Abstract: The invention relates to methods for synthesizing amanitin derivatives having an amino group attached to position 6? of the central tryptophan moiety. The invention furthermore relates to an amanitin derivative having an amino group attached to position 6? of the central tryptophan moiety, conjugates of such amanitin derivative, and pharmaceutical compositions comprising such conjugates.

Abstract: The invention relates to a conjugate comprising (a) an amatoxin comprising (i) an amino acid 4 with a 6?-deoxy position; and (ii) an amino acid 8 with an S-deoxy position; (b) a target-binding moiety; and (c) optionally a linker linking said amatoxin and said target-binding moiety. The invention furthermore relates to a pharmaceutical composition comprising such conjugate.

Abstract: The invention relates to novel methods for synthesizing amanitin derivatives having a hydroxy group attached to the central tryptophan moiety. The invention furthermore relates to novel amanitin derivatives having a hydroxy group attached to position 4?, 5? or 7? of the central tryptophan moiety, novel conjugates of such amanitin derivatives, and pharmaceutical compositions comprising such conjugates.

Abstract: The present invention relates to prodrugs comprising a linker comprising five- or six-membered cyclic acetals and an adjacent specific cleavage site, and to precursor compounds for the synthesis of said prodrugs. In one aspect the present invention relates to antibody-targeted amatoxin conjugates comprising said linkers, to methods for their synthesis, and to the use of said antibody-targeted amatoxin conjugates. In a further aspect, the invention relates to pharmaceutical compositions comprising said conjugates, and to the use of said conjugates or compositions for therapeutic purposes, in particular for tumor therapy and oncology.

Abstract: The invention relates to a conjugate comprising (a) an amatoxin comprising (i) an amino acid 4 with a 6?-deoxy position; and (ii) an amino acid 8 with an S-deoxy position; (b) a target-binding moiety; and (c) optionally a linker linking said amatoxin and said target-binding moiety. The invention furthermore relates to a pharmaceutical composition comprising such conjugate.

Abstract: The invention relates to a PSMA-targeting conjugate comprising (a) an amatoxin; (b) a small molecule PSMA-targeting moiety; and (c) optionally a linker linking said amatoxin and said small molecule PSMA-targeting moiety. The invention furthermore relates to a pharmaceutical composition comprising such conjugate.

Abstract: The invention relates to a conjugate comprising (a) an amatoxin comprising (i) an amino acid 4 with a 6?-deoxy position; and (ii) an amino acid 8 with an S-deoxy position; (b) a BCMA-binding moiety comprising (i) the variable domains of humanized antibody J22.9-ISY, and (ii) a heavy chain constant region comprising a D265C mutation; and (c) a protease-cleavable linker linking said amatoxin and said target-binding moiety. The invention furthermore relates to a pharmaceutical composition comprising such conjugate, particularly for use in the treatment of multiple myeloma.

Abstract: The invention relates to novel methods for synthesizing amanitin derivatives having an amino group attached to position 6? of the central tryptophan moiety. The invention furthermore relates to a novel amanitin derivative having an amino group attached to position 6? of the central tryptophan moiety, novel conjugates of such amanitin derivative, and pharmaceutical compositions comprising such conjugates.

Abstract: The invention relates to novel methods for synthesizing amanitin derivatives having an amino group attached to position 6? of the central tryptophan moiety. The invention furthermore relates to a novel amanitin derivative having an amino group attached to position 6? of the central tryptophan moiety, novel conjugates of such amanitin derivative, and pharmaceutical compositions comprising such conjugates.

Abstract: The present application relates to a composition comprising (a) at least one immune checkpoint inhibitor and (b) at least one conjugate, wherein said conjugate is comprising (i) a target binding moiety, (ii) at least one amatoxin, and (iii) optionally at least one linker connecting said target binding moiety with said at least one amatoxin. The present application further relates to said composition for use in treating a patient having a cancer, and to a pharmaceutical formulation comprising said composition and additional excipients, as well as to methods of producing and using said composition.

Abstract: The present invention relates to novel methods and compounds for synthesizing amanitin derivatives. The invention in particular relates to methods for synthesizing (S)-6-hydroxy-tryptophan derivatives which can be used as building blocks for synthesizing amanitin derivatives or amatoxin drug conjugates. The invention further relates to intermediate compounds of said synthesis pathways for use in amanitin derivative and amatoxin drug conjugate synthesis, and to the use of particular catalysts suited for mediating said synthesis pathways.

Abstract: The invention relates to a conjugate comprising (a) an amatoxin comprising (i) an amino acid 4 with a 6?-deoxy position; and (ii) an amino acid 8 with an S-deoxy position; (b) a target-binding moiety; and (c) optionally a linker linking said amatoxin and said target-binding moiety. The invention furthermore relates to a pharmaceutical composition comprising such conjugate.

Abstract: The invention relates to novel methods for synthesizing amanitin derivatives having a hydroxy group attached to the central tryptophan moiety. The invention furthermore relates to novel amanitin derivatives having a hydroxy group attached to position 4?, 5? or 7? of the central tryptophan moiety, novel conjugates of such amanitin derivatives, and pharmaceutical compositions comprising such conjugates.

Abstract: The invention relates to novel methods for synthesizing amanitin derivatives having a hydroxy group attached to the central tryptophan moiety. The invention furthermore relates to novel amanitin derivatives having a hydroxy group attached to position 4?, 5? or 7? of the central tryptophan moiety, novel conjugates of such amanitin derivatives, and pharmaceutical compositions comprising such conjugates.

Abstract: The present invention relates to an amatoxin-linker construct comprising an amatoxin according to formula (I) wherein: R1 and R2 are each —OH, R3 is NH2, or a linker which carries a reactive group Y for linking said amatoxin to a target-binding moiety, R4 is H or a linker which carries a reactive group Y for linking said amatoxin to a target-binding moiety, R5 is absent or ?O, wherein R3 and R4 cannot be the same, for use in the manufacture of a binding moiety-toxin conjugate for the treatment of a solid tumor, and a respective binding moiety-toxin conjugate for the treatment of a solid tumor.

Abstract: The invention relates to novel methods for synthesizing amanitin derivatives having an amino group attached to position 6? of the central tryptophan moiety. The invention furthermore relates to a novel amanitin derivative having an amino group attached to position 6? of the central tryptophan moiety, novel conjugates of such amanitin derivative, and pharmaceutical compositions comprising such conjugates.

Abstract: Amatoxins, as well as antibody-drug conjugates (ADCs) comprising an amatoxin are provided, as well as compositions and methods of using the same. The compositions and methods provided herein can also be used to prepare a patient for hematopoietic stem cell transplant therapy and to improve the engraftment of hematopoietic stem cell transplants by selectively depleting endogenous hematopoietic stem cells prior to the transplant procedure. Methods and compositions for the treatment of various hematopoietic diseases, metabolic disorders, cancers, and autoimmune diseases, as well as prevention of graft-versus-host-disease (GVHD), are provided.

Abstract: The invention relates to a PSMA-targeting conjugate comprising (a) an amatoxin; (b) a small molecule PSMA-targeting moiety; and (c) optionally a linker linking said amatoxin and said small molecule PSMA-targeting moiety. The invention furthermore relates to a pharmaceutical composition comprising such conjugate.

Abstract: The invention relates to ?-amaninamide (1; x=0, 1 or 2), ?-amaninamidic acid (2; x=0, 1 or 2), and ?-amaninamidic hydroxamic acid (3; x=0, 1 or 2), novel derivatives of ?-amanitin (4), and methods and novel building blocks for the synthesis thereof.

Abstract: The invention relates to novel methods for synthesizing amanitin derivatives having a hydroxy group attached to the central tryptophan moiety. The invention furthermore relates to novel amanitin derivatives having a hydroxy group attached to position 4?, 5? or 7? of the central tryptophan moiety, novel conjugates of such amanitin derivatives, and pharmaceutical compositions comprising such conjugates.