On April 18, 2018 Xencor, Inc. (NASDAQ: XNCR), a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies for the treatment of autoimmune diseases, asthma and allergic diseases and cancer, reported that preclinical data on XmAb24306, an IL15/IL15-receptor alpha complex fused to a bispecific XmAb Fc domain (IL15/IL15Rα-Fc) for the treatment of multiple oncology indications (Press release, Xencor, APR 18, 2018, View Source [SID1234525514]). Data show that the engineered complex enhanced the duration and magnitude of T and NK cell proliferation in vitro and in vivo. XmAb24306 is designed for reduced potency and extended half-life, and exhibited a steady, tolerable and sustained increase in T-cells in primates.

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Key findings from the study presented today at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2018 Annual Meeting include:

Fusing IL15/IL15Rα with Xencor’s highly stable heterodimer Fc platform and Xtend Fc domain creates a long-acting CD122 agonist, without targeting CD25
Potency reduction of the complex promotes improved exposure and sustained pharmacodynamics
Preserves native CD122/CD132 signaling despite potency reduction
Marked and sustained peripheral NK and T cell expansion at well-tolerated doses
"The plug and play nature of our XmAb technology provides tremendous opportunity to build a suite of tumor microenvironment activators with tunable potency and sustained activity, which have the potential for improved performance over current approaches," said Bassil Dahiyat, president and chief executive officer of Xencor. "With the IL15/IL15Rα-Fc platform, we have an engine to develop these candidates quickly, and are on track to file an IND for XmAb24306 in 2019."

XmAb24306 is the first of a suite of tumor microenvironment activators using the IL15 bispecific platform. Additional IL15 bispecific candidates, which target specific sub-populations of T cells, in preclinical development include:

A PD1 targeted IL15/IL15Rα (PD1 x IL15) candidate to promote selective expansion and activation of exhausted T cells
Additional targeted IL15/IL15Rα candidates
About XmAb IL15 Bispecific Platform

Xencor’s XmAb IL15 bispecific antibody platform provides a more druggable version of IL15 with reduced potency to improve tolerability, slow receptor-mediated clearance, and prolong half-life. IL15 is an extremely potent cytokine that stimulates the proliferation of lymphocytes, however its potential as a therapeutic has been limited by low tolerability and very fast clearance that limits therapeutic window. IL15 naturally targets CD122 without targeting CD25. Xencor has engineered the IL15/IL15Rα-Fc complex to create lead candidate XmAb24306 and to provide a basis for rapid generation of targeted T-cell activators. These Fc-fusions have been tuned for enhanced in vivo lymphocyte proliferation as a result of more sustained exposure.

On April 18, 2019 Calithera Biosciences, Inc. (Nasdaq:CALA), a clinical stage biotechnology company focused on the development of novel cancer therapeutics, reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to CB-839 in combination with cabozantinib for the treatment of patients with metastatic renal cell carcinoma who have received one or two prior lines of therapy, including at least one vascular endothelial growth factor tyrosine kinase inhibitor or the combination of nivolumab and ipilimumab (Press release, Calithera Biosciences, APR 18, 2018, View Source [SID1234535241]). CB-839 is a first-in-class, oral, selective, potent inhibitor of glutaminase being evaluated in the CANTATA trial. The trial is a randomized double-blind clinical study of cabozantinib in combination with CB-839 or placebo in 298 patients with clear cell renal cell carcinoma. The primary endpoint is progression free survival and the global study is open for enrollment.

"Despite a number of new therapies for the treatment of renal cell carcinoma, there remains a significant unmet need among advanced patients who have received prior treatment," said Susan Molineaux, PhD, President and Chief Executive Officer of Calithera. "We are pleased that CB-839 has been granted Fast Track designation, demonstrating the FDA’s commitment to facilitate the development and expedite the review of our glutaminase inhibitor as an important new therapy for patients with advanced or metastatic renal cell carcinoma who have failed prior systemic therapy."

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The FDA’s Fast Track designation is designed to facilitate the development and expedite the review of drugs and biologics, to treat serious or life threatening conditions, and to fill an unmet medical need. Specifically, Fast Track designation facilitates frequent interactions with the FDA review team, including meetings to discuss all aspects of development to support approval, and also provides the opportunity to submit sections of an NDA on a rolling basis as data become available. About CB-839 Calithera’s lead product candidate, CB-839, is a potent, selective, reversible and orally bioavailable inhibitor of glutaminase. CB-839’s onco-metabolism activity takes advantage of the unique metabolic requirements of tumor cells and cancer-fighting immune cells such as cytotoxic T-cells. It is currently being evaluated in Phase 2 clinical trials in multiple tumor types, in combination with standard of care agents.

On April 18, 2018 MabVax Therapeutics Holdings, Inc. (NASDAQ: MBVX), a clinical-stage oncology drug development company, reported that three poster presentations on the Company’s antibody development programs were made at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held April 14-18, 2018 in Chicago, Illinois at McCormick Place (Press release, MabVax, APR 18, 2018, View Source [SID1234525497]).

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MabVax Therapeutics Logo (PRNewsfoto/MabVax Therapeutics Holdings, I)

Paul Maffuid, Ph.D., Executive Vice President of Research and Development of MabVax, stated, "We successfully shared the significant progress we have made through these clinical and preclinical studies that continue to establish our growing body of data supporting the development of MVT-1075 for the treatment of pancreatic cancer and other CA19-9 cancers, MVT-2163 as a immunoPET imaging agent, and our most advanced research program focused on the Tn and sTn cancer antigen targets."

MabVax Poster Presentation Details

Jonah Rainey, Ph.D., Executive Director, Antibody Research at MabVax presented a poster on Sunday April 15th entitled: "A fully human antibody binds Tn and sTn carbohydrate antigens specifically on serine residues, without need for polypeptide interaction."

Dr. Rainey’s presentation included results from the Company’s successful human antibody discovery and engineering efforts that resulted in creating a panel of anti-Tn antibodies with specificity and affinity for the Tn and sTn epitopes. This observation was confirmed by a binding array analysis performed by a well-known independent academic based consortium. These antibodies bind preferentially to a particular presentation of the Tn epitope that exhibits a pharmaceutically useful pattern that is expressed on ovarian and breast cancers, including triple-negative breast cancer.

Paul Maffuid, Ph.D., Executive Vice President, Research & Development MabVax Therapeutics presented a poster on Tuesday April 17th entitled: "Phase 1 dose escalation study of 177Lu-HuMab-5B1 (MVT-1075) in combination with MVT-5873 as radioimmunotherapy (RIT) in subjects with relapsed / refractory pancreatic cancer or other CA19-9+ malignancies."

Dr. Maffuid’s presentation summarized results from the first cohort of three patients treated in the Phase 1 clinical trial of the Company’s MVT-1075 radiopharmaceutical product in late stage pancreatic cancer. These results at the initial dose support a high uptake of the on-target lesions with a prolonged time of residence and accumulation on target lesions. The predominant treatment-related toxicities in the first cohort included expected and manageable (Grade 1-3) changes in hematologic and liver function parameters.

Though the current data set is small, clinical biodistribution studies with the immunoPET imaging agent MVT-2163 in a prior Phase 1 study were used to successfully predict the absorbed organ doses of MVT-1075 and in particular red marrow which is the dose limiting organ. In addition, the studies completed to date were sufficient to establish a fractionated dosing schedule of MVT-1075 combined with image-based dosimetry as a feasible RIT Phase 1 dosing strategy, permitting within cycle patient specific dose adjustments to achieve a selected target red marrow exposure. A fourth patient has been treated in a second cohort at a planned escalated dose.

Jonah Rainey, Ph.D., Executive Director, Antibody Research at MabVax was a co-presenting author of a second poster on Tuesday April 17th entitled: "PEGylated Hyaluronidase Increases Tumor Uptake of 89Zr-DFO-HuMab-5B1 (MVT-2163) in a CA19-9 Positive Hyaluronan-Accumulating Pancreatic Cancer Model"

This poster was the result of a preclinical collaboration with Halozyme Therapeutics, Inc. combining the use of MabVax’s immunoPET imaging agent MVT-2163 with Halozyme’s PEGylated Hyaluronidase, PEGPH20 to determine if the enzymatic degradation of HA could improve the uptake of MVT-2163 on tumor lesions as measured by in vivo PET imaging and ex vivo gamma counting, in a CA19-9-positive, HA-rich human pancreatic tumor xenograft model. PEGPH20 increased both the tumor uptake and the tumor-to-liver ratios of MVT-2163 as well as decreased liver uptake in a CA19-9 positive xenograft mouse model of HA-accumulating pancreatic cancer. The increased tumor uptake and the decreased liver uptake support further investigation into the potential diagnostic utility for the combination of PEGPH20 and MVT-2163.

To access the three full abstracts, please click here.

About MVT-1075

MVT-1075 is a radioimmunotherapy product that combines established efficacy of radiation therapy with tumor specific targeting. MVT-1075 has the potential to deliver a more potent HuMab-5B1-based product, by using small doses of a radioisotope coupled to the Company’s MVT-5873 antibody to target pancreatic cancer cells and kill them.

About the HuMab-Tn Antibody Targeting Tn and sTn

HuMab-Tn is a fully human antibody discovered by MabVax from a patient vaccinated with a pool of cancer glycans, including Tn. The antibody has been affinity-matured and demonstrates highly selective Tn/sTn glycan binding. Further, the antibody recognizes a wide array of cancers, particularly ovarian and breast including approximately 90% of triple negative breast cancers tested.

About MVT-2163

MVT-2163 is an immunoPET imaging agent product that combines the established PET imaging capabilities of 89Zr with HuMab-5B1 tumor specific targeting. It has the potential to aid in identifying the best surgical treatment options for patients with pancreatic cancer and as a potential companion diagnostic with treatment options.

On April 18, 2018 Medigene AG (FSE: MDG1, Prime Standard, TecDAX) reported its participation at the following upcoming conferences (Press release, MediGene, APR 18, 2018, View Source [SID1234525515]):

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Kempen Life Sciences Conference
Date: 18 – 19 April 2018
Location: Amsterdam, Netherlands

16th CIMT (Free CIMT Whitepaper) Annual Meeting
Date: 15 – 17 May 2018
Location: Mainz, Germany

The American Society of Gene and Cell Therapy (ASGCT) (Free ASGCT Whitepaper) Annual Meeting
Date: 16 – 19 May 2018
Location: Chicago, USA

UBS Global Life Science Conference
Date: 21 – 23 May 2018
Location: New York, USA
Dr. Thomas Taapken, CFO of Medigene, will hold a company presentation on 22 May.

3rd Annual Advances in Immuno-Oncology Congress
Date: 24 – 25 May 2018
Locations: London, UK
Prof. Dolores Schendel, CEO and CSO of Medigene AG, will present on "T cell receptor discovery to match medical needs worldwide" on May 24.

Medigene AG (FSE: MDG1, ISIN DE000A1X3W00, Prime Standard, TecDAX) is a publicly listed biotechnology company headquartered in Martinsried near Munich, Germany. The company is developing highly innovative immunotherapies to target various forms and stages of cancer. Medigene concentrates on the development of personalized T cell-based therapies, with associated projects currently in pre-clinical and clinical development.

For more information, please visit www.medigene.com

On April 18, 2018 OncoMed Pharmaceuticals Inc. (NASDAQ:OMED), a clinical-stage biopharmaceutical company focused on discovering and developing novel anti-cancer therapeutics, presented preclinical data during the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting related to two of its therapeutic candidates, anti-TIGIT (OMP-313M32), currently in the Phase 1a portion of a Phase 1a/b study, and GITRL-Fc trimer (OMP-336B11), currently in a Phase 1a study (Press release, OncoMed, APR 18, 2018, View Source [SID1234525498]). In addition, preclinical data was presented exploring the ability of OncoMed’s Wnt antagonist vantictumab (anti-FZD, OMP-18R5) to potentiate immune responses to checkpoint agents.

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TIGIT (T-cell immunoreceptor with Ig and ITIM domains) is an inhibitory checkpoint receptor that binds to PVR ligand, a protein broadly expressed on tumor cells and tumor-infiltrating cells, and, in doing so, blocks T-cell activation. OncoMed’s presentation (Abstract 5627) showed that anti-TIGIT treatment reduced the abundance of regulatory T-cells (Tregs) within tumors in animal models, and mechanistic studies demonstrated an important contribution of effector function for anti-tumor efficacy. "These investigations highlight the potential of our anti-TIGIT antibody," said Ann Kapoun, Ph.D., OncoMed’s Vice President of Translational Medicine. "These translational research efforts inform our biomarker strategies and may help us identify patients whose tumors are most likely to benefit from our therapeutic candidates."

A series of preclinical studies (Abstract 70, Abstract 2726, Abstract 3826) from OncoMed highlighted the ability of GITRL-Fc, a novel linkerless ligand trimer that binds to the co-stimulatory receptor GITR (glucocorticoid-induced TNF receptor family-related protein), to function as a robust GITR agonist by both stimulating T-cell and NK responses and reducing the abundance of Tregs in tumors. The studies also investigated the impact of aging on anti-tumor immune response, an important and often underappreciated parameter impacting the efficacy of immuno-oncology strategies.

Another preclinical study (Abstract 1733) examined the synergistic impact of OncoMed’s Wnt pathway antagonist vantictumab on the ability of checkpoint agents to promote an effective anti-tumor immune response. These data add to a growing recognition of the importance of the Wnt pathway in shaping immune function.

"The data detailed in these AACR (Free AACR Whitepaper) presentations exemplify the ongoing extensive efforts to deepen our understanding of the mechanisms of action of our agents" said Austin Gurney Ph.D., OncoMed’s Senior Vice President of Research and Chief Scientific Officer. "With both our anti-TIGIT and GITRL-Fc programs advancing in Phase 1 studies, these research efforts will have direct impact on informing our clinical programs."

Below are additional highlights from the OncoMed poster presentations:

Abstract 5627 – Anti-TIGIT biomarker study: Inhibition of TIGIT induces loss of Tregs from tumors and requires effector function for tumor growth inhibition

Using a surrogate anti-TIGIT antibody, potent single-agent dose-dependent anti-tumor efficacy was demonstrated on large established CT26 WT tumors. Anti-TIGIT efficacy was shown to require effector function for tumor growth inhibition and biomarker analysis demonstrated reduction of Treg frequency and activation of T-cells and NK cells as part of the mechanism of action of anti-TIGIT. CD226, a co-receptor for TIGIT’s ligands PVR and PVRL2, was significantly upregulated in T-cells, Tregs and NK cells, reflecting a feedback loop activated by the inhibition of TIGIT activity. Anti-TIGIT gene signatures in tumors and in blood were identified from multiple syngeneic models and may be potential biomarkers for measuring anti-TIGIT activity. Additionally in a human tissue study, TIGIT expression on Tregs was found to be considerably higher than on CD8+ T-cells in multiplexed IHC panels across a panel of multiple solid tumors types.

Abstract #70 – Effect of aging on the antitumor activity of GITRL-Fc

It is now appreciated that the immune system changes in response to aging. In this study, the activity of GITRL-Fc protein was compared in both young and older mice. Compared to young mice, tumors grew faster in older mice. This may be due in part to an observed greater prevalence of myeloid-derived suppressor cells (MDSC) in older mice. GITRL-Fc significantly inhibited tumor growth in both older and younger mice with efficacy more pronounced in young mice. In older mice, GITRL-Fc (mIgG2a) was still able to deplete Tregs in tumor and increase Tregs in the spleen as has been previously shown with GITRL-Fc in young mice. A GITRL-Fc protein deficient in effector function (mIgG2a (N297A)) did not deplete Tregs in the tumor but did retain anti-tumor growth activity. Collectively, these data demonstrate that Treg depletion and activation of GITR signaling contribute to the anti-tumor efficacy of GITRL-Fc in older mice.

Abstract #2726 – In vitro functional activity of OMP-336B11, a GITRL-Fc fusion protein, on primary human immune cells

In this study, functional characterization of OMP-336B11 in various human immune cell assays was presented. OMP-336B11 enhanced activated human T-cell proliferation and augmented IL-2 induced IFNγ from human NK cells. Notably, OMP-336B11 demonstrated superior activity compared to agonist anti-GITR antibodies. OMP-336B11 is designed with an IgG1 Fc domain in order to elicit NK-mediated cytotoxicity of high GITR-expressing cells (i.e., Tregs). Co-incubation of primary human NK cells (effector) and GITR expressing cells (target) resulted in an OMP-336B11 dependent dose-titratable increase in target cytotoxicity.

Abstract #3826 – GITRL-Fc biomarker and mechanism study: GITRL-Fc reduces Treg frequency in tumors and requires effector function for inhibition of tumor growth

Using a surrogate GITRL-Fc molecule, potent single agent dose-dependent anti-tumor efficacy was demonstrated on large established CT26.WT tumors. Biomarker analysis showed that loss of Tregs, activation of T-cells and Fc-mediated effector function are key elements in the mechanism of action of the molecule. Immuno-phenotyping of tumor-associated immune cells revealed a reduction in Treg frequency in the tumor by 24 hours post-dose that was maintained at 7 and 14 days. GITRL-Fc treatment increased proliferation and activation markers on tumor-associated CD4+ and CD8+ T-cells, suggesting an increased cytotoxic environment within the tumor. GITRL-Fc gene signatures were identified in tumors and blood from multiple syngeneic models and may be used as potential biomarkers along with multiplexed IHC panels (e.g. GITR+CD4+ T-cells, GITR+CD8+ T-cells) that were developed. Additional studies comparing intratumoral (IT) vs intraperitoneal GITRL-Fc injection demonstrated both routes of administration produced similar efficacy, suggesting IT administration may be an alternative route of administration.

Abstract #1733 – Wnt antagonists synergize with immune checkpoint inhibitors to enhance anti-tumor responses

While enhanced Wnt signaling has been shown to play a major role in cancer stem cell biology, more recent studies have implicated Wnt in the development of resistance to anti-tumor immune responses. In murine tumor models, targeting Wnt signaling using the Fzd receptor monoclonal antagonist antibody vantictumab in combination with immune checkpoint inhibitors anti-CTLA-4 or anti-PD1 induces enhanced anti-tumor responses leading to decreased tumor volume and increased infiltration of activated CD8+ T-cells into the tumor microenvironment. In addition, the data showed that combined Wnt and immune checkpoint inhibition decreased Tregs and immune suppressive myeloid cell populations, enhanced cytotoxic T-cell activity and increased antigen presentation by APCs. These results suggest that co-targeting Wnt and immune checkpoint proteins may provide valuable opportunities for novel combination strategies for immunotherapeutic clinical development.

These posters are available on the Pipeline section of OncoMed’s website, www.oncomed.com.

Additional information on the meeting can be found on the AACR (Free AACR Whitepaper) website www.aacr.org.