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EP-4735047-A1 - PEGYLATED LINKERS AND USES THEREOF

EP4735047A1EP 4735047 A1EP4735047 A1EP 4735047A1EP-4735047-A1

Abstract

The present invention concerns a compound having the following formula (I) wherein: - m represents an integer comprised from 1 to 3, - L 1 represents a bioconjugation unit, - L 2 and L 3 represent a spacer group, - L 4 represents a release system, - L 5 represents an anticancer agent, and - L 6 represents a PEG moiety.

Inventors

  • JOUBERT, NICOLAS
  • DENEVAULT-SABOURIN, Caroline
  • LETAST, Stéphanie
  • AUVERT, Etienne

Assignees

  • Université de Tours

Dates

Publication Date
20260506
Application Date
20240628

Claims (10)

  1. 1. A compound having the following formula (I): wherein: - m represents an integer comprised from 1 to 3, - Li represents a bioconjugation unit capable of binding to at least one antibody or antibody fragment by reacting with an amino, hydroxyl, amide or thiol function, - L 2 represents a spacer group of formula -Ai-C(=O)-, Ai representing a linear or branched alkylene radical, comprising from 2 to 20 carbon atoms, optionally interrupted with at least one oxygen atom, - L 3 represents a spacer group of formula -A 2 -C(=O)-, A 2 representing a linear or branched alkylene radical, comprising from 2 to 20 carbon atoms, optionally interrupted with at least one oxygen atom, - L 4 represents a release system selected from the group consisting of: * the group having the following formula (II): -[NH-CH(Ai)-C(=O)]i-[A 9 ]j- (II) wherein: . i is 0 or is an integer from 1 to 8, . j is 0 or 1 , provided that i is not 0 when j=0, and when i=0 then j=1 , . each Ai represents, independently from each other, the side chain of an amino acid residue, in particular a linear or branched (Ci-Ce)alkyl chain, and . A 9 represents a -NH-CH 2 - group or a group having the following formula * the group having the following formula (III): wherein: . X’ is H or NO 2 , . L 7 is a group of formula H-[NH-CH(Ai)-C(=O)]i-, i and A being as defined above in formula (II), or l_7 is selected from the group consisting of: beta-glucuronic acid, beta- D-galactose, beta-D-glucose, alpha-D-mannose, N-acetyl-D- glucosaminyle, N-acetyl-D-galactosaminyle, D-glucuronyle, L-iduronyle, D-glucopyranosyle, D-galactopyranosyle, D-mannopyranosyle, and L- fucopyranosyle, . L 8 represents a group -CH 2 -CH 2 -C(=O)-NH-, a bond or a linear or branched alkylene radical comprising from 2 to 20 carbon atoms, optionally interrupted with at least one oxygen atom, * the group having the following formula (IV): wherein: . X” is H or NO2, and . L 7 and L 8 are as defined in formula (III); - L 5 represents an anticancer agent, and - L 6 represents a PEG moiety selected from the group consisting of: * the group of formula -(CH2-CH2-O) n -CH 3 , n representing an integer from 1 to 24, and * the group of the following formula (V): -(CH 2 )3-C(=O)-NH-(CH2-CH2-O)4-(CH2)2-C(=O)-NH-C(R) 3 (V) wherein R is a group of the following formula (V-1 ): -CH2-O-(CH2)2-C(=O)-NH-(CH2)2-(O-CH2-CH 2 )7-OCH 3 .
  2. 2. The compound of formula (I) according to claim 1 , wherein L2 and L3, independently from each other, represent a spacer group of formula -(CH 2 ) P -C(=O)-, p being an integer comprised from 2 to 20, or a spacer group of formula -(CH2-CH2- O)m-(CH 2 ) r -C(=O)-, m being an integer comprised from 1 to 10 and r being 1 or 2.
  3. 3. The compound of formula (I) according to claim 1 or 2, wherein Li comprises or is a maleimide group, a NHS ester group or an isothiocyanate group.
  4. 4. The compound of formula (I) according to any one of the preceding claims, wherein L4 is selected from the group consisting of: - the group having the following formula (VI): - the group having the following formula (VII): - and the group having the following formula (VIII):
  5. 5. The compound of formula (I) according to any one of the preceding claims, wherein: - L 4 has the formula (VI) as defined in claim 5 and L 5 is monomethyl auristatin E; or - L 4 has the formula (VIII) as defined in claim 5 and L 5 is exatecan.
  6. 6. The compound of formula (I) according to any one of the preceding claims, wherein L 6 is a group having the formula -(CH2-CH2-O) n -CH 3 , n being 12 or 24.
  7. 7. A conjugate comprising at least one compound according to any one of the preceding claims, said compound being covalently bound to at least one cell binding agent, in particular selected from the antibodies and the antibody fragments.
  8. 8. The compound according to any one of claims 1 to 6 or a conjugate according to claim 7, for its use as drug.
  9. 9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a conjugate according to claim 7, and also at least one pharmaceutically acceptable excipient.
  10. 10. The compound according to any one of claims 1 to 6 or a conjugate according to claim 7, for its use for treating cancer.

Description

PEGYLATED LINKERS AND USES THEREOF The present invention concerns new pegylated linkers, in particular for antibodydrug conjugates (ADC), as well as uses thereof, in particular for the preparation of conjugates, especially for treating cancer. In the past few years, since the advent of Glivec®, cancer treatment has been revolutionized by the arrival of several targeted therapies that have greatly increased the efficacy and tolerance of treatments. Along with tyrosine kinase inhibitors, antibody-drug conjugates (ADCs) are among the personalized targeted therapies that have been widely developed in recent years, since the approval of Mylotarg® by the Food and Drug Administration (FDA) in 2000. Today, the FDA approved 13 ADCs. ADCs are targeted biotherapies against one antigen, vectorized for the transport of cytotoxic molecules and injectable via intravenous route. An important characteristic of ADCs is the drug-to-antibody ratio (DAR) defined by the average number of cytotoxic drugs conjugated onto the antibody. The general structure of this molecular architecture is thus characterized by an immunoglobulin, a bioconjugation head, a linker (cleavable or not) and a vectorized drug. In oncology, the first ADC approved by the FDA in 2013 to treat a solid tumor was trastuzumab emtansine (T-DM1 , Kadcyla®), used as a monotherapy against HER2-positive metastatic (or locally advanced unresectable) breast cancer. Its indication has now been extended to the treatment of patients with HER2-positive early breast cancer (after neoadjuvant therapy). Unfortunately, T-DM1 is a second- generation ADC, associated with several limitations. The stochastic conjugation of the hydrophobic maytansine derivative DM1 , through a hydrophobic non-cleavable linker onto the side chains of accessible lysines, lead to a very heterogeneous distribution of immunoconjugates characterized by an average DAR of only 3.5. The release of its active metabolite (lysine-linker-DM1 ), charged at physiological pH, prevents it to exhibit a bystander killing effect and limits its activity. Moreover, Kadcyla® is already associated with emerging resistances in patients, urging the need for improved design in ADCs. In December 2018, the FDA approved the trastuzumab deruxtecan (T-Dxd, Enhertu®) as a treatment for patients with unresectable or metastatic HER2-positive or HER2-low breast cancer (IHC score 1 + or IHC 2+/HIS-). T-Dxd is a third generation ADC, characterized by a homogeneous DAR of 8, where trastuzumab is conjugated to a membrane-permeable payload Dxd (exhibiting a bystander killing effect to kill HER2-low cancer cells), through an innovative enzymatically cleavable linker designed to control hydrophobicity. The innovative linker (with a tetrapeptidyl-spacer MC-GlyGlyPheGly) and the more hydrophilic aminomethylene self-immolative spacer and drug DXd allowed the development of a stable ADC with a high homogeneous DAR of 8, as tolerable as a second-generation ADC with an average DAR of 4. These two ADCs are derived from an lgG1 , so they can bind to FcRn, which is ubiquitous and responsible for recycling immunoglobulins in the body, and to FcyR, during plasma circulation and biodistribution in the body. These nonspecific bindings therefore results in unwanted off-target off-site toxicity, which are associated to strong side effects (thrombocytopenia and hepatic cytolysis). In addition, the use of high molecular weight proteins such as IgG (150 kDa), could lead to a suboptimal tumor penetration. To overcome the limitations associated with the IgG format to develop immunoconjugates, more and more studies are focusing on conjugated smaller antibody formats or fragments. They have the advantage of being much smaller than IgG-based ADCs, have no Fc part (responsible for non-specific binding and antigenindependent internalization) and potentially diffuse better in the tumor microenvironment. It has been shown in the literature that the larger the macromolecule is, the more rapidly it is eliminated from the extravascular tumor environment. Indeed, Zhe Li's study shows that the tissue penetration of entities increases as the size of the molecules decreases. Deonarain et al. also argued that small antibody conjugate sizes may have better tumor penetration properties. The minibody format was first described in preclinical studies in 1996 and in clinical first- in-human phase I trial in 2004 as an anti-CEA radiotracer in colon cancer patients. This type of conjugated antibody format showed a rapid distribution in the tumor associated with a fast clearance of the body. To date, interestingly the use of minibody fragments has been scarcely reported in a only some preclinical studies and few clinical trials as a radiotracer (completed: NCT02092948, NCT05279027, in progress: NCT04874818, NCT03542669; “Clinical Trials”). Although, a very recent study proved promising results about the efficacy of a minibody conjugated to 2 molecules of monomethyl auristatin E (M