Stability Modulating Linkers for Antibody Drug Conjugates

Abstract

The present invention provides stability-modulated antibody-drug conjugates, stability-modulating linker components for the preparation of these stability-modulated antibody-drug conjugates, using stability-modulated antibody-drug conjugates and methods of making stability-modulating linkers and stability-modulating antibody-drug conjugates.

Description

technical field

[0001] The present invention relates to linkers for use in association with antibody-drug conjugates (ADCs) capable of up-regulating and down-regulating the extracellular and / or intracellular stability of the antibody-drug conjugates. The invention also relates to therapeutic uses and treatment regimens employing such clinically advantageous stability-modulated antibody-drug conjugates. Finally, the invention relates to methods of preparing stability-modulating linkers and stability-modulated antibody-drug conjugates.

[0002] References to Sequence Listings

[0003] This application is filed electronically via EFS-Web and includes the electronically filed Sequence Listing in .txt format. The .txt file contains a sequence listing titled "PC72108A_SEQ_LISTING_ST25.txt" created on August 14, 2015 and having a size of 10 KB. The sequence listing contained in this .txt file is an integral part of the specification and is incorporated herein by reference in its e...

Examples

preparation example Construction

[0278] The pharmaceutical compositions of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington's Pharmaceutical Sciences, 22nd Edition (Mack Publishing Company, 2012). The pharmaceutical compositions are preferably prepared under GMP conditions.

[0279] The pharmaceutical compositions of the invention may be prepared, packaged or sold in bulk, as a single unit dose or as a plurality of single unit doses. A "unit dose" as used herein is a discrete quantity of pharmaceutical composition containing a predetermined quantity of active ingredient. The amount of active ingredient is usually equal to the dose of active ingredient to be administered to the individual, or a convenient fraction of such a dose, for example, 1 / 2 or 1 / 3 of such a dose. Any art-accepted method for administering a peptide, protein or antibody may be suitably e...

Embodiment 1

[0325] Example 1: N~2~-benzoyl-L-lysyl-L-valyl-N-{4-[(8S,11S,12R)-11-[(2S)-butan-2- Base]-12-(2-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl -1-(1,3-Thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-2-oxoethyl)-5,5,10-trimethyl-3, 6,9-trioxo-8-(propan-2-yl)-2,13-dioxa-4,7,10-triazatetradec-1-yl]phenyl}-N~5 Preparation of ~-carbamoyl-L-ornithine (6)

[0326]

[0327] Step 1: N~2~-benzoyl-N~6~-(tert-butoxycarbonyl)-L-lysyl-L-valyl-N~5~-carbamoyl-N-[4- Synthesis of (Hydroxymethyl)phenyl]-L-ornithine (2). To N~2~-benzoyl-N~6~-(tert-butoxycarbonyl)-L-lysine (100mg, 0.285mmol) and L-valyl-N~5~-carbamoyl-N -[4-(Hydroxymethyl)phenyl]-L-ornithine (1,108 mg, 0.285 mmol) in 1 mL of N,N-dimethylformamide was added O-(7-azabenzo Triazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 111mg, 0.285mmol), followed by N,N-diisopropylethylamine (201ul , 149mg, 1.14mmol). The mixture was monitored by LC-MS and stirred at room temperature for 16 hours. The r...

Embodiment 2

[0331]Example 2: N~2~-(2,2-dimethylpropionyl)-L-lysyl-L-valyl-N-{4-[(8S,11S,12R)-11-[ (2S)-But-2-yl]-12-(2-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[ (1S)-2-Phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-2-oxoethyl)-5,5, 10-Trimethyl-3,6,9-trioxo-8-(propan-2-yl)-2,13-dioxa-4,7,10-triazatetradec-1-yl Preparation of ]phenyl}-N~5~-carbamoyl-L-ornithine (12)

[0332]

[0333] Step 1: N-(tert-Butoxycarbonyl)-L-valyl-N-{4-[(8S,11S,12R)-11-[(2S)-Butan-2-yl]-12-(2 -{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3 -thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-2-oxoethyl)-5,5,10-trimethyl-3,6,9-trioxo -8-(Propan-2-yl)-2,13-Dioxa-4,7,10-Triazatetradec-1-yl]phenyl}-N~5~-carbamoyl-L - Synthesis of ornithine (8). To 2-methylalanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2- Methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}- 5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (4,80 mg, 0.11 mmo...

technical field

[0001] The present invention relates to linkers for use in association with antibody-drug conjugates (ADCs) capable of up-regulating and down-regulating the extracellular and / or intracellular stability of the antibody-drug conjugates. The invention also relates to therapeutic uses and treatment regimens employing such clinically advantageous stability-modulated antibody-drug conjugates. Finally, the invention relates to methods of preparing stability-modulating linkers and stability-modulated antibody-drug conjugates.

[0002] References to Sequence Listings

[0003] This application is filed electronically via EFS-Web and includes the electronically filed Sequence Listing in .txt format. The .txt file contains a sequence listing titled "PC72108A_SEQ_LISTING_ST25.txt" created on August 14, 2015 and having a size of 10 KB. The sequence listing contained in this .txt file is an integral part of the specification and is incorporated herein by reference in its e...

Examples

preparation example Construction

[0278] The pharmaceutical compositions of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington's Pharmaceutical Sciences, 22nd Edition (Mack Publishing Company, 2012). The pharmaceutical compositions are preferably prepared under GMP conditions.

[0279] The pharmaceutical compositions of the invention may be prepared, packaged or sold in bulk, as a single unit dose or as a plurality of single unit doses. A "unit dose" as used herein is a discrete quantity of pharmaceutical composition containing a predetermined quantity of active ingredient. The amount of active ingredient is usually equal to the dose of active ingredient to be administered to the individual, or a convenient fraction of such a dose, for example, 1 / 2 or 1 / 3 of such a dose. Any art-accepted method for administering a peptide, protein or antibody may be suitably e...

Embodiment 1

[0325] Example 1: N~2~-benzoyl-L-lysyl-L-valyl-N-{4-[(8S,11S,12R)-11-[(2S)-butan-2- Base]-12-(2-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl -1-(1,3-Thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-2-oxoethyl)-5,5,10-trimethyl-3, 6,9-trioxo-8-(propan-2-yl)-2,13-dioxa-4,7,10-triazatetradec-1-yl]phenyl}-N~5 Preparation of ~-carbamoyl-L-ornithine (6)

[0326]

[0327] Step 1: N~2~-benzoyl-N~6~-(tert-butoxycarbonyl)-L-lysyl-L-valyl-N~5~-carbamoyl-N-[4- Synthesis of (Hydroxymethyl)phenyl]-L-ornithine (2). To N~2~-benzoyl-N~6~-(tert-butoxycarbonyl)-L-lysine (100mg, 0.285mmol) and L-valyl-N~5~-carbamoyl-N -[4-(Hydroxymethyl)phenyl]-L-ornithine (1,108 mg, 0.285 mmol) in 1 mL of N,N-dimethylformamide was added O-(7-azabenzo Triazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 111mg, 0.285mmol), followed by N,N-diisopropylethylamine (201ul , 149mg, 1.14mmol). The mixture was monitored by LC-MS and stirred at room temperature for 16 hours. The r...

Embodiment 2

[0331]Example 2: N~2~-(2,2-dimethylpropionyl)-L-lysyl-L-valyl-N-{4-[(8S,11S,12R)-11-[ (2S)-But-2-yl]-12-(2-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[ (1S)-2-Phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-2-oxoethyl)-5,5, 10-Trimethyl-3,6,9-trioxo-8-(propan-2-yl)-2,13-dioxa-4,7,10-triazatetradec-1-yl Preparation of ]phenyl}-N~5~-carbamoyl-L-ornithine (12)

[0332]

[0333] Step 1: N-(tert-Butoxycarbonyl)-L-valyl-N-{4-[(8S,11S,12R)-11-[(2S)-Butan-2-yl]-12-(2 -{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3 -thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-2-oxoethyl)-5,5,10-trimethyl-3,6,9-trioxo -8-(Propan-2-yl)-2,13-Dioxa-4,7,10-Triazatetradec-1-yl]phenyl}-N~5~-carbamoyl-L - Synthesis of ornithine (8). To 2-methylalanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2- Methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}- 5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (4,80 mg, 0.11 mmo...

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