Anti-CD74 antibody conjugates, compositions comprising anti-CD74 antibody conjugates and methods of using anti-CD74 antibody conjugates
Inventors
Stafford, Ryan • Yam, Alice • Gill, Avinash • Penta, Kalyani • Li, Xiaofan • Sato, Aaron
Assignees
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Publication Number
US-11708413-B2
Publication Date
2023-07-25
Expiration Date
Abstract
Provided herein are antibody conjugates with binding specificity for CD74 and compositions comprising the antibody conjugates, including pharmaceutical compositions, methods of producing the conjugates, and methods of using the conjugates and compositions for therapy.
Core Innovation
The invention provides an antibody conjugate comprising an antibody that specifically binds to CD74 linked site-specifically to at least one payload moiety directly or via a linker. The antibody incorporates a non-natural amino acid at a specified heavy-chain or light-chain site for covalent payload attachment. In addition, the antibody comprises heavy-chain and light-chain CDRs from specified VH-VL region pairings, and the conjugate conforms to formulas 101a-104b.
Conjugation chemistries utilize non-natural amino acids bearing reactive groups such as azide, alkyne, carbonyl, hydrazine, and aminooxy groups to form triazole-containing heterocycles, sulfur linkages, or oxime linkages. Linker architectures include release-trigger, eliminator, hydrophilic PEG, and spacer groups connecting cytotoxic or polymer payloads. The resulting conjugates selectively target and kill CD74-positive B-lymphoma, myeloma, and leukemia cells while sparing cells lacking detectable CD74 binding.
Claims Coverage
The provided claims identify one independent claim directed to a site-specifically linked CD74-binding antibody conjugate comprising five inventive features.
CD74-specific antibody binding
The antibody conjugate comprises an antibody that specifically binds to CD74.
Non-natural amino acid attachment site
The antibody comprises a non-natural amino acid positioned at a site selected from specified heavy-chain and light-chain positions.
Site-specific payload attachment
At least one payload moiety is covalently linked to the non-natural amino acid residue, directly or via a linker.
Specified antibody variable-region pairings
The antibody comprises three heavy-chain CDRs and three light-chain CDRs of a specified VH-VL region pairing.
Defined conjugate structure
The conjugate is according to one of formulas 101a-104b, wherein COMP is the non-natural amino acid residue of the antibody and PAY is a payload moiety.
The independent claim defines the conjugate by integrating CD74-specific binding, incorporation of a non-natural amino acid at a specified position, direct or linker-mediated payload attachment, specified VH-VL region pairings, and defined conjugate formulas.
Stated Advantages
The anti-CD74 conjugates kill CD74-positive B-lymphoma, myeloma, and leukemia cells, while cells lacking detectable CD74 binding are not killed.
In reported mouse models, Conjugate A reduces myeloma burden, inhibits lymphoma tumor growth, and demonstrates survival through the observation period with no detectable bone-marrow hCD138+ cells in the MM.1S model compared with vehicle.
In the SU-DHL-6 lymphoma model, tumor-growth inhibition occurs without significant body-weight toxicity.
Documented Applications
Therapeutic, diagnostic, and analytical uses of anti-CD74 antibody conjugates, including targeting CD74-expressing cancers and other disease conditions.
Treatment of CD74-expressing cancer by administering an effective amount of the antibody conjugate.
Evaluation against B-lymphoma, myeloma, and leukemia cells, as well as in mouse models of ARP-1 and MM.1S myeloma and SU-DHL-6 lymphoma.
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