Mesothelin binding proteins
Inventors
Wesche, Holger • LEMON, Bryan D. • Austin, Richard J. • Dubridge, Robert B.
Assignees
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Publication Number
US-11607453-B2
Publication Date
2023-03-21
Expiration Date
Abstract
Disclosed herein are MSLN binding proteins with improved binding affinities and improved ability to mediate T cell dependent killing of cancer cells expressing mesothelin. Pharmaceutical compositions comprising the binding proteins disclosed herein and methods of using such formulations are further provided.
Core Innovation
The invention relates to single domain mesothelin binding proteins that comprise defined sequences and a defined domain framework/CDR structure. The proteins include single domain mesothelin binding protein sequences selected from specified SEQ ID numbers and proteins comprising SEQ ID No: 31. The described structure follows a framework/CDR arrangement designated f1-r1-f2-r2-f3-r3-f4, where r1 is CDR1, r2 is CDR2, and r3 is CDR3, and f1, f2, f3 and f4 are framework residues.
The single domain mesothelin binding proteins are specified with multiple alternative CDR1/CDR2/CDR3 amino-acid sequence combinations. The protein sequences further define mesothelin epitopes located in mesothelin regions I, II, and/or III, including epitopes located in regions I (296-390), II (391-486), and/or III (487-598) of the mesothelin sequence. Conserved-region substitutions and humanization are described in connection with the single domain mesothelin binding proteins.
The invention additionally provides related molecules for tumor targeting that selectively bind mesothelin-expressing cells and mediate T cell dependent cytotoxicity. The described tumor targeting use includes mesothelin-targeting trispecific constructs that direct T cells from multiple donors to kill mesothelin-positive ovarian cancer and mesothelioma cells, while not killing mesothelin-negative controls. The described functional readouts include T cell dependent cellular cytotoxicity killing and measurements such as TNF-α secretion and CD69 upregulation, with binding characterized as membrane-preferential binding versus soluble mesothelin.
Claims Coverage
The provided independent claims (three) cover the identity and structure of single domain mesothelin binding proteins, including specific sequence selections and defined framework/CDR compositions.
Single domain mesothelin binding protein comprising SEQ ID No: 31
A single domain mesothelin binding protein wherein said protein comprises SEQ ID No: 31.
Single domain mesothelin binding protein with selected SEQ ID sequences
A single domain mesothelin binding protein wherein said protein comprises a sequence selected from the group consisting of SEQ ID Nos: 1-16, 18-25 and 28-29.
Single domain mesothelin binding protein with defined f1-r1-f2-r2-f3-r3-f4 CDR framework and alternative CDR combinations
A single domain mesothelin binding protein comprising the formula f1-r1-f2-r2-f3-r3-f4, wherein r1 is CDR1, r2 is CDR2, and r3 is CDR3, and wherein f1, f2, f3 and f4 are framework residues, wherein CDR1, CDR2, and CDR3 comprise one of several specified amino-acid sequence sets (i) through (vii).
Overall, the claim coverage in the provided independent claims focuses on specified single-domain mesothelin-binding protein sequences (including SEQ ID No: 31 and selected SEQ ID ranges) and on a defined f1-r1-f2-r2-f3-r3-f4 framework with multiple alternative CDR1/CDR2/CDR3 amino-acid combinations.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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