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-10758556-B2
Publication Date
2020-09-01
Expiration Date
Abstract
The present invention relates to antibody drug conjugates (ADCs) presenting improved properties of in vivo tolerability.
Core Innovation
The patent describes antibody drug conjugates (ADCs) that retain target binding properties and include an antibody, antibody fragment, or derivative comprising at least one light chain constant region C-terminus. Each ADC includes at least one anthracycline-based small molecule that is exclusively linked to the light chain constant region C-terminus of the antibody, antibody fragment, or derivative, and the linkage is made via a linker comprising a peptidic sequence.
In the disclosed ADCs, the antibody or antibody fragment is specified to bind human ROR1. In one example scope, the antibody or antibody fragment comprises CDRs, based on Kabat numbering, of hu4-2-17, including HC CDR1, HC CDR2, HC CDR3, and LC CDR1, LC CDR2, and LC CDR3. In another scope, the antibody or antibody fragment or derivative comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 4 and a light chain comprising the amino acid sequence of SEQ ID NO: 5, and binds human ROR1.
The document further defines the anthracycline-conjugation architecture as dependent on a peptidic sequence linker, including GGGGSLPQTGG (SEQ ID NO: 32). It reports improved in vivo tolerability relative to comparable ADCs with anthracycline linked to heavy chain C-termini or to both heavy and light C-termini at equivalent toxin loads, while maintaining largely comparable efficacy.
The disclosed solution is motivated by the problem of developing anthracycline-based ADCs with improved tolerability, therapeutic index, and stability, while preserving target binding and cell killing or tumor growth efficacy. The patent also covers pharmaceutical compositions and medical uses for treating neoplastic diseases and immune disorders.
Claims Coverage
The provided material includes two independent ADC claims. Across these, the inventive scope centers on exclusive light-chain C-terminus conjugation of an anthracycline-based small molecule via a peptidic sequence linker, including ROR1-binding antibody specifications and defined linker sequence refinements.
Exclusive light-chain C-terminus anthracycline conjugation via peptidic linker
An ADC including an antibody, antibody fragment, or derivative comprising at least one light chain constant region C-terminus, and at least one anthracycline-based small molecule exclusively linked to at least one light chain constant region C-terminus of the antibody, antibody fragment, or derivative, wherein the linkage is through a linker comprising a peptidic sequence.
ROR1-binding hu4-2-17 CDR-defined antibody with peptidic linker anthracycline linkage
The ADC of claim 1 wherein the antibody, antibody fragment, or derivative comprises the CDRs, based on Kabat numbering, of hu4-2-17 and binds to human ROR1, with the anthracycline-based small molecule linked via a linker comprising a peptidic sequence.
Specified heavy- and light-chain sequences with exclusive light-chain peptidic linker anthracycline
An ADC wherein the antibody, antibody fragment, or derivative comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 4 and a light chain comprising the amino acid sequence of SEQ ID NO: 5, binds to human ROR1, and the anthracycline-based small molecule is exclusively linked, via a linker comprising a peptidic sequence, to at least one light chain constant region C-terminus.
Defined peptidic linker sequence GGGGSLPQTGG
The ADC wherein the peptidic sequence of the linker is GGGGSLPQTGG (SEQ ID NO: 32).
Overall, the claim coverage emphasizes exclusive anthracycline attachment to the antibody light chain constant region C-terminus via a peptidic sequence linker, paired with ROR1-binding antibody definitions and a defined peptidic linker sequence (GGGGSLPQTGG, SEQ ID NO: 32).
Stated Advantages
Improved in vivo tolerability versus comparable ADCs with anthracycline linked to heavy chain C-termini or to both heavy and light C-termini at equivalent toxin loads.
Efficacy is largely comparable, while tolerability and stability advantages favor light-chain conjugation.
Improved therapeutic profile supported by tolerability and mortality data and in vitro cell killing comparisons.
Documented Applications
Treating neoplastic disease in a human subject with human ROR1 expression by administering a therapeutically effective amount of an antibody drug conjugate.
Treating neoplastic disease associated with elevated expression of human ROR1.
Treating HER2-positive breast cancer as a neoplastic disease application within the described treatment methods.
Treating neoplastic disease associated with human ROR1 expression using an antibody drug conjugate disclosed in the document.
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