Anthracycline-based antibody drug conjugates having high in vivo tolerability
Inventors
Grawunder, Ulf • Beerli, Roger • GEBLEUX, Remy
Assignees
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Publication Number
US-12121527-B2
Publication Date
2024-10-22
Expiration Date
Abstract
The present invention relates to antibody drug conjugates (ADCs) presenting improved properties of in vivo tolerability.
Core Innovation
The invention relates to an antibody drug conjugate in which an anthracycline-based small molecule is exclusively linked to the light chain constant region C-terminus of an antibody, antibody fragment, or antibody derivative retaining target binding properties. The anthracycline-based small molecule comprises the structure of formula (i), and the exclusive light-chain C-terminal linkage is achieved via a linker comprising a peptidic sequence.
A central aspect of the invention is the use of a peptidic linker for site-specific conjugation at the light chain constant region C-terminus, rather than linkage to heavy-chain constant region C-termini. The disclosed concepts emphasize improved in vivo tolerability and therapeutic index compared with comparable ADCs in which the same anthracycline is attached to heavy-chain C-termini or to both heavy- and light-chain C-termini.
The invention is further characterized by tumor-associated antigen targeting using antibodies retaining target binding properties that target antigens including ROR1, HER2, CS1, ROR2, and mesothelin. The document provides example results indicating markedly lower mortality in mouse models for light-chain-linked anthracycline ADCs at equivalent doses, while maintaining comparable or antigen-mediated in vitro cytotoxicity.
Claims Coverage
Independent claim clm-00001 defines the overall ADC architecture, including exclusive light-chain C-terminus linkage of an anthracycline-based small molecule through a peptidic sequence linker and, in the two-light-chain embodiment, two anthracycline molecules linked to two light-chain C-termini.
Exclusive anthracycline attachment to light chain constant region C-terminus
The anthracycline-based small molecule is exclusively linked to the light chain constant region C-terminus of the antibody, antibody fragment or antibody derivative retaining target binding properties.
Peptidic-sequence linker linking anthracycline to light chain C-terminus
The anthracycline-based small molecule is linked, via a linker comprising a peptidic sequence, to the antibody, antibody fragment or antibody derivative retaining target binding properties.
Anthracycline structure of formula (i)
The anthracycline-based small molecule comprises the structure of formula (i).
Two light-chain C-termini and two exclusively linked anthracycline molecules
The ADC comprises two light chain constant region C-termini and two anthracycline-based small molecules, wherein the anthracycline-based small molecules are each exclusively linked to the light chain constant region C-termini of the antibody, antibody fragment, or antibody derivative.
Across the explicitly provided independent claim, the inventive coverage centers on ADCs where an anthracycline-based small molecule (formula (i)) is exclusively attached to the light chain constant region C-terminus via a peptidic-sequence linker, including embodiments with two light-chain C-termini carrying two anthracycline molecules.
Stated Advantages
Improved in vivo tolerability.
Improved therapeutic index.
Stability compared with comparable ADCs having the anthracycline attached to heavy-chain C-termini or to both heavy- and light-chain C-termini.
Markedly lower mortality in mouse models at equivalent doses for light-chain-linked anthracycline ADCs.
Documented Applications
Therapeutic use through targeting tumor-associated antigens using antibodies retaining target binding properties, including targeting ROR1, HER2, CS1, ROR2, and mesothelin.
Treatment of neoplastic diseases, with an example described for breast cancer.
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