Heidelberg Pharma Research Gmbh

Heidelberg Pharma Gmbh

Deutsches Krebsforschungszentrum

Heinz Faulstich

Faulstich, Heinz, Dr.

Christoph Müller

Werner Simon

Christian Lutz

Torsten Hechler

Susanne Werner-Simon

Michael Kulke

Jan Anderl

Andreas Pahl

Gerhard Moldenhauer

Anikó Pálfi

Simon Werner

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.

Synthesis of (S)-6-hydroxytryptophan and derivatives thereof

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.

Method of treating cancer using amanitin derivatives

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&#x2032; or 7&#x2032; of the central tryptophan moiety, novel conjugates of such amanitin derivatives, and pharmaceutical compositions comprising such conjugates.

Method for synthesizing amanitins

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.

Amanitin conjugates

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.

Amanitin antibody conjugates

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&#x2032; of the central tryptophan moiety, novel conjugates of such amanitin derivative, and pharmaceutical compositions comprising such conjugates.

The invention relates to conjugates comprising amatoxins and antibodies, in particular amatoxins linked to antibodies comprising specific cysteine residues.

Amatoxin-antibody conjugates

The invention relates to &#x3b3;-amaninamide (1; x=0, 1 or 2), &#x3b3;-amaninamidic acid (2; x=0, 1 or 2), and &#x3b3;-amaninamidic hydroxamic acid (3; x=0, 1 or 2), novel derivatives of &#x3b3;-amanitin (4), and methods and novel building blocks for the synthesis thereof. 

Derivatives of gamma-amanitin

The invention relates to tumor therapy. In one aspect, the present invention relates to conjugates of an amatoxin and a target-binding moiety, e.g. an antibody, connected by certain linkages, which are useful in the treatment of cancer and other disorders and diseases. In a further aspect the invention relates to pharmaceutical compositions comprising such conjugates.

Amatoxin derivatives

The invention relates to tumour therapy. In one aspect, the present invention relates to conjugates of a toxin and a target-binding moiety, e.g. an antibody, which are useful in the treatment of cancer. In particular, the toxin is an amatoxin, and the target-binding moiety is preferably directed against tumour-associated antigens. In particular, the amatoxin is conjugated to the antibody by linker moieties. In particular the linker moieties are covalently bound to functional groups located in positions of the amatoxin proved as preferred positions for the attachment of linkers with respect to optimum antitumor activity. In a further aspect the invention relates to pharmaceutical compositions comprising such target-binding moiety toxin conjugates and to the use of such target-binding moiety toxin conjugates for the preparation of such pharmaceutical compositions. The target-binding moiety toxin conjugates and pharmaceutical compositions of the invention are useful for the treatment of cancer.

Growing community of inventors

Birkenau, Germany

Christoph Müller