EP-4741423-A2 - ANTIBODY-DRUG CONJUGATES AND THEIR USES

Abstract

The present invention relates to antibody-drug conjugates, wherein the antibody specifically binds to folate receptor α, and wherein the drug is preferably chosen among a cytotoxic drug. Such antibody-drug conjugates are useful in particular in treating proliferative diseases including cancers, such as ovarian, breast and non-small cell lung cancers.

Inventors

• VIRICEL, Warren

Assignees

• Mablink Bioscience

Dates

Publication Date

20260513

Application Date

20230310

Claims (5)

1. An antibody-drug conjugate of formula (VII): wherein Ab is an anti-FRα antibody comprising a heavy chain polypeptide of SEQ ID NO:9 and a light chain polypeptide of SEQ ID NO:10 and p is from 6 to 8.
2. The antibody-drug conjugate of claim 1, wherein p is 8.
3. A pharmaceutical composition comprising the antibody-drug conjugate according to claim 1 or 2, in combination with one or more pharmaceutically acceptable excipients, diluents or carriers.
4. The antibody-drug conjugate according to any one of claims 1 or 2 or the pharmaceutical composition according to claim 3 for use in the treatment of a cancer in a subject in need thereof.
5. The antibody-drug conjugate or pharmaceutical composition for use according to claim 4, wherein the cancer is selected from the group consisting of ovarian cancer, triple negative breast cancer, non-small cell lung cancer or mesothelioma.

Description

Technical field It is hereafter disclosed antibody-drug conjugates, wherein the antibody specifically binds to folate receptor alpha (FRα), and wherein the drug is preferably chosen among inhibitors of topoisomerase I, for example camptothecine analogues such as exatecan. Such antibody-drug conjugates are useful in particular in treating proliferative diseases including cancers, such as ovarian cancer, breast cancer or lung cancer. Background Antibody-drug conjugates (hereafter referred as "ADCs") are a new class of therapeutics, notably cancer therapeutics. Such ADCs comprise at least an antibody and a payload (e.g. a cytotoxic drug), both covalently bonded by a linker. ADCs are therefore designed to combine the specificity of antibody target with the efficiency of the payload (e.g. the cytotoxic activity of a chemotherapeutic agent). Efficient ADCs should exhibit high specificity and low systemic toxicity. Within the context of toxicity, antibody used in ADCs needs to bind accurately and efficiency to its antigen, meaning that the suitable target antigen is preferentially or exclusively expressed on targeted cells. When designing an ADC, there is a need to covalently attach the final active drug to the ligand targeting unit, while allowing the final release of the active drug unit by a selective enzymatic mechanism after cellular internalization, or in the diseased tissue microenvironment. In this regard, several peptidase- and glycosidase-sensitive cleavable linker chemical strategies (associated with self-immolative chemistries) were developed. These cleavable linkers and their corresponding cleavage mechanisms are well known and have been described in several publications (e.g. Bargh JG et al., Chem. Soc. Rev., 2019, 48, 4361, Toki et al. J. Org. Chem. 2002, 67, 6, 1866-1872, Scott et al. Bioconjugate Chem. 2006, 17, 3, 831-840). The choice of this enzyme-sensitive cleavable entity is a critical design attribute of the ADC, impacting efficacy and tolerability of the conjugate. Examples of linker types that have been used to conjugate a cytotoxin or a drug to an antibody include, but are not limited to, hydrazones, thioethers, esters, disulfides and peptide-containing linkers. Linkers are for example chosen among those susceptible to cleavage by low pH within the lysosomal compartment or susceptible to cleavage by proteases, such as proteases preferentially expressed in tumor tissue, for example cathepsins (e.g. cathepsins B, C, D). Efficient linker can ensure an accurate and timely release of the payload. Within the context of toxicity, it also appears that the stability of the linker can impact the toxicity exerted by the payload, even if the linker itself does not appear to drive toxicity. Indeed, a stable linker can release the payload in a target-specific manner whereas a not-stable linker is more likely to undergo a non-accurate release of the payload (for example due to a non-specific cleavage), leading to a non-specific systemic toxicity. Payloads used in ADCs are highly potent, often cytotoxic drugs having in vitro inhibitory concentrations in the picomolar range. Common payloads are for example microtubule inhibitors (such as maytansine derivatives (DM1/DM4), auristatins (MMAE/MMAF), eribulin) and DNA alkylators (such as calicheamicin, pyrrolobenzodiazepines, indolinobenzodiazepines, or duocarmycins). Although ADCs appear to be promising therapeutics, some ADC can be too toxic, which limit the therapeutic window of these compounds or prevent further clinical development. Furthermore, most of the ADCs that are currently approved or under clinical investigation are based on microtubule- and DNA-targeting agents as cited above. As such, there is a need for new differentiated ADCs based on payloads having other mechanism of action, in order to efficiently treat tumors that are or become resistant to microtubule- and DNA-targeting agents. Efficient ADCs exhibiting high specificity, maximum efficiency and low toxicity require therefore an appropriate combination of each of its components. For a review of possible strategies, see for example Khongorzul et al 2019 (Molecular cancer research, DOI: 10.1158/1541-7786.MCR-19-0582). WO2019081455 and Conilh et al (2021, Pharmaceuticals, 14(3), 247) further report HER2-targeting antibody-drug conjugate, in particular based on the topoisomerase I inhibitor payload Exatecan, and using a hydrophilic monodisperse polysarcosine (PSAR) drug-linker platform. Cheng et al (2018, DOI: 10/1158/1535-7163.MCT-17-1215) and WO2017151979 reports ADCs with farletuzumab conjugated to typically 3 to 4 molecules of eribulin (MORAb-202) and its use in treating tumors. The mechanism of action of the eribulin payload of this ADC is microtubule inhibition. Moore et al (2018, Future Oncol. 14(17) 1669-1678) report the results of a phase III study with the ADC mirvetuximab soravtansine, comprising mirvetuximab, a humanized anti-FRα antibody, conjugated with an average of 3 to 4 mayta