JP-2026514252-A - Antibody-drug conjugates using a novel linker-payload system to enhance the targeting of cancer-related antigens.

Abstract

An antibody-drug conjugate (ADC) is provided, comprising an antibody conjugated to a drug via a linker, which is bound to a glycan terminated with sialyl Tn (STn) or alpha-2,6-linked sialic acid, wherein the linker comprises a cleavable linker, and the drug comprises a growth inhibitor which is exatecan, deruxtecan, or a derivative thereof. The antibody-drug conjugate (ADC) of the present invention comprises a linker which is cleavable with glucuronidase, for example, the linker which comprises a β-glucuronide moiety such as that shown in Formula I. The antibody-drug conjugate (ADC) comprises a linker which is bound to the drug via a carbamate linkage or is modified to be bound to the drug, or a linker which is bound to the drug via a quaternary ammonium salt linkage or is modified to be bound to the drug. The antibody-drug conjugate (ADC) may comprise a linker which is PEG-modified with a group containing polyethylene glycol (PEG). Novel linkers for use in ADCs are also described. [Chemical formula 1]

Inventors

• ベルナルデス ゴンサロ
• ラモス ヌノ プレゴ
• ナターレ マリアンジェラ

Assignees

• バイオンテック・エスイー

Dates

Publication Date

20260507

Application Date

20240502

Priority Date

20230505

Claims (20)

1. An antibody-drug conjugate (ADC) comprising an antibody conjugated to a drug via a linker, wherein the antibody binds to a glycan terminated with sialyl Tn (STn) or alpha-2,6-linked sialic acid, the linker comprises a linker cleavable by glucuronidase, and the drug comprises a growth inhibitor.
2. The antibody-drug conjugate (ADC) according to claim 1, wherein the linker comprises a β-glucuronide moiety.
3. Linker, equation I': Equation (I') The formula includes the β-glucuronide moiety shown in [wherein X is NH, N- CH3 , or CF2 ], The antibody-drug conjugate (ADC) according to claim 1 or 2.
4. The linker, Equation I: Equation (I) An antibody-drug conjugate (ADC) according to claim 1, 2, or 3, comprising the β-glucuronide moiety shown in [reference].
5. The antibody-drug conjugate (ADC) according to any one of claims 1 to 4, wherein the linker is conjugated to the drug via a carbamate bond, or modified to be conjugated thereto.
6. The antibody-drug conjugate (ADC) according to any one of claims 1 to 4, wherein the linker is conjugated to the drug via a quaternary ammonia bond, or modified to be conjugated via a quaternary ammonia bond.
7. The antibody-drug conjugate (ADC) according to any one of claims 1 to 6, wherein the linker is PEG-modified with a group containing polyethylene glycol (PEG).
8. The antibody-drug conjugate (ADC) according to claim 7, wherein the linker comprises a β-glucuronide moiety PEG-modified with a group containing polyethylene glycol (PEG).
9. The linker has the following structure: An antibody-drug conjugate (ADC) according to claim 7 or 8, which is PEGylated with a group containing polyethylene glycol (PEG) based on the formula [wherein n is 1 to 5].
10. The antibody-drug conjugate (ADC) according to claim 9, wherein n is 2 to 4.
11. The antibody-drug conjugate (ADC) according to claim 10, wherein n is 3.
12. An antibody-drug conjugate (ADC) formed by conjugating a drug to the antibody described in claim 1 using a linker, wherein the linker is a group of formula II: The antibody-drug conjugate (ADC) is as described above.
13. An antibody-drug conjugate (ADC) comprising the antibody according to claim 1, conjugated to a drug via a linker, wherein the linker is a base of formula IIA: Formula (IIA) The antibody-drug conjugate (ADC) comprising the above.
14. An antibody-drug conjugate (ADC) comprising the antibody according to claim 1, conjugated to a drug via a linker, wherein the linker is of formula IIIA': Formula IIIA' The antibody-drug conjugate (ADC) is the group shown in [wherein X is NH, N- CH3 , or CF2 ].
15. An antibody-drug conjugate (ADC) comprising the antibody according to claim 1, conjugated to a drug via a linker, wherein the linker is of formula IIIA: Formula (IIIA) The antibody-drug conjugate (ADC) is the group shown in [reference].
16. An antibody-drug conjugate (ADC) formed by conjugating a drug to the antibody described in claim 1 using a linker, wherein the linker is of formula III: The antibody-drug conjugate (ADC) is as shown in [reference].
17. An antibody-drug conjugate (ADC) comprising the antibody according to claim 1, conjugated to a drug via a linker, wherein the linker is of formula IVA': Formula IVA' The antibody-drug conjugate (ADC) as shown in [wherein X is NH, N- CH3 , or CF2 ].
18. An antibody-drug conjugate (ADC) comprising the antibody according to claim 1, conjugated to a drug via a linker, wherein the linker is of formula IVA: Formula (IVA) The antibody-drug conjugate (ADC) is as shown in [reference].
19. An antibody-drug conjugate (ADC) formed by conjugating a drug to the antibody described in claim 1 using a linker, wherein the linker is of formula IV: The antibody-drug conjugate (ADC) is as shown in [reference].
20. An antibody-drug conjugate (ADC) comprising the antibody according to claim 1, conjugated to a drug via a linker, wherein the drug-linker portion of the ADC is of formula VA': Formula VA' The antibody-drug conjugate (ADC) as shown in [wherein X is NH, N- CH3 , or CF2 ].

Description

This invention relates to the development of novel antibody-drug conjugates (ADCs) using monoclonal antibodies, functional antibody fragments thereof, or probes thereof, that are specific to a group of antigens, including but not limited to, sialyl Tn (STn) antigens, which are very common in various types of cancer. Such ADCs utilize the use of exatecan-based constructs, with particular emphasis on two different types of beta-glucuronide linkers, to target tumor antigens and leverage the bystander effect observed with other exatecan-based ADCs, such as trastuzumab deruxtecan, as described in International Publication No. 2022/048883. Furthermore, this invention encompasses potential applications in human and animal health, expanding the scope of its therapeutic utility. Sialyl Tn (STn) antigen is a cleaved O-glycan structure that plays a crucial role in various types of cancer. STn, a disaccharide, consists of sialic acid (Neu5Acα) bonded to N-acetylgalactosamine (GalNAc) in a 2,6 configuration, forming an O-glycosidic bond between the GalNAc residue and either a serine or threonine amino acid residue within the polypeptide chain. Julian, Videira, & Delannoy (2012) reported that the presence of this cleaved glycan has been detected at varying frequencies in different cancer types. Notably, STn is not found in normal, healthy tissue, highlighting its importance as a target for cancer therapy. STn has been identified as a crucial factor in metastasis, drug resistance, and high-grade tumors, and exhibits several distinctive characteristics that make it a promising target for cancer treatment. 1. Association with Early-Stage and Metastatic Cancer Cells: STn expression has been linked to early-stage cancer and metastatic cancer cells, and has been shown to play a role in tumor progression and dissemination to other parts of the body (Okasaki et al., 2012). This association highlights the potential of STn-targeted therapy to inhibit cancer progression and metastasis. 2. Correlation with poor prognosis and reduced overall survival: Increased STn expression in patients is correlated with poor prognosis, reduced overall survival, and poor response to chemotherapy (Choi et al., 2000). This correlation suggests that STn may play a role in promoting tumor invasiveness and treatment resistance, making it an attractive target for the development of novel cancer therapies. 3. Evasion of Immune Surveillance: STn has been suggested to be involved in evading immune cell surveillance, contributing to the tumor's ability to evade detection and elimination by the immune system (Carrascal et al., 2014). Novel cancer therapies targeting STn may overcome this immune evasion mechanism and thus enhance the immune system's ability to recognize and eliminate tumor cells. 4. Antibody-Drug Conjugates (ADCs) in Cancer Therapy: ADCs are a type of therapeutic agent that combines the target specificity of antibodies with the cytotoxic efficacy of small molecule drugs. This targeted approach helps maximize the destruction of cancer cells while minimizing the impact on healthy tissue. ADCs are emerging as a promising strategy in cancer treatment, with several already approved for clinical use and many more in clinical development (Chari et al., 2014; Sievers & Senter, 2013). 5. STn-Targeted ADCs: Several efforts are underway to develop STn-targeted ADCs for cancer therapy, including the development of ADCs using humanized anti-STn antibodies conjugated to cytotoxic drugs such as the mytansinoid DM1 (SYL-001) (Li et al., 2018). However, there is still room for improvement in STn-targeted ADCs, including the development of novel linker-payload systems that provide better stability, more efficient drug release, and improved therapeutic efficacy. 6. Exatecan Linker-Payload System: Exatecan is a water-soluble topoisomerase I inhibitor that has shown potent antitumor activity in preclinical models and clinical trials (Kummar et al., 2006). Recently, exatecan derivatives have been explored as payloads for ADCs (e.g., DS-8201, a HER2-targeted ADC with an exatecan derivative as a payload) (Doi et al., 2017). The exatecan linker-payload system has demonstrated desirable characteristics such as high efficacy, improved stability, and efficient drug release in the tumor microenvironment, making it attractive for ADC development. Prendergast et al. mAbs 2017, 9(4), 615-627 describes novel anti-sialyl Tn monoclonal antibodies and ADCs containing them. The ADC-linker technology used is MC-vc-PAB-MMAE. The MMAE moiety is monomethyl auristatin, a growth inhibitory agent, and the MC-vc-PAB cleavable linker contains a maleimidocaproyl moiety, a valine-citrulline dipeptide moiety, and a p-aminobenzyloxycarbonyl moiety. This document also discloses further ADCs containing an MMAF moiety further containing a maleimidocaproyl moiety. However, none of the above linkers are cleavable with glucuronidase. Starbuck et al., Oncotarget, 2018, 9(33), 23289-23305, describes