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EP-4735046-A1 - BIOCONJUGATION SYSTEMS AND USES THEREOF

EP4735046A1EP 4735046 A1EP4735046 A1EP 4735046A1EP-4735046-A1

Abstract

The present invention relates to a compound having the following formula (I) wherein: - A represents an aryl or heteroaryl group, - n is 1 or 3, - L 1 represents a linear or branched alkylene radical, comprising from 2 to 20 carbon atoms, - L 2 represents a release system, and - L 3 represents an anticancer agent.

Inventors

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

Assignees

  • Université de Tours

Dates

Publication Date
20260506
Application Date
20240628

Claims (11)

  1. 1 . A compound having the following formula (I): wherein: - A represents an aryl or heteroaryl group, said aryl or heteroaryl group being optionally subsituted with at least one substituent selected from the group consisting of: halogen atoms, (Ci-Ce)alkyl groups, OH, CN, NO2, and (Ci-Ce)alkoxy groups, - n is 1 or 3, - Li represents a linear or branched alkylene radical, comprising from 1 to 20 carbon atoms, optionally interrupted with at least one oxygen atom and/or at least one -C(=O)-NH- or -NH-C(=O)- group, at least one of the carbon atoms of said radical being optionally substituted with at least one alkylene side chain comprising 2 to 80 carbon atoms, optionally interrupted with at least one oxygen atom and/or at least one -C(=O)-NH- or -NH-C(=O)- group; - L 2 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 (H-1 ): X representing H or NO 2 ; * the group having the following formula (III): wherein: . X’ is H or NO2, . L 4 is a group of formula H-[NH-CH(Ai)-C(=O)]i-, i and Ai being as defined above in formula (II), or l_4 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 5 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 NO 2 , anda . L 4 and L 5 are as defined in formula (III); - L 3 represents an anticancer agent.
  2. 2. The compound of formula (I) according to claim 1 , wherein A represents an aryl group comprising 6 to 10 carbon atoms, optionally substituted with at least one substituent selected from the group consisting of: halogen atoms, (Ci-Ce)alkyl groups, OH, CN, NO2, and (Ci-Ce)alkoxy groups.
  3. 3. The compound of formula (I) according to claim 1 , wherein A represents an aromatic monocyclic group comprising 5 or 6 atoms and including at least one heteroatom selected from N, S, or O, optionally substituted with at least one substituent selected from the group consisting of: halogen atoms, (Ci-Ce)alkyl groups, OH, CN, NO2, and (Ci-Ce)alkoxy groups.
  4. 4. The compound of formula (I) according to any one of the preceding claims, wherein A has one of the following formulae: the symbols showing the bonds with the groups -NH-C(=O)-CH=CH2 and -NH-C(=O)-LI-C(=O)-L 2 -L 3 .
  5. 5. The compound of formula (I) according to any one of the preceding claims, wherein Li represents 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.
  6. 6. The compound of formula (I) according to any one of the preceding claims, wherein L 2 is selected from the group consisting of: - the group having the following formula (V): - the group having the following formula (VI): - and the group having the following formula (VII):
  7. 7. The compound of formula (I) according to any one of the preceding claims, wherein: - L 2 has the formula (V) as defined in claim 5 and L 3 is monomethyl auristatin E; or - L 2 has the formula (VII) as defined in claim 5 and L 3 is exatecan.
  8. 8. A conjugate comprising at least one compound of formula (I) as defined in 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.
  9. 9. The compound according to any one of claims 1 to 7 or a conjugate according to claim 8, for its use as drug.
  10. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a conjugate according to claim 8, and also at least one pharmaceutically acceptable excipient.
  11. 11. The compound according to any one of claims 1 to 7 or a conjugate according to claim 8, for its use for treating cancer.

Description

BIOCONJUGATION SYSTEMS AND USES THEREOF The present invention concerns new bioconjugation systems, in particular for antibody-drug 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. In parallel, the FDA approved four ADCs (Adcetris®, Polivy®, Padcev®, Tivdak®) on the market with vedotin, comprising the drug monomethyl auristatin E (MMAE), with an average DAR of 4. On one hand, the maleimide included in this linker is associated with partial deconjugation during plasma circulation, through a retro- Michael reaction, thus releasing vedotin, which is then conjugated to any sulfur component of the plasma (glutathione, albumin, etc), which mediates payload- mediated toxicities leading to side effects in patients. On the other hand, MMAE remains a very interesting molecule with a cytotoxic activity in the subnanomolar range and with the potential to exert a bystander effect on neighboring tumor cells. Therefore, enhancing plasma stability, in particular at the conjugation site onto antibodies by replacing classical first generation maleimide (e.g. maleimidocaproic unit), is of particular interest, to reach better-designed ADC with enhanced stability in plasma, leading to more favorable pharmacokinetic properties for the resulted immunoconjugates, in particular to improved internalization. Careful linker design is thus essential to reach better tolerance and efficacy of ADCs, and to this end, stability control during plasma circulation appears to be a key parameter. Indeed, the linker has a major role in the stability of immunoconjugates during plasma circulation and in the controlled release of the drug into the tumor. An aim of the present invention is thus to provide new bioconjugation systems for the preparation of antibody-drug conjugates, for improving the bioconjugation on the antibodies and the pharmacokinetic properties of the corresponding bioconjugated compounds, in particular in terms of serum stability and internalization in targeted cells. Another aim of the present invention is to provide new bioconjugation systems for the preparation of antibody-drug conjugated, allowing doubling the DAR on each disulfide bridge in compa