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couple articles of interestPreclinical Data Shows c-Met to be a Potential Target for Antibody-drug Conjugates December 17, 2014NewsPeter Hofland Preclinical data on Sorrento Therapeutics’ bi-specific antibodies (BsAbs; also known as “dual specificity” antibodies) and antibody drug conjugates (ADCs) against c-Met in breast cancer presented during the 37th Annual San Antonio Breast Cancer Symposium (SABCS) being held at The Henry B. Gonzalez Convention Center in San Antonio, Texas, December 9 – 13, 2014, confirms that c-Met is a potential therapeutic target for antibody-drug conjugates in breast cancer. The highlights of the findings, presented during the general poster session by Kouros Motamed, PhD, Vice President of Strategic Alliances & Clinical Communications, Sorrento Therapeutics, Inc., include preclinical data on generation and evaluation of an anti-c-Met/anti-PD-L1 and anti-c-Met/anti-ErbB3 bi-specific, and an anti-c-Met antibody-drug conjugate or ADC as new immunotherapeutic strategies in breast cancer. [1][2] STI-D0602 The proto-oncogene transmembrane receptor tyrosine kinase c-MET is involved in cellular proliferation, survival, migration, and invasion in normal and tumor cells and plays a key role in malignant transformation of epithelial cells. MET is widely expressed and associated with poor prognosis in a number of cancers, including breast, lung, liver, kidney, and brain cancers. Over expression of c-MET in breast cancer, with or without gene amplification, has been reported in primary breast cancers and correlates with poor prognosis and adverse survival outcomes. [2] This may make c-MET it a promising target for antibody drug conjugates. Because inhibition of c-MET signaling, via tyrosine kinase inhibitors (TKIs) or antagonistic antibodies, is usually not sufficient for sustained treatment efficacy, Yanwen Fu, Edwige Gros, Alice Lee and their colleagues at Sorrento Therapeutics believe that antibody drug conjugates offer the promise and potential of delivering more potent anti-tumor activity. To support their hypothesis, the researchers generated antibody-drug conjugates containing a proprietary human anti-c-MET antibody (STI-D0602) with either a tubulin inhibitor or a DNA damaging agent. STI-D0602, a fully human antibody (IgG1) selected from Sorrento’s G-MAB antibody library, one of the largest and most diverse fully human antibody libraries in the industry designed to facilitate the rapid identification and selection of highly specific monoclonal antibody therapeutic product candidates, was conjugated with a cytotoxin via site-specific bio-conjugation. The conjugates retained binding affinity and showed potent cell killing in a variety of c-MET-positive cell lines. Inhibition of MET and HER signaling Hepatocyte growth factor or HGF is the only known ligand of the MET receptor. The MET/HGF promotes cancer cell migration and invasion. MET/HGF is also implicated in mediating resistance to current anticancer therapies, including radiation. Furthermore, overexpression of MET is associated with poor prognosis in HER2-positive breast cancer patients, which is confirmed by a shorter progression free survival (PFS) following HER1/HER2-targeted treatment with lapatinib (Tykerb®; GSK). [3] Ongoing research has show that dual EGFR/MET inhibition is synergistic in EGFR-directed therapy resistance triple negative breast cancer [4][5]. Based on this data, the researchers proposed a combination therapy with inhibitors of MET and HER signaling for a subset of metastatic breast cancer patients with MET- amplified/overexpressed tumors. The anti-c-Met antibodies inhibited signaling by stimulating c-Met internalization in the absence of receptor activation. Anti-c-Met ADCs retained binding affinity and demonstrated potent cell killing in a variety of TNBC cell lines. STI-D0602-DM1 conjugate showed potent in vivo efficacy without significant toxicity. Bi-specific Antibodies Hybridoma technology, first described in the august 1975 edition of Nature by Kohler and Milstein, made targeted antibody therapy a reality. Therapy with unconjugated or ‘naked’ antibodies depends of host immune effector mechanisms, including antibody-dependent cell-mediated cytotoxicity or ADCC, complement-dependent cytotoxicity or CDC and/or direct anti proliferative effects induced by antibodies binding to a tumor cell. In clinical studies, ADCC has been demonstrated to significantly enhance the efficacy of various antibodies, including rituximab, trastuzumab, and cetuximab [2]. While therapies with single-agent unconjugated antibodies are benefiting a substantial number of patients, most of the currently approved therapeutic anti-cancer antibodies are monospecific and therefore only capable of interfering with the biological function of a single molecular target. However, breast cancers mostly involve crosstalk of often synergistic signal transduction pathways.[6][7] As a result, isolated blockade of a single signal transduction pathway is generally met by escape mechanisms, including up-regulation of redundant pathways. This makes monospecific immunotherapy less effective. To contract, numerous strategies have been development for selectively redirecting effector cells/molecules towards tumor cells designed to overcome dose limiting toxicities and to increase efficacy of immunotherapy of cancer. The majority of these strategies applied look at the specificity of tumor associated antigen recognition of antibodies. By using either hybridoma fusion, chemical derivatization or molecular biology technology, scientists are able to construct antibodies with dual specificity. The resulting bi-specific antibodies or bsAbs combine the binding specificity of two antibodies in one molecule. This construct can be used to redirect the cytolytic activity of a number of immune effector cells including cytotoxic T lymphocytes, natural killer cells, neutrophils and monocytes/macrophages to tumor cells, enhancing tumor destruction.[1][8] What’s more, by targeting two different receptors in combination on the same cell, bsAbs can induce modifications of cell signaling, including the inactivation of proliferation or inflammatory pathways. In a second poster presented at the San Antonio Breast Cancer Symposium (Bi-specific Antibodies Targeting Signaling Pathway Crosstalk are a New Breast Cancer Immunotherapeutic Strategy” – poster number P2-16-02), Yanliang Zhang, Edwige Gros, Sarabjit Chagar, and their colleagues describe how using both chemical and molecular biology techniques, they have developed new approaches to generate IgG-like bi-specific antibodies (BsAbs) designed to target either two compensating signal transduction pathways (i.e. HER family members) or a breast cancer specific antigen and an immuno-regulatory molecule (i.e. PD-L1 or PD1). To generate an anti-c-Met and anti-PD- L1 chemical bi-specific antibody (CBA), the researchers applied a chemical biology method which involves specific hetero-dimerization of two half antibody molecules using bioorthogonal chemistry, a chemical reaction that can occur inside of living systems without interfering with native biochemical processes. Further, applying a molecular biology approach, the scientists also produced anti-c-Met and ErbB3 scFv-Fc bi-specific antibody. Bi-specific antibodies of many different formats have been developed with superior anti cancer activities. While the idea of bi-specific antibodies is not new, so far, the major obstacles in producing bi-specific antibodies is the so-called chain association issue. which means that 16 different possible combinations for each antibody’s two heavy chains with its two light chains result in 10 different antibodies (all heavy chains can pair with each other and every light chain can bind unspecifically to two regions at the top of the heavy chains). To ensure correct pairing of heavy chains from different antibodies while at the same time preventing formation of unwanted side products the bioengineers at Sorrento applied the so-called “Knob-into-Hole” technology originally invented in the late 1990’s by scientists at Genentech. Using this process, the company’s bioengineers showed that scFv fragment based approach and conjugation based method are viable methods of generating bi-specific antibodies. Superior binding The final result was that anti-c-Met/ErbB3 bi-specfic BA-0702 in scFv-Fc format demonstrated superior binding activity towards tumor cell lines MDA-MA-468 and MCF7 to each parental monospecific IgG1s. Also, BA-0702 showed activity in suppressing HGF induced c-Met phosphorylation in cancer cell line MDA-MB- 231 and also showed much higher cell killing activity (HS578T) than each parental IgG1s when they all were complexed with monomethyl auristatin F (MMAF)-conjugated Protein-G, indicating its potential application in antibody-drug conjugates. Similarly, Anti-c-Met/PD-L1 chemical bi-specific CBA-0710 retained excellent affinity for their respective cellular target and demonstrated potent in vitro activity. ------------------------------------------------------------------------------ Novel CD33-targeting Antibody-drug Conjugate IMGN779 Is Highly Active In Vitro and In Vivo Against AML with FLT3-ITD Mutations December 15, 2014News.acute myeloid leukemia | AML | FLT3-ITDPeter Hofland Acute myeloid leukemia (AML), the most common type of acute leukemia in adults which is also known as acute nonlymphocytic leukemia, is a cancer of the blood and bone marrow. In healthy individuals, the bone marrow makes blood stem cells (immature cells). Over time, these blood stem cells become mature blood cells — either myeloid or a lymphoid stem cells. In acute myeloid leukemia the presence of acquired genetic alterations in hematopoietic progenitor cells found in the bone marrow alter the normal mechanisms of cell growth, proliferation and differentiation, affecting these cells that would normally turn into white blood cells. As a consequence of the disease, myeloid stem cells become a type of immature white blood cell called myeloblasts (or myeloid blasts). Blocking differentiation as well as unchecked proliferation, AML results in the accumulation of myeloblasts at the expense of normal hematopoietic precursors.[1] If untreated, AML spread to the blood and to other parts of the body including lymph nodes, liver, spleen, brain and spinal cord and testicles, and quickly becomes fatal. The American Cancer Society estimates approximately 18,860 new cases of AML and 10,460 deaths from the disease in the United States in 2014. Most patients will be adults. The disease is slightly more common among men than among women. The lifetime risk of getting AML for the average man is about 1 in 227; for the average woman the risk is about 1 in 278.[2] CD33 and acute myeloid leukemia CD33, a 67-kDa glycoprotein, is expressed on the surface of about 90% myeloid leukemia cells as well as on normal myeloid and monocytic precursors. In AML, elevated levels of CD33 are found in cases having molecular markers associated with poor prognosis, including mutations in FMS-like tyrosine kinase 3 (FLT3). This makes CD33 an attractive target for monoclonal antibody-based therapy of acute myeloid leukemia. Gemtuzumab ozogamicin (Mylotarg®; Wyeth/Pfizer), an anti-CD33 antibody conjugated to the antitumor antibiotic calicheamicin, improved survival in a subset of AML patients when combined with standard chemotherapy. Safety concerns led to US marketing withdrawal of this drug in 2010. However, as result of the demonstrated activity of gemtuzumab ozogamicin, CD33 remained a viable therapeutic target for AML. FLT3 mutation Research has shown that activating mutations in the FMS-like tyrosine kinase 3 (FLT3) gene are recognized one of the most frequently encountered, and clinically challenging, class of mutations in acute myeloid leukemia.[5] The internal tandem duplication mutation (FLT3-ITD), in turn, is the most common FLT3 mutation. This mutation is present in about 20-25% of cases of de novo acute myeloid leukemia. Patients with FLT3-ITD AML have a particularly poor prognosis – notable worse – compared to patients with wild-type (WT) FLT3. with an increased rate of relapse and a shorter duration of response to induction chemotherapy. These patients often present with a more aggressive disease, have a significantly increase rate of relapse after remission and a shorter duration of response to induction chemotherapy. IMGN779 In preclinical trials, IMGN779, a novel, CD33-targeting antibody-drug conjugate or ADC utilizing DGN462, a novel DNA-alkylating agent consisting of an indolino-benzodiazepine dimer containing a mono-imine moiety, being developed by ImmunoGen, Inc., Waltham, MA, showed to be a potential treatment for acute myeloid leukemia. Initial data confirming IMGN779’s potential were presented in June 2014 at the 19th Congress of the European Hematology Association (EHA) meeting in Milan, Italy (abstract# P802).[4] Now, in updated preclinical research, results presented at the 56th annual meeting and exposition of the American Society of Hematology, being held in San Francisco, December 6 – 9, 2014, IMGN779 was found to demonstrate targeted activity against AML cell lines in vitro, with IC50 values ranging from 2-3,000 pM. The MV4-11 cell line, which has a FLT3-ITD mutation, was the most sensitive to IMGN779 of the cell lines tested, with an IC50 of 2 pM. Kathleen Whiteman, MS, and a team of researchers at ImmunoGen, and Paul Noordhuis, PhD, and his colleagues from the Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands, evaluated the in vivo activity of IMGN779 against MV4-11 xenografts in SCID mice – which are severely deficient in B and T lymphocytes. At a single dose of 0.6 mg/kg (conjugate dose, 10 µg/kg DGN462 dose), IMGN779 was highly active (T/C = 1 %). The results was complete tumor regressions (CR) in 3/6 animals and partial regressions (PR) in 6/6 animals. [5] The researchers also looked at DGN462-ADC to a non-relevant target and found that this was inactive (T/C = 95%) at the same dose, suggesting that the activity of IMGN779 was realy due to its CD33 targeting. IMGN779 has previously been shown to be highly active against AML xenograft models without FLT3-ITD mutations, at minimally efficacious doses of 0.6 mg/kg (10 µg/kg DGN462), demonstrating that the presence of FLT3-ITD does not confer resistance to IMGN779 treatment. Peripheral blood or bone marrow samples IMGN779 was also highly active in vitro against primary patient acute myeloid leukemia cells isolated from peripheral blood or bone marrow samples. Patient acute myeloid leukemia cells with FLT3-ITD were more sensitive to IMGN779 compared with FLT3 WT (“Wild Type”) acute myeloid leukemia samples. IC50 values in FLT3-ITD samples ranged from 10 to 300 pM. CD33 expression was generally greater on FLT3-ITD leukemic blast cells than on FLT3 WT (“Wild Type”) blasts. This may have, most likely, contributed to their increased sensitivity to IMGN779. Long term The researchers also noted that in long term cultures, IMGN779 showed a dose dependent decrease in leukemic stem cell or LSC colony formation using an acute myeloid leukemia patient sample with both FLT3-ITD and NPM1 mutations, which are an even worse prognostic marker than FLT3-ITD alone. In contrast, colony formation increased in normal bone marrow, indicating that normal hematopoietic stem cells or HSCs were spared. Attractive target The differential expression of CD33 on leukemic stem cell compared to hematopoietic stem cells makes CD33 an attractive target for treatment of acute myeloid leukemia, with the potential to eliminate leukemic stem cell and, thus, minimal residual disease in FLT3-ITD acute myeloid leukemia. The potent in vitro activity of IMGN779 against FLT3-ITD acute myeloid leukemia cell lines and primary patient FLT3-ITD acute myeloid leukemia progenitor cells and leukemic stem cell and its high level of CD33-targeted in vivo activity in a FLT3-ITD acute myeloid leukemia xenograft model support the advancement of IMGN779 as a potential treatment for acute myeloid leukemia, including FLT3-ITD acute myeloid leukemia. ------------------------------------------------------------------------------ IMGN529 Achieves Objective Responses in 40% of Evaluable Patients with Heavily Pretreated Diffuse Large B-cell Lymphoma December 11, 2014NewsPeter Hofland Results from a clinical trial with IMGN529, ImmunoGen’s experimental therapy for B-cell malignancies presented at the American Society of Hematology (ASH) annual meeting being held in San Francisco’s Moscone Center, December 6 – 9, 2014, shows that the trial drug achieved objective responses in four of ten evaluable patients with heavily pretreated diffuse large B-cell lymphoma or DLBCL. The study by Anastasios Stathis, MD (Oncology Institute of Southern Switzerland, Bellinzona, Switzerland), Arnold S. Freedman, MD (Dana-Farber Cancer Institute, Boston, MA), Ian W. Flinn, MD (Sarah Cannon Research Institute, Nashville, TN) and others, includes a complete response at the dose levels evaluated to date. While dose finding is ongoing, and the maximum tolerated dose (MTD) has not yet been established, the results include objective responses at doses that were generally well tolerated. [1] B-cell lymphoma’s are a type of cancer that forms in B cells. They are either indolent (slow-growing) or aggressive (fast-growing). The majority of B-cell lymphomas are non-Hodgkin lymphomas. There are many different types of B-cell non-Hodgkin lymphomas, including Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma or CLL/SLL, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma. Prognosis and treatment depend on the actual type and stage of the particular cancer. More than 70,000 people will be diagnosed with non-Hodgkin lymphoma (NHL) in the US in 2014.[2] DLBCL is an aggressive lymphoma that represents approximately one third of the new NHL cases diagnosed annually.[2] Potential new treatment ImmunoGen’s IMGN529 is a potential new treatment for DLBCL and other non-Hodgkin lymphoma (NHL) subtypes. An antibody-drug conjugate or ADC, IMGN529 comprises a monoclonal antibody that targets CD37, a surface antigen widely expressed on malignant B cells, attached to the maytansinoid DM1, a potent anti-microtubule agent, via the thioether linker N-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC). Preclinical data shows that the resulting ADC retained the intrinsic antibody activities and showed enhanced cytotoxic activity from targeted payload delivery. The antibody serves to deliver the DM1 specifically to B cells to kill them and, based on preclinical research, also contributes anticancer activity.[3][4] Furthermore, in normal tissues, CD37 expression is restricted to lymphoid tissues and blood cells, with high levels of expression on B lymphocytes and low levels on non-B lymphoid and myeloid cells.[3] Dose finding IMGN529 is currently in the dose-finding portion of a Phase I clinical trial, which assesses increasing doses of this experimental therapy in new groups of patients with relapsed/refractory NHL. Findings with the first doses evaluated were reported previously.[5] Presented Clinical Data The IMGN529 dose levels evaluated to date range from 0.1 to 1.4 mg/kg, administered once every three weeks. Its MTD has not yet been established, and evaluation of the 1.4 mg/kg level is ongoing. Twenty four (24) of the 33 patients enrolled to date were evaluable for efficacy. Ten evaluable patients had DLBCL, which had been heavily pretreated, and four (40%) of these patients had an objective response: one had a complete response (CR) and three had partial responses (PRs). The CR and one of the PRs were among patients treated with 1.0 mg/kg, the highest IMGN529 dose level to complete evaluation to date. Both of these patients had received multiple prior treatments, including autologous stem cell transplant (ASCT). Ten of the 24 evaluable patients had follicular lymphoma and one of these patients also had a PR. This patient, too, had received multiple treatments including ASCT. Preclinical research As reported previously by Jutta Deckert, PhD, Jose F. Ponte, PhD, Jennifer A. Coccia and other researchers at ImmunoGen, an early onset, transient drop in neutrophil counts was seen in several patients receiving IMGN529 at low doses. [3] This was believed to be due to a redistribution of the neutrophils – induced by antibody-mediated cytokine release – rather than to bone marrow suppression; subsequent preclinical research supports this hypothesis. In vitro studies with peripheral blood cells from normal human donors demonstrated that incubation with IMGN529 for 1 hour or 24 hours resulted in significant B-cell depletion with no apparent neutrophil depletion detected, similar to observations after rituximab treatment. In contrast, alemtuzumab treatment in vitro resulted in both B-cell and neutrophil depletion. This is consistent with the high level of CD37 expression on target B cells and the relatively low CD37 expression level on other blood cells. [6] With the addition of peri-infusional steroids to the treatment protocol, the incidence and severity of neutropenia decreased markedly and dose escalation resumed. As reported previously, the first patients treated with 1.0 mg/kg had delayed onset neutropenia or febrile neutropenia.2 G-CSF was subsequently added to the treatment protocol and there have been no new reports of febrile neutropenia at doses of 1.0 or 1.4 mg/kg; the one incidence of high grade neutropenia seen with 1.4 mg/kg was of short (2 day) duration. Hematologic side effects are not unexpected in such heavily pretreated patients. Other frequent side effects were fever, fatigue, nausea, and diarrhea, which were typically Grade 1/2. “It is encouraging that patients with such heavily pretreated disease responded to IMGN529,” commented Charles Morris, MB, ChB, MRCP, Executive Vice President (EVP) and Chief Development Officer. “We are particularly pleased with the responses seen in the patients with diffuse large B-cell lymphoma given the limited treatment options for such patients today, and look forward to advancing IMGN529 into disease-specific testing in 2015.” ------------------------------------------------------------------------------ |
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Msg # | Subject | Author | Recs | Date Posted |
42176 | Re: couple articles of interest | Topexec | 0 | 1/22/2015 3:26:25 PM |