Delving into drug delivery

F-star and Denali to develop multispecific antibody platform for crossing blood-brain barrier

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CAMBRIDGE, U.K. & SAN FRANCISCO—F-star, a biopharmaceutical company developing novel bispecific antibodies, has announced a collaborative agreement with Denali Therapeutics Inc., a biotechnology company focused on neurodegenerative disorders, to research and develop antibodies for the delivery of medicines across the blood-brain barrier (BBB) into the central nervous system (CNS).
John Haurum, CEO of F-star, commented, “Our Modular Antibody Technology is ideally suited to deliver biologic drugs into the central nervous system across the blood-brain barrier. Denali’s scientists are world leaders in understanding the complex mechanisms of the blood-brain barrier, and we look forward to collaborating with the team to unlock the potential of our platform and develop more efficient treatments for neurological disorders.”
The collaboration will leverage F-star’s Modular Antibody Technology and Denali’s expertise in the development of therapeutics for neurological diseases to generate Fcabs (constant Fc-domains with antigen-binding activity) that can bind to transporters in the BBB. Using the “plug-and-play” properties of the platform, these Fcabs reportedly can be rapidly inserted into any existing antibody to generate a full-size bispecific antibody (mAb²) which can both cross the BBB and bind to specific targets in the CNS. This mechanism has the potential to treat neurological diseases by acting on specific targets in the brain.
“The Modular Antibody Technology (MAT) is F-star’s proprietary technology for the rapid generation of bispecific antibodies. The MAT is the only platform enabling the creation of bispecific antibodies by introducing additional binding sites to the constant (Fc) region of an antibody to create an Fcab. The resulting Fcab is then used as a building block for other drug formats,” Haurum tells DDNews.
“In particular, an Fcab can be easily combined with the variable region (Fab) of an existing antibody to generate a full-length bispecific antibody or mAb² that retains the full structure, functionality, manufacturability and stability of a conventional monoclonal antibody. The platform allows the Fcabs binding transporters in the BBB to be rapidly inserted into any existing antibody, or other biologic drug formats,” Haurum explains. “The resulting mAb² therefore have the potential to treat a wide range of diseases within the BBB, not only neurodegenerative disorders but also, e.g., glioblastoma and inflammatory diseases. This enables us to rapidly and efficiently explore numerous target combinations and identify novel biology.”
Ryan Watts, CEO of Denali, remarked that, “We are excited to partner with F-star to tackle one of the toughest problems in medicine: delivery of biologics across the blood-brain barrier. F-star’s deep expertise and proven track record of engineering novel antibodies offer a promising approach for the treatment of neurological disease.”
The agreement is with F-star Gamma Ltd., a new asset-centric vehicle in the F-star family. Under the agreement, Denali will make upfront payments to F-star totaling $6 million. Denali has the option to nominate a prespecified number of Fcab targets. F-star Gamma will also receive research funding and is eligible for technical milestone payments. In addition, Denali also has the option to acquire F-star Gamma prior to the initiation of the first Phase 1 clinical trial, in return for aggregate exercise and milestone payments to the F-star Gamma shareholders of up to $450 million. If Denali does not exercise the option to acquire F-star Gamma, it has the right to license a pre-specified number of mAb² based on each Fcab generated by F-star Gamma, in return for license fees, development, regulatory and commercial milestones payments with a potential aggregate value of $1 billion and tiered royalties on product sales.
Haurum says Denali first approached F-star with the idea for collaboration.
“They were familiar with our Modular Antibody Technology, and recognized that it was ideally suited to the development of a multispecific antibody platform to deliver therapeutics across the blood-brain barrier,” he notes. “Although Denali is a relatively new company, it brings a wealth of experience in neurological diseases, and we were excited by the opportunity of working with their scientists who are world leaders in this field. Talks started at the end of last year, and our first meeting was at the JP Morgan conference.”
According to Haurum, the partnership with Denali will allow F-star to extend its platform to neurodegenerative disease, a therapy area where there is a substantial unmet need and the opportunity to make a significant impact.
“The companies will bring together their respective capabilities to collaborate on establishing the platform; development of drugs using the platform will then be largely carried out independently,” continues Haurum. “The innovative deal structure provides Denali with the option to secure exclusive rights to the platform and the development of drugs using it through acquisition of F-star Gamma, the asset-centric vehicle housing the collaboration. If Denali does not exercise its option, both companies (Denali and F-star Gamma) will be able to exploit the platform.”

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