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Preclinical promise for FS102
CAMBRIDGE, U.K.—F-star, a biopharmaceutical company focused on immuno-oncology and inflammation, has announced a publication in Molecular Therapy describing the antitumor effects of the lead compound, FS102, in preclinical animal models. The data published show that FS102 bound human epidermal growth factor receptor 2 (HER2) with high affinity and recognizes an epitope which does not overlap with those of trastuzumab or pertuzumab. Furthermore, FS102 induced complete tumor regression and tumor cell apoptosis in animal models due to internalization and degradation of HER2.
An epitope is essentially the binding target for an antibody, explains John Haurum, F-star CEO. “It is a specific part of a protein, and typically includes proteins on a cancer cell surface, such as HER2 receptors. An antibody or similar molecule such as FS102 recognizes and binds to an epitope. There may be several different epitopes on a given protein, such as HER2, and different antibodies may bind to different epitopes on the same protein. FS102 indeed binds to a different epitope of HER2 than the epitopes recognized by trastuzumab (Herceptin) or pertuzumab (Perjeta). This may lead to novel biological effects.”
“Some drugs inhibit cancer growth by blocking the function of HER2 on the cancer cell surface. FS102 instead works by removing HER2 from the cell surface through a process called internalization and degradation. Internalization means that the HER2 receptor is moved from the outside surface of a cancer cell to the inside of the cancer cell, where the HER2 receptor is subsequently destroyed or degraded and hence completely eliminated from the cell. The cancer cells are dependent on the HER2 receptor for survival and therefore this leads to profound cancer cell death and tumor regression in experimental cancer models, through a process called apoptosis or programmed cell death.”
FS102 is a HER2-specific Fcab (Fc fragment with antigen binding) derived from F-star’s Modular Antibody Technology and is in Phase 1 clinical testing in HER2-positive breast and gastric cancer patients. The trial is being conducted by Bristol-Myers Squibb, which entered into an agreement in October 2014 with F-star Alpha Ltd. and its stockholders that provides BMS the exclusive option to acquire F-star Alpha and gain worldwide rights to the FS102 program.
“The activity we observed in our preclinical testing of FS102 in the laboratory and in animal tumor models was extraordinary, and we decided to identify a partner for the clinical development phase of FS102,” Haurum states. “We were seeking a partner with a very strong track record in developing products in oncology, and fortunately BMS, as well as one or two other companies, showed a clear interest in FS102 when they first saw the data from our in-vivo model testing. Beforehand, we had created a separate company entity as the sole owner of FS102 (F-star Alpha Ltd.), and this made it relatively straightforward to establish the partnership transaction as an option-to-buy deal where BMS initially purchased an exclusive option to acquire F-star Alpha from the shareholders of F-star Alpha including the asset (FS102) in return for an upfront payment for certain rights and licenses from F-star Alpha Ltd. and a clinical milestone payment upon initiation of the Phase 1 trial ($50 million in aggregate).
“The option to acquire F-star Alpha can be exercised at BMS’ discretion up until initiation of a Phase 2b clinical trial of FS102 in return for additional payments of $425 million, which are comprised of an option exercise fee and milestone payments to the F-star Alpha shareholders upon the commencement of a Phase 3 clinical trial and regulatory approvals in the U.S. and Europe. All F-star’s other programs, as well as its staff and other partnerships, are not controlled by F-star Alpha. Hence the partnership with BMS only pertains to FS102 as owned by F-star Alpha.”
F-star’s Modular Antibody Technology platform introduces an antigen binding site into the constant region of an antibody. The resulting Fcab has activity in its own right, as for FS102, or it can be used as a building block for other drug formats. Thus, an Fcab can easily be engineered into any existing antibody to create a bispecific antibody (mAb2) or it can be used as an antibody-drug conjugate by the addition of a toxin.
Normal antibodies, called monoclonal antibodies, only recognize one target, for example on a cancer cell, Haurum tells DDNews. “Bispecific antibodies are designed to simultaneously recognize and bind to two targets. This can, for example, shut down two disease pathways at the same time, resulting in a synergistic increase in the total potency of the drug. Novel biology can also be obtained, such as re-targeting of immune effector cells through one of the binding sites of the bispecific antibody, and this may lead to improved potency, safety profile and cost efficiency compared to using a combination of two normal antibodies,” Haurum notes.
FS102 is a HER2-targeted Fcab that in preclinical studies has been found to eliminate cancer cells in patient-derived xenograft models through a novel mechanism of action in a biomarker- defined population. FS102 works differently to current HER2-targeted therapies, with the potential to overcome resistance to these drugs. It binds to a unique site on HER2 and then induces programmed cell death in HER2-positive tumor cells. In preclinical studies FS102 shows remarkable efficacy against certain HER2-positive cancers. In some cases it completely eliminated tumors, including those that are refractory to treatment with trastuzumab plus pertuzumab. Moreover, F-star has identified a tumor biomarker that highly correlates with efficacy in preclinical models.
Since its founding in 2006, F-star has secured funding and support from leading venture capital investors: Aescap Venture, Atlas Venture, TVM Capital and Novo Ventures; as well as from strategic corporate investors: Merck Serono Ventures, MP Healthcare Venture Management and SR One.
Bristol-Myers Squibb obtained a world-wide exclusive license to FS102, as well as an exclusive option to acquire all outstanding shares in F-star Alpha in October 2014. F-star also has alliances with Boehringer Ingelheim and Merck Serono covering multiple targets. In 2011, F-star was selected by FierceBiotech as one of the Fierce 15 winners. F-star currently employs over 45 people at its research site in Cambridge, U.K.