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Werewolf Therapeuticswerewolftx.com

Designing conditionally activated immunestimulators that attack cancer cellsUsing its proprietary PREDATOR protein engineering platform, Werewolf designs biotherapeutics that are systemicallydelivered and activated selectively in the tumor microenvironment to recruit a powerful antitumor immune response.

Cancer cells are able to switch off the body’s immuneresponse by inactivating immune cells or avoidingdetection. Immunotherapies, such as checkpointinhibitors, act by switching the immune systemback on. These have become an important part ofcancer treatment. However, not all tumors respondbecause there is not enough of an endogenousimmune response. Other approaches, such as pro-inflammatory cytokines and costimulatory receptoragonists, are able to stimulate the body’s responseto cancer. Although this is effective, the clinical useand benefit can be limited; these agents can causeinflammation in healthy tissues, leading to autoim-mune or inflammatory side effects and organ toxic-ity. Historically, it has been challenging to developthese agents with the appropriate pharmaceuticalproperties and without off-tissue toxicities.

Cambridge, MA-based Werewolf Therapeutics’focus is to create a novel class of proinflammatoryimmunomodulator therapeutics that act selectivelyin the tumor, stimulating the body’s responseagainst cancer.

Bringing in the PREDATORWerewolves are mythological creatures that liveunnoticed as humans and then shape-shift to preda-tors at a conditional signal—the full moon. Werewolf’sPREDATOR protein engineering technology createsbiological prodrugs that remain inactive in the sys-temic circulation. These prodrugs are activated intoimmune stimulants only in the tumor microenvi-ronment, where they trigger the immune system to‘predate’ on cancer cells (Fig. 1). This has the potentialto reduce off-target effects on healthy tissues, whileensuring that the final, activated drug retains fullpotency for maximum therapeutic potential.

“There are well-validated pro-inflammatory tar-gets and pathways that we know will trigger thetumor immune response, but these are associatedwith side effects. The PREDATOR technology meansthat we can tap into these known mechanismsand exploit a wider therapeutic window, with thepotential for a greater clinical response and reducedimpact on healthy tissue,” said Daniel Hicklin,founder, president and CEO.

The PREDATOR technology was developed in-house following the company’s launch in 2017, andthe tactic has been validated in proof-of-conceptstudies.

Hunting candidates to build the pipelineWerewolf’s pipeline is made up of prodrugs ofpro-inflammatory cytokines and costimulatorymultivalent receptor agonists.

“We are currently progressing a number of develop-ment candidates, and are near the decision point toprioritize our first IND candidate before the end of thesecond quarter of 2020,” said Hicklin. “These pro-grams cover a diverse set of immune mechanisms sothat we can target a broad spectrum of cancer types.”

The company’s initial approaches are likely toinclude IL-12, IL-2, interferon and molecules targetingthe costimulatory receptor 4-1BB. These are all well-validated pathways that are recognized by biopharmacompanies, but toxicities limit their ability to be usedeffectively as systemic drugs.

“Because we know the targets so well and themechanisms are well-validated, we hope to be ableto demonstrate clinical evidence of whether our pro-drugs are working early on in development, whichcould lead to shorter, more efficient clinical trials,”said Hicklin.

The majority of experimental immunotherapies arebeing developed in combination with other immu-notherapies and/or traditional chemotherapy. Thisaims to improve clinical responses but potentiallyincreases the risk of side effects. Hicklin believesthat the Werewolf technology will allow its drugsto be developed initially as monotherapies by virtueof controlled delivery of potent immune-activatingmechanisms.

Conditional activation of biologics is being pursuedby a number of companies for various therapeuticmodalities, acknowledges Hicklin. The Werewolftechnology uses design elements that addresspharmaceutical, potency and tissue selectivityproperties, previously a challenge for conditionallyactivated agents.

Werewolf completed its $56 million Series Afinancing in November 2019. This financing pro-vided enough capital to progress two moleculesinto the clinic and progress other molecules inthe pipeline, and will also allow the headcount toincrease from 17 to around 30. Werewolf expects toconduct its next round of financing in 2021.

Creating the Werewolf packAccording to Hicklin, getting the right people inplace has helped Werewolf make its transitionfrom a semi-virtual company in stealth mode to areal-world organization heading rapidly towards aclinical pipeline.

“We have a proven leadership team that includespeople with a lot of experience from biotech andbig pharma companies, including the developmentof several approved oncology drugs. Many of ushave worked together for a long time—we trustone another to make wise, data-driven decisionsthat will drive our pipeline forward,” said Hicklin.

“Together, we are focused on developing effec-tive drugs against well-validated targets to delivera clinically meaningful impact for patients,” con-cluded Hicklin.

Systemicallydeliveredtherapy

Tumor-activatedtherapeutics Healthy

Molecule remains inactivein systemic circulationand within healthy tissue

TumorMolecule is conditionally activatedin the tumor microenvironment to stimulate the immune systemto selectively target cancer cells

Fig. 1 | The Werewolf molecule in action. The prodrugs are activated into immune stimulants only in thetumor microenvironment, where they trigger the immune system to ‘predate’ on cancer cells.

Reid Leonard, COOWerewolf TherapeuticsCambridge, MA, USAEmail: rleonard@werewolftx.comCO

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B10 | March 2020 | biopharmadealmakers.nature.com