On April 26, 2016 Adimab LLC, the global leader in the discovery and optimization of fully human monoclonal and bispecific antibodies, reported a multi-target partnership with Takeda Pharmaceutical Company Ltd. Under the terms of the agreement, Adimab will use its proprietary platform to discover and optimize antibodies against multiple targets chosen by Takeda, who will have the right to develop and commercialize therapeutic programs resulting from the collaboration (Press release, Adimab, APR 26, 2016, View Source [SID1234536592]).

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"We are pleased to be working with a company with such deep expertise in antibody discovery and engineering," stated Christopher Claiborne, Ph.D., Head of Oncology Discovery at Takeda. "Adimab’s breadth of technical offerings, including bispecifics, as well as their reputation in the industry enables us to continue fulfilling our mission of aspiring to cure cancer."

"We are excited to have Takeda as a partner, and we look forward to demonstrating Adimab’s advantages to the Takeda team," said Tillman Gerngross, Chief Executive Officer and Co-Founder of Adimab. "This partnership, like most of our initial partnerships, will focus on a handful of projects. Our goal is to have our partners see the output from the collaboration and fall in love with the platform. We are always happy to expand the initial collaboration into additional funded discovery projects, or even transfer the platform to our partner’s facilities – to date most of our partnerships have expanded in some way."

Under the terms of the agreement, Adimab will use its proprietary yeast-based discovery and optimization platform or its proprietary rapid B cell sorting capabilities to identify fully human antibodies and against selected targets. For each target, Adimab will grant Takeda the right to research antibodies generated during the collaboration for potential use in therapeutic products. Adimab will receive an undisclosed upfront payment, research fees and technical milestones. In addition, for each target Takeda will have the option to exclusively license antibodies generated during the collaboration as a therapeutic lead, for which Adimab would receive license fees, clinical milestones and royalties on product sales.

Over the past seven years, Adimab has established funded discovery collaborations with over 35 companies. With this collaboration, Takeda joins Adimab’s other large pharmaceutical funded discovery partners, including Novo Nordisk, Biogen, GSK, Roche, Novartis, Eli Lilly, Genentech, Celgene, Gilead, Kyowa Hakko Kirin, Sanofi and others. Adimab has also partnered with many mid-size and early-stage venture-backed companies, including Merrimack, Five Prime, Jounce, Innovent, Alector, Acceleron, Oncothyreon, Surface Oncology, Potenza, Arsanis and others, as well as academic institutions such as Memorial Sloan Kettering and MD Anderson. In addition to funded discovery programs, the Adimab antibody discovery and optimization platform and custom antibody libraries have been transferred to Merck, Novo Nordisk, Biogen and GSK for internal use.

Design and synthesis of a new class of inhibitors for the treatment of osteoporosis and its comparative h17β-HSD2 and m17β-HSD2 SAR study are described. 17a is the first compound to show strong inhibition of both h17β-HSD2 and m17β-HSD2, intracellular activity, metabolic stability, selectivity toward h17β-HSD1, m17β-HSD1 and estrogen receptors α and β as well as appropriate physicochemical properties for oral bioavailability. These properties make it eligible for pre-clinical animal studies, prior to human studies.

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On April 26, 2016 Zymeworks Inc., a leader in the development of bi-specific and multi-specific antibodies and antibody drug conjugates, reported that it has entered into a new licensing agreement with GSK for the research, development, and commercialization of novel bi-specific antibodies enabled using Zymeworks’ Azymetric drug discovery platform (Press release, Zymeworks, APR 26, 2016, View Source [SID1234536466]). Under the agreement, GSK will have the option to develop and commercialize multiple bi-specific drugs across different disease areas. Zymeworks will receive upfront and preclinical payments of up to USD$36 million and is eligible to receive up to USD$152 million in development and clinical milestone payments, along with commercial sales milestone payments of up to USD$720 million, and tiered royalties on potential sales.

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As previously announced in December 2015, Zymeworks and GSK entered into a collaboration and license agreement to further develop Zymeworks’ Effector Function Enhancement and Control Technology (EFECT) platform and to research, develop, and commercialize novel Fc-engineered monoclonal and bi-specific antibody therapeutics that have been optimized for specific therapeutic effects. As part of this second agreement, GSK has also gained the right to combine the Azymetric platform with novel engineered Fc domains developed under the previously announced collaboration.

"We are excited to be expanding our relationship with GSK to include our Azymetric bi-specific platform. We view this new collaboration as evidence of our valuable role as a partner and the strength of our proprietary drug development platforms," said Ali Tehrani, Ph.D., President and CEO of Zymeworks. "The proceeds from this collaboration will be used to advance our pipeline of therapeutic candidates, including the Azymetric antibody ZW25 and the Azymetric antibody drug conjugate ZW33, into human clinical trials this year. They will also be utilized to support the continued expansion and strengthening of our core capabilities in antibody discovery, protein engineering, and antibody drug conjugates."

About the Azymetric Platform
Bi-specific antibodies developed using the Azymetric platform resemble conventional mono-specific antibodies while being able to simultaneously bind to two different targets resulting in additive or synergistic therapeutic responses. Azymetric antibodies spontaneously assemble into a single molecule with two different Fab domains comprising of unique heavy and light chain pairings. Azymetric antibodies are manufactured using conventional monoclonal antibody processes and can also be easily adapted to rapidly screen target and sequence combinations for bi-specific activities in the final therapeutic format thereby significantly reducing drug development timelines.

About the EFECT Platform
The EFECT platform is a library of antibody Fc modifications engineered to modulate the activity of the antibody-mediated immune response, which includes both the up and down-regulation of effector functions. This platform is compatible with traditional monoclonal as well as Azymetric bi-specific antibodies to further enable the customization of therapeutic responses for different diseases.

Adhesion turnover is critical for cell motility and invasion. We previously demonstrated that the adaptor molecule breast cancer antiestrogen resistance 3 (BCAR3) promotes adhesion disassembly and breast tumor cell invasion. One of two established binding partners of BCAR3 is the adaptor molecule, p130(Cas). In this study, we sought to determine whether signaling through the BCAR3-Cas complex was responsible for the cellular functions of BCAR3. We show that the entire pool of BCAR3 is in complex with Cas in invasive breast tumor cells and that these proteins colocalize in dynamic cellular adhesions. Although accumulation of BCAR3 in adhesions did not require Cas binding, a direct interaction between BCAR3 and Cas was necessary for efficient dissociation of BCAR3 from adhesions. The dissociation rates of Cas and two other adhesion molecules, α-actinin and talin, were also significantly slower in the presence of a Cas-binding mutant of BCAR3, suggesting that turnover of the entire adhesion complex was delayed under these conditions. As was the case for adhesion turnover, BCAR3-Cas interactions were found to be important for BCAR3-mediated breast tumor cell chemotaxis toward serum and invasion in Matrigel. Previous work demonstrated that BCAR3 is a potent activator of Rac1, which in turn is an important regulator of adhesion dynamics and invasion. However, in contrast to wild-type BCAR3, ectopic expression of the Cas-binding mutant of BCAR3 failed to induce Rac1 activity in breast cancer cells. Together, these data show that the ability of BCAR3 to promote adhesion disassembly, tumor cell migration and invasion, and Rac1 activity is dependent on its ability to bind to Cas. The activity of BCAR3-Cas complexes as a functional unit in breast cancer is further supported by the co-expression of these molecules in multiple subtypes of human breast tumors.Oncogene advance online publication, 25 April 2016; doi:10.1038/onc.2016.123.

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Mucin 1 (MUC1 [CD227]) is a high-molecular weight (>400 kDa), type I membrane-tethered glycoprotein that is expressed on epithelial cells and extends far above the glycocalyx. MUC1 is overexpressed and aberrantly glycosylated in adenocarcinomas and in hematological malignancies. As a result, MUC1 has been a target for tumor immunotherapeutic studies in mice and in humans. MUC1 has been shown to have anti-adhesive and immunosuppressive properties, protects against infections, and is involved in the oncogenic process as well as in cell signaling. In addition, MUC1 plays a key role in the reproductive tract, in the immune system (affecting dendritic cells, monocytes, T cells, and B cells), and in chronic inflammatory diseases. Evidence for all of these roles for MUC1 is discussed herein and demonstrates that MUC1 is truly a multitasked molecule.

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