Tagworks Pharmaceuticals B.v.

Koninklijke Philips Corporation N.v.

Syncom B.v.

Raffaella Rossin

Marc Stefan Robillard

Ronny Mathieu Versteegen

Wolter Ten Hoeve

Hendricus Marie Janssen

Johan Lub

Sandra Martina Van Den Bosch

Henricus Marie Janssen

Freek Johannes Maria Hoeben

Arthur Henry Antoon Marie Van Onzen

Tilman Laeppchen

Sandra Martina Van Ben Bosch

Laurens Henri Kleijn

Martijn Hendrikus Martinus Gerardus Maria Den Brok

Lieke Willemijn Maria Wouters

Kim Elisa De Roode

Lucas Hendricus Maria Zijlmans

Dirk Burdinski

Pascal Renart Verkerk

Disclosed is an advancement in provoked chemical cleavage. Thereby the invention provides the use of a diene as a chemically cleavable group attached to a Construct, and the use of a dienophile to provoke the release of the Construct by allowing the diene to react with a dienophile capable of undergoing an inverse electron demand Diels Alder reaction with the diene. The invention includes a kit for releasing a Construct Cbound to a Trigger T, the kit having a tetrazine and a dienophile, wherein the Trigger is the tetrazine. The invention also includes the use of the formation of a pyridazine by reacting a tetrazine having a Construct Cbound thereto and a dienophile, as a chemical tool for the release, in a chemical, biological or physiological environment, of the Construct.

Cleavable tetrazine used in bio-orthogonal drug activation

The invention relates to a Prodrug activation method, for therapeutics, wherein use is made of abiotic reactive chemical groups that exhibit bio-orthogonal reactivity towards each other. The invention also relates to a Prodrug kit comprising at least one Prodrug and at least one Activator, wherein the Prodrug comprises a Drug and a first Bio-orthogonal Reactive Group (the Trigger), and wherein the Activator comprises a second Bio-orthogonal Reactive Group. The invention also relates to targeted therapeutics used in the above-mentioned method and kit. The invention particularly pertains to antibody-drug conjugates and to bi- and trispecific antibody derivatives.

Bio-orthogonal drug activation

Disclosed is the use of the reactive components of the inverse electron-demand Diels Alder reaction for chemical masking and unmasking in vitro. This can be applied in complex chemical reactions and, particularly in the synthesis of biomolecules, e.g. on solid supports. The reactive components are a dienophile, particularly a trans-cyclooctene, and a diene, particularly a tetrazine.

Chemically cleavable group

Described is a pretargeting method, and related kits, for targeted medical imaging and/or therapeutics, wherein use is made of abiotic reactive chemical groups that exhibit bio-orthogonal reactivity towards each other. The invention involves the use of [4+2] inverse electron demand (retro) Diels-Alder chemistry in providing the coupling between a Pre-targeting Probe and an Effector Probe. To this end one of these probes comprises an electron-deficient tetrazine or other suitable diene, and the other an E-cyclooctene which has a flattened structure as a result of the position of at least two exocyclic bonds.

Pretargeting kit for imaging or therapy comprising a trans-cyclooctene dienophile and a diene

Described is a pretargeting method, and related kits, for targeted medical imaging and/or therapeutics, wherein use is made of abiotic reactive chemical groups that exhibit bio-orthogonal reactivity towards each other. The invention involves the use of [4+2] inverse electron demand (retro) Diels-Alder chemistry in providing the coupling between a Pre-targeting Probe and an Effector Probe. To this end one of these probes comprises an electron-deficient tetrazine or other suitable diene, and the other an E-cyclooctene which has one or more axial substituents.

Pretargeting kit, method and agents used therein

Described is a method, and a combination of agents for used therein, by which an agent administered to a subject can be rapidly cleared from circulation. This is achieved by providing an Administration Agent (e.g. a probe for pretargeting) with a reactive group and providing a Clearing Agent with another reactive group, said reactive groups forming a bio-orthogonally reactive pair. Preferably, the reactive pair comprises a cyclooctene or cyclooctyn as one reactant, and a diene as the other reactant. The method and combination can be used for the removal of any bindable molecule from circulation, such as an excess of a pre-targeting probe in the course of a pre-targeting method, a targeting or imaging agent delivered, or the removal of any biomolecule already present in circulation.

Agents for clearing biomolecules from circulation

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Eindhoven, Netherlands

Raffaella Rossin