On April 18, 2016 Kymab has announced a strategic collaboration with Heptares Therapeutics to discover, develop and commercialise novel antibody therapeutics targeting a number of G-protein-coupled receptors (GPCR) with an initial focus on immuno-oncology (Press release, Kymab, APR 18, 2016, View Source [SID1234537011]).

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GPCRs are widely expressed on cells of the innate and adaptive immune system and play key roles in modulating cell migration and recruitment to the tumour environment, activation, survival, proliferation and differentiation. GPCRs act at critical checkpoints that can be targeted by novel immunotherapy antibodies.

"GPCRs have long been intractable targets for antibody discovery resulting in dearth of products," said Dr Malcolm Weir, Chairman and CEO of Heptares, "We believe that our proven StaR technology can unlock this substantial opportunity, not just in immuno-oncology but also across other therapeutic areas where GPCR-targeted biologics could have a significant impact. By entering into strategic collaborations with companies with world-leading antibody discovery technologies, such as Kymab, we have the potential to discover, develop and commercialise a highly valuable pipeline of new biologic products."

Immuno-oncology is an exciting new area in the treatment of cancer where the body’s immune system is activated to produce an immune response targeted at tumour cells. Immunotherapy drugs are poised to revolutionise the way cancer is treated and a number of immunotherapy antibody treatments have recently been approved.

"Antibodies are important therapeutic agents for cancer and other indications," said Dr David Chiswell, Chairman and CEO of Kymab. "Our collaboration with Heptares will allow us to combine stable antigens based on multiple GPCR targets with our world class Kymouse platform which has unparalleled diversity and will therefore rapidly identify and yield highly selective potent human monoclonal antibodies for unmet medical needs."

Under the agreement, Heptares Therapeutics ("Heptares"), the wholly-owned subsidiary of Sosei Group Corporation (TSE Mothers Index: 4565), will apply its StaR platform to create stable antigens based on multiple GPCR targets chosen by the companies. Kymab will then use its Kymouse human antibody discovery platform to generate antibodies in response to immunisation with these antigens. The Kymouse platform will assure the highest probability of finding the best-in-class antibodies with highly attractive drug properties.

Promising leads will be progressed using the partners’ complementary skills, resources and development capabilities in order to bring innovative products into the clinic. Under the agreement, the companies will jointly conduct and share the costs of each antibody discovery and development programme.

On April 18, 2016 Seattle Genetics, Inc. (NASDAQ: SGEN) reported multiple data presentations that support several of the company’s antibody-drug conjugate (ADC) and immuno-oncology programs featured at the upcoming 107th Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) being held April 16 through 20, 2016 in New Orleans, LA (Press release, Seattle Genetics, APR 18, 2016, View Source;p=RssLanding&cat=news&id=2157809 [SID:1234510980]). The presentations describe preclinical data with SGN-LIV1A and SEA-CD40, which are in ongoing clinical trials, and highlight two preclinical programs, a novel ADC for the treatment of multiple myeloma (SGN-CD352A) and a small molecule that enhances T-cell mediated antitumor activity (2-fluorofucose). Additional data highlight the growing body of knowledge regarding the ability of auristatin-based ADCs, including ADCETRIS (brentuximab vedotin), to initiate immunogenic cell death, supporting evaluation in combination with checkpoint inhibitors.

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"Our ADC expertise currently empowers a robust pipeline of more than a dozen clinical and preclinical programs," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "At AACR (Free AACR Whitepaper), we will be presenting preclinical data that demonstrate encouraging activity with SGN-LIV1A, an ADC in phase 1 clinical development for breast cancer, and the preclinical development of a novel ADC for multiple myeloma, SGN-CD352A, which uses our newest ADC technology. We will also highlight the progress we have made in the important field of immuno-oncology, demonstrating that auristatin-based ADCs may be particularly well suited for combination with checkpoint inhibitors and presenting exciting preclinical data for SEA-CD40 and a small molecule, 2-fluorofucose."

Multiple presentations are being featured at AACR (Free AACR Whitepaper) that highlight advances with Seattle Genetics’ proprietary ADC and empowered antibody pipeline and research programs. Abstracts can be found at www.aacr.org and include the following:

Preclinical data from a novel ADC candidate SGN-CD352A for multiple myeloma will be highlighted in a poster presentation on Monday, April 18, 2016 (Abstract #1195). SGN-CD352A utilizes Seattle Genetics’ newest ADC technology and is composed of an anti-CD352 antibody attached to a highly potent cytotoxic DNA-crosslinking agent called a pyrrolobenzodiazepine (PBD) dimer via a proprietary site-specific conjugation technology to a monoclonal antibody with engineered cysteines (EC-mAb).
SGN-LIV1A will be highlighted in a poster presentation on Tuesday, April 19, 2016 (Abstract #2966) focusing on the potential of combination use with standard of care chemotherapeutic agents, including doxorubicin, paclitaxel (Abraxane), carboplatin and various kinase inhibitors, for the treatment of breast cancer. SGN-LIV1A is in a phase 1 trial for the treatment of LIV-1-expressing metastatic breast cancer.
A preclinical analysis will highlight the novel small molecule, 2-fluorofucose (2FF) in a poster presentation on Tuesday, April 19, 2016 (Abstract #4005). 2FF blocks cellular incorporation of a sugar (fucose) and has been shown in preclinical studies to stimulate T-cell receptor signaling leading to enhanced activation of dendritic cells.
The path of SEA-CD40 from research to clinical development will be highlighted in a poster presentation on Wednesday, April 20, 2016 (Abstract #4994). SEA-CD40 is in an ongoing phase 1 trial for patients with advanced malignancies. SEA-CD40 is a novel immuno-oncology agent targeted to CD40 utilizing Seattle Genetics’ proprietary sugar-engineered antibody (SEA) technology to produce a non-fucosylated antibody.
Preclinical data evaluating brentuximab vedotin (ADCETRIS) immune activity will be presented in a poster presentation on Wednesday, April 20, 2016 (Abstract #4914). The preclinical data being presented demonstrate that brentuximab vedotin treated tumor cells may initiate an antitumor immune response and supports combination strategies with immuno-oncology regimens, such as the ongoing phase 1/2 clinical trials evaluating ADCETRIS and nivolumab (Opdivo) in relapsed Hodgkin and non-Hodgkin lymphoma.
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On Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH) today presented data demonstrating enhanced anti-tumor efficacy and survival by combining anti-NKG2A with PD-1/PD-L1 pathway inhibitors in murine models at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans, Louisiana, USA (Press release, Innate Pharma, APR 18, 2016, View Source [SID:1234511005]).

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The NKG2A checkpoint receptor is expressed on a subset of NK cells. Similar to the PD-1 receptors, NKG2A can also be induced on tumor-infiltrating CD8 T cells. Therefore, PD-1 and NKG2A may both inhibit anti-tumor immune responses in situations where cancers express the ligands of both these checkpoint receptors. Conversely, anti-tumor immune responses might be enhanced by combined NKG2A and PD-1 pathway blockade.

Poster #2342 reports preclinical data based on an in vivo model of PD-L1 expressing solid tumors. In this model, treatment with either an antibody blocking PD-1 or NKG2A as single agents resulted in modest anti-tumor efficacy. The frequency of tumor-infiltrating NKG2A+ CD8 T cells was increased in anti-PD-1 resistant mice, suggesting that NKG2A is a pathway involved in adaptive PD-1 resistance. Treatment with combination of NKG2A and PD-1 checkpoint inhibitors resulted in significantly enhanced anti-tumor responses. Nearly twice as many mice achieved complete tumor cell regression compared to treatment with anti PD-1 alone.

Nicolai Wagtmann, CSO of Innate Pharma, said: "We are very excited by these data showing that the NKG2A pathway acts as a major mechanism of tumor escape in this model. Considering the high frequency of patients who respond inadequately to PD-1 pathway blockade, we are intrigued by the observations that NKG2A expression on CD8 T cells was increased in PD-1 resistant mice". He added: "These data and the striking efficacy of the combination treatment in this model provide strong support for the clinical trial that was just initiated, testing the combination of monalizumab, Innate’s first-in-class NKG2A checkpoint inhibitor, and durvalumab, AstraZeneca/Medimmune’s investigational PD-L1 checkpoint inhibitor".

On April 18, 2016 Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH) reported data on a research program to develop a CD73 checkpoint inhibitor antibody in oncology at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans, Louisiana, USA (Press release, Innate Pharma, APR 18, 2016, View Source [SID:1234511075]). This new anti-CD73 project complements Innate’s first-in-class anti-CD39 program strengthening the Company’s positioning in targeting the tumor microenvironment.

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CD73 and CD39 are two enzymes which play a major role in promoting immunosuppression through the pathway degrading adenosine triphosphate (ATP) into adenosine. CD73 is active on the last step of the degradation pathway, where it is the enzyme that actually degrades AMP* into adenosine.

Poster #2344 presented a panel of newly generated antibodies that block CD73 function. They all bind with high affinity and specificity to the CD73 enzyme, but to distinct epitopes and display different mechanisms of inhibition, including direct blocking of CD73 enzymatic activity or down-modulation of CD73 membrane expression. All antibodies strongly reduce AMP catabolism and efficiently reverse adenosine-mediated T cell suppression in vitro. The antibodies displaying the most interesting features were humanized and further evaluation of their activity is ongoing.

Nicolai Wagtmann, CSO of Innate Pharma, said: "This program adds to our innovative and diversified portfolio of checkpoint inhibitors. We are entering the very exciting and novel area of microenvironment checkpoint inhibition which complements other immuno-oncology approaches. Our anti-CD73 and anti-CD39 antibodies each have potential as single-agent therapeutics and for combination with other checkpoint blockers notably targeting T or NK cells".

On April 18, 2016 TG Therapeutics, Inc. (Nasdaq:TGTX) reported the presentation of preclinical data describing the differential regulation of human T-cells by TGR-1202 in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016, which is being held April 16 – 20, 2016 at the Ernest N. Morial Convention Center in New Orleans, Louisiana (Press release, TG Therapeutics, APR 18, 2016, View Source [SID:1234510981]).

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As part of an ongoing research collaboration with the H. Lee Moffitt Cancer Center and Research Institute in Tampa, FL, data was generated comparing TGR-1202 with the PI3K-delta inhibitors idelalisib and duvelisib in in-vitro models assessing the impact on T-cell subsets. Key conclusions from the poster are as follows:

TGR-1202 exhibits dose dependent cytotoxicity against human T cells beginning 25uM, comparable to the PI3K-delta inhibitors idelalisib and duvelisib,
TGR-1202 allows relative conservation of TH2 cytokine expression and GATA-3 mRNA compared to other PI3K-delta inhibitors idelalisib and duvelisib
Regulatory T cell (Treg) population number and function is reduced overall after treatment with all three agents but to a lesser degree in TGR-1202 treated samples
TGR-1202 does not robustly reduce the expression of PD-1 and CTLA-4 on Tregs, suggesting that a suppressive phenotype is maintained to a greater extent compared to idelalisib and duvelisib.
Michael S. Weiss, the Company’s Executive Chairman and Interim Chief Executive Officer, stated, "Many of the adverse events associated with existing PI3K-delta inhibitors such as colitis and hepatic toxicity, and most recently with opportunistic infections, are thought to be related to T-cell immune mediated mechanisms. This pre-clinical data now begins to elucidate key differences in the impact of these inhibitors on human T-cell subsets, which may explain the differentiated safety profile observed with TGR-1202 to date in the clinic. These data represent the first step in improving our understanding and we look forward to continuing our research collaboration with the team at Moffitt."

PRESENTATION DETAILS

A copy of the poster is available on the Company’s website at www.tgtherapeutics.com, located on the Publications Page, within the Pipeline section.