotherapy.

"Furthermore, there is evidence that treatment with DI17E6 (in monotherapy) reduces pain, which usually occurs in prostate cancer. Thus, the drug presents benefits in terms of pain and pain interference score (FIGS. 4B, 5B). It could be observed that the decrease of pain during treatment is correlated with the decreasing PSA level in said patients.

"DI17E6 is well tolerated without premedication, and does not show clinically relevant does-related changes in assessed safety parameters, such as drug-related treatment emergent adverse events (TEAE) (Table 3).

"In a further aspect of the invention, it could be shown that there is a strong correlation between bone metabolism biomarkers, including STC-1, ADAMTS-1, M30, M65, IL6 and IL8, and dose levels (FIG. 7). At high doses>1500 mg a significant drop in osteopontin can be observed in the majority of CRCP patients.

"The pharmacokinetic profile of DI17E6 is dependent on dose after single and multiple doses with a half-life of approximately 250 h at the 1500 mg dose level.

"The safety results of the phase 1, open-label study show that repeated infusions of single-agent DI17E6 (EMD 525797) at each of four dose levels are generally well tolerated and appear to be safe in patients with mCRPC and progressive disease preferably following prior chemotherapy. There are no dose-limiting toxicities (DLT) and no infusion reactions. With regard to dose, no trends in the distribution of TEAEs, NCI-CTCAE (version 3.0) grade or drug relationship are observed. In addition, there is no evidence of accumulation of any specific event within individual cohorts. Eleven patients experienced TEAEs that are considered to be drug-related. In this regard, skin symptoms such as pruritus, erythema and rash, which are reported in a total of four patients, are predictable adverse events associated with DI17E6 (EMD 525797) given that integrins are responsible for the maintenance of the epithelial phenotype. Symptoms of mucosal inflammation and swollen tongue may also be characteristic of the mechanism of action of EMD 525797, but together with fatigue, might also be signs of the underlying disease. The hematologic and biochemic toxicity shifts observed in eight patients could also be explained by underlying disease, as well as concomitant medications.

"PK assessment after single and multiple doses of study drug suggest that DI17E6 (EMD 525797) behaved in accordance with a receptor-mediated clearance model as described for other antibodies targeting membrane-associated receptors. Consistent with the findings of an earlier study in healthy volunteers, PKs of DI17E6 (EMD 525797) in mCRPC patients are dose-dependent with clearance determined predominantly by the availability of unbound receptors. At the doses used in the present study, it can be assumed that at doses of 1000 mg or higher, almost all receptors are saturated and have a minor contribution to drug clearance. Immunologically triggered antibodies directed against DI17E6 can be detected in some (16%) patients; however, no impact on PKs or safety could be found.

"In castrate-resistant prostate cancer patients with bone metastases following prior chemotherapy, the median progression free survival is expected to be 8 to 10 weeks. Antitumor activity evaluations showed that DI17E6 (EMD 525797), as single-agent therapy, achieved an objective partial tumor response in a single patient in the 500 mg cohort. In 9 of 18 patients (50%) receiving DI17E6 (EMD 525797) at a dose of 500 mg or higher, no radiographic disease progression can be observed for 16 weeks or longer. In two patients, long-term treatment with DI17E6 (EMD 525797) at a dose of 500 mg is associated with significant reductions in PSA levels and clinical benefit in terms of pain interference. At least one patient also showed primary tumor shrinkage and normalization of target lymph node size. Thus, DI17E6 (EMD 525797) appears to show single-agent activity in at least some patients with late-stage mCRPC.

"In conclusion, single-agent EMD 525797 given as single and multiple doses is shown to be well tolerated in patients with mCRPC with bone metastases and progressive disease following prior chemotherapy with no spontaneous remissions. 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 combination therapy.

"To sum up, the subject matter of this invention is directed to the following: The use of anti-av integrin antibody DI17E6 or a biologically active variant, or modification thereof, for the treatment of patients, or for the manufacture of a medicament for the treatment of patients, said patients suffering from prostate cancer, preferably castrate-resistant prostate cancer (CRPC), preferably wherein said CRPC is accompanied by high levels of serum PSA in a range of 25-10.000 ng/ml, more specifically in levels of more than 25 ng/ml, or more than 50 ng/ml, or more than 100 ng/ml, or more than 250 mg/ml, or more than 500 ng/ml, or more than 1000 ng/ml, or more than 2500 ng/ml or more than 5000 ng/ml, or more than 7500 ng/ml. The respective use of DI17E6 antibody, wherein the cancer is metastasizing, preferably into bone and/or lymph node tissue. The respective use of DI17E6 antibody, wherein the prostate-specific antigen (PSA) value is declined more than 5-fold, 10-fold, 20-fold, preferably 10-fold during treatment compared to the value before starting antibody treatment. The respective use of DI17E6 antibody, wherein the reduction of the PSA value was achieved within 4-8 months of treatment, preferably after 4 months, more preferably after 6 months. The respective use of DI17E6 antibody, wherein the number of the circulating tumor cells (CTC) is declined during antibody treatment. The respective use of DI17E6 antibody in a CRPC patient whose prostate has been removed, or alternatively, has been treated by radiation. The respective use of DI17E6 antibody for reducing pain which occurs in prostate cancer, preferably in CRPC preferably accompanied by bone metastasis. The respective use of DI17E6 antibody, wherein the patient was pretreated with chemotherapeutics and/or hormonal agents, preferably when the cancer is progressive after said pretreatment with the chemotherapeutic and/or hormonal agent. The respective use of DI17E6 antibody, wherein the effective dose of the antibody is 500 mg-1500 mg per two weeks, preferably 500-1000 mg per two weeks, or 1000-2000 mg per month. The respective use of DI17E6 antibody, wherein the effective dose of 500-1000 mg is administered by a single infusion. The respective use of DI17E6 antibody, wherein the antibody is administered in a monotherapy setting without additional chemotherapeutic agents. The respective use of DI17E6 antibody, wherein the antibody is administered in a combinatory setting with a cytotoxic/cytostatic or an hormonal agent sequentially or simultaneously. The respective use of DI17E6 antibody, wherein in said combinatory setting the cytostatic or cxytotoxic agent is selected from the group consisting of: a chemotherapeutic agent, radiation, a tyrosine kinase inhibitor, and an angiogenesis inhibitor; said tyrosine kinase inhibitor being an anti-ErbB antibody selected from the group consisting of an anti-EGFR antibody, an anti-Her2 antibody, and an anti-Her3 antibody, and said angiogenesis inhibitor being an alpha-v integrin inhibitor, preferably an RGD peptide, such as cilengitide. The respective use of DI17E6 antibody, 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. The respective use of DI17E6 antibody, wherein the biological active variant or modification comprises a constant region, which is at least 80%-98% identical with the amino acid sequence compared to the constant region of DI17E6. The respective use of DI17E6 antibody, comprising one or more modifications within the heavy chain framework regions


"wherein one or more of the bold and underlined positions are mutated and are different compared to the original respective sequence. The respective use of a modified DI17E6 antibody comprising a human IgG1 constant region instead of human IgG2, or a human IgG2 hinge region instead of the human IgG1 hinge. A method of treating castrate-resistant prostate cancer (CRPC) in a patient, preferably accompanied by bone metastases, comprising administering the anti-av integrin antibody DI17E6 or a biologically active variant, or modification thereof preferably in a dose of 500-1000 mg each two weeks preferably for a period of at least three months. A method of declining the pathologically increased PSA serum level of a patient suffering from prostate cancer, preferably castrate-resistant prostate cancer (CRPC) more than 5-fold, preferably more than 10-fold by administering to said patient the hybrid monoclonal antibody DI17 in an effective dose of at least 500 mg each two weeks, or at least 1000 mg per month, wherein the pathological increased PSA serum level before staring antibody treatment is at least 25 ng/ml, preferably at least 50 ng/ml. A respective method, wherein the cancer is metastasizing in bone and/or lymph node tissue.


"FIG. 1: shows a table summarizing the results of the measuring of circulating tumor cells (CTC) in six selected CRPC patients of dose level (1) 250 mg, (2) 500 mg, and (3) 1000 mg. X-axis indicates days of treatment. Y-axis indicates circulating tumor cells (CTC).

"FIG. 2: shows dose-depend pharmacokinetic profile of DI17E6 (EMD 525797) for 250 mg, 500 mg, 1000 mg and 1500 mg Ab administered per each 4 weeks. X-axis indicates time after first infusion (h); Y-axis indicates serum concentration (.mu.g/ml).

"FIG. 3: shows the treatment duration of a cohort of CRPC patients after the treatment with DI17E6; X-axis: number of weeks treatment; Y-axis: Dose levels (dose level 1: 250 mg, dose level 2: 500 mg, dose level 3: 1000 mg, dose level 4: 1500 mg)

"FIG. 4: (A) shows the change of the PSA level (ng/ml serum) in a specific CRPC patient (2001) without prostatectomy showing bone metastases during the treatment with DI17E6 (treatment start 24 Aug. 2009). (A). X-axis indicates the duration of treatment (days); Y-axis indicates PSA level (ng/ml) (B) shows the average pain interference score as defined below of the same patient of (A). X-axis indicates the duration of treatment (days); Y-axis indicates average pain interference score.

"FIG. 5: (A) shows the PSA course of a second CRPC patient with progressive disease after chemotherapy showing bone metastases and prostatectomy during the treatment with DI17E6 (treatment start 1 Sep. 2009). (A). X-axis indicates the duration of treatment (days); Y-axis indicates PSA level (ng/ml) (B) shows the average pain interference score as defined below of the same patient of (A). X-axis indicates the duration of treatment (days); Y-axis indicates average pain interference score.

"FIG. 6: shows a CT scan of a patient from the 500 mg cohort showing significant shrinkage of primary tumor lesions: (a) before treatment with DI-17E6, (b) after the 17.sup.th treatment with DI-17E6 (after 4 months).

"FIG. 7: shows the occurrence of bone markers/circulating bone markers after the treatment with DI17E6. 1=dose level 1; 2=dose level 2"

For more information, see this patent application: Hoffmann, Axel; Lannert, Heinrich; Brischwein, Klaus; Pipp, Frederic Christian; Reindl, Juergen; Groll, Karib; Zuehlsdorf, Michael; Pfaff, Otmar; Raab, Sabine; Dau, Ulrike; Destenaves, Benoit. Anti-Alpha-V Integrin Antibody for the Treatment of Prostate Cancer. Filed February 7, 2012 and posted April 3, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=3229&p=65&f=G&l=50&d=PG01&S1=20140327.PD.&OS=PD/20140327&RS=PD/20140327

Keywords for this news article include: Antibodies, Antineoplastics, Pharmaceuticals, Drugs, Cancer, Surgery, Genetics, Hormones, Oncology, Peptides, Docetaxel, Immunology, Proteomics, Engineering, Lymph Nodes, Angiogenesis, Chemotherapy, Radiotherapy, Therapeutics, Bone Research, Prostatectomy, Blood Proteins, Immunoglobulins, Tyrosine Kinase, Merck Patent GmbH.

Our reports deliver fact-based news of research and discoveries from around the world. Copyright 2014, NewsRx LLC

(c) 2014 Biotech Week via NewsRx.com
Agriculture and Fishing
      Agricultural Biotechnology
Chemicals and Allied Products
      Chemical Industry Services
            Chemical Disposal and Cleaning Services
      Medical Devices
            Medical Treatment Devices
                  Radiosurgery Devices
      Agricultural Biotechnology
      Medical Device Manufacturing
            Medical Devices
                  Medical Treatment Devices
                        Radiosurgery Devices
North America
Western Europe
United States
District of Columbia
Frankfurt am Main
Washington, D.C.
Science and Technology
      Scientific Research
            Natural Sciences
            Applied Biotechnology
Business and Commerce
      Intellectual Property
            Patents and Trademarks
Health and Wellness
      Medical Conditions and Diseases
                  Prostate Cancer
            Men's Health Issues
                  Prostate Cancer
            Sexual Disorders
      Health Sciences
            Pharmaceutical Development
      Treatments and Therapies
            Medicinal Drugs
                  Antibody Therapy
Structured Content
      Structured Science and Technology Content
            Patent Applications


Facebook - UsToo.org  Twitter - UsToo.org  LinkedIn - UsToo.org Inspire prostate cancer discussions  UsToo.org 

Contact Us | Privacy Policy | Terms & Conditions | Disclaimer   

Copyright 2005-2014 Us TOO International, Inc.
Designed and hosted by ACCESS Medical Group, Ltd.