CROSS REFERENCE TO RELATED APPLICATIONS

This application is a national stage application under 35 U.S.C. § 371 of International Application No. PCT/EP2017/083313, filed internationally on Dec. 18, 2017, which claims the benefit of European Application No. 16205870.5, filed Dec. 21, 2016.

SUBMISSION OF SEQUENCE LISTING ON ASCII TEXT FILE

The content of the following submission on ASCII text file is incorporated herein by reference in its entirety: a computer readable form (CRF) of the Sequence Listing (file name: 777052035300SEQLIST.TXT, date recorded: Jun. 18, 2019, size: 62 KB).

INTRODUCTION AND STATE OF THE ART

The invention relates to specific binder-drug conjugates (ADCs) of kinesin spindle protein inhibitors, to effective metabolites of these ADCs, to processes for preparing these ADCs, to the use of these ADCs for the treatment and/or prevention of diseases and to the use of these ADCs for preparing medicaments for treatment and/or prevention of diseases, in particular hyperproliferative and/or angiogenic disorders such as, for example, cancer diseases. Such treatments can be effected as monotherapy or else in combination with other medicaments or further therapeutic measures.

Cancers are the consequence of uncontrolled cell growth of the most diverse tissues. In many cases the new cells penetrate into existing tissue (invasive growth), or they metastasize into remote organs. Cancers occur in a wide variety of different organs and often have tissue-specific courses. The term “cancer” as a generic term therefore describes a large group of defined diseases of different organs, tissue and cell types.

Some tumours at early stages can be removed by surgical and radiotherapy measures. Metastasized tumours as a rule can only be treated palliatively by chemotherapeutics. The aim here is to achieve the optimum combination of an improvement in the quality of life and prolonging of life.

Conjugates of binder proteins with one or more drug molecules are known, in particular in the form of antibody drug conjugates (ADCs) in which an internalizing antibody directed against a tumour-associated antigen is covalently attached via a linker to a cytotoxic agent. Following introduction of the ADCs into the tumour cell and subsequent dissociation of the conjugate, either the cytotoxic agent itself or a cytotoxic metabolite formed therefrom is released within the tumour cell and can unfold its action therein directly and selectively. In this manner, in contrast to conventional cancer chemotherapy, damage to normal tissue is contained in significantly narrower limits [see, for example, J. M. Lambert,Curr. Opin. Pharmacol.5, 543-549 (2005); A. M. Wu and P. D. Senter,Nat. Biotechnol.23, 1137-1146 (2005); P. D. Senter,Curr. Opin. Chem. Biol.13, 235-244 (2009); L. Ducry and B. Stump,Bioconjugate Chem.21, 5-13 (2010)]. Thus, WO2012/171020 describes ADCs in which a plurality of toxophore molecules are attached via a polymeric linker to an antibody. As possible toxophores, WO2012/171020 mentions, among others, the substances SB 743921, SB 715992 (Ispinesib), MK-0371, AZD8477, AZ3146 and ARRY-520.

The substances mentioned last are kinesin spindle protein inhibitors. Kinesin spindle protein (KSP, also known as Eg5, HsEg5, KNSL1 or KIF11) is a kinesin-like motorprotein which is essential for the bipolar mitotic spindle to function. Inhibition of KSP leads to mitotic arrest and, over a relatively long term, to apoptosis (Tao et al., Cancer Cell 2005 Jul. 8(1), 39-59). After the discovery of the first cell-penetrating KSP inhibitor, Monastrol, KSP inhibitors have established themselves as a class of novel chemotherapeutics (Mayer et al., Science 286: 971-974, 1999), and they are subject matter of a number of patent applications (e.g. WO2006/044825; WO2006/002236; WO2005/051922; WO2006/060737; WO03/060064; WO03/040979; and WO03/049527). However, since KSP is active only during a relatively short period of time during the mitosis phase, KSP inhibitors have to be present in a sufficiently high concentration during this phase. WO2014/151030 discloses ADCs including certain KSP inhibitors.

Further ADCs with KSP inhibitors have been disclosed in the patent applications WO2015/096982 and WO2016/096610.

SUMMARY OF THE INVENTION

Despite various disclosures of antibody-drug conjugates, it is an object of the present invention to provide substances which, after administration at a relatively low concentration, exhibit long-lasting apoptotic action and may therefore be of benefit for cancer therapy. Here, the profile of the metabolites released intracellularly from the ADCs plays an important role. Frequently, the metabolites formed from ADCs are substrates of efflux pumps and/or have high cell membrane permeability. Both phenomena may contribute to a short residence time and thus suboptimal apoptotic action in the tumour cell.

The present invention provides ADCs having a specific toxophor linker composition which in particular have an improved activity profile both in association with a specific anti-CD123 antibody and with an anti-CXCR5 antibody.

The antibody is preferably a humanized or chimeric monoclonal anti-CD123 antibody or an anti-CXCR5 antibody. Particular preference is given to the humanized anti-CD123 antibodies TPP-8987, TPP-8988 and TPP-9476 and to the humanized or chimeric anti-CXCR5 antibodies TPP-9024, TPP-9574 and TPP-9580.

It has now been found that antibody-drug conjugates (ADCs) of the formula (I)


in whichn represents 1 to 8,AK represents an anti-CD123 antibody selected from the group consisting of TPP-8987, TPP-9476 and TPP-8988orAK represents an anti-CXCR5 antibody, preferably selected from the group consisting of TPP-9574, TPP-9580 and TPP-9024,orAK represents an antigen-binding fragment of these antibodies,
where the antibody or the antigen-binding fragment is attached via a sulfur atom of a cysteine side group,
and their salts, solvates and salts of these solvates, have superior properties compared to the known conjugates.

Preference is given to those antibody-drug conjugates (ADCs) of the formula (I), in which n represents 4 to 8.

Preference is given to those antibody-drug conjugates (ADCs) of the formula (I), in which AK represents an anti-CD123 antibody selected from the group consisting of TPP-8987, TPP-9476 and TPP-8988 and an antigen-binding fragment of these antibodies; particularly preferably AK represents TPP-9476, and an antigen-binding fragment of this antibody.

