Single domain serum albumin binding protein
Inventors
Dubridge, Robert B. • LEMON, Bryan D. • Austin, Richard J. • Evnin, Luke • Guenot, Jeanmarie
Assignees
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Publication Number
US-11453716-B2
Publication Date
2022-09-27
Expiration Date
Abstract
Disclosed herein are single domain serum albumins binding proteins with improved thermal stability, binding affinities, and robust aggregation profiles. Also described are multispecific binding proteins comprising a single domain serum albumin binding protein according to the instant disclosure. Pharmaceutical compositions comprising the binding proteins disclosed herein and methods of using such formulations are provided.
Core Innovation
The invention relates to a multispecific protein that comprises a serum albumin binding domain, a target antigen binding domain, and a domain that binds to a protein within a T cell receptor complex (TCR). The serum albumin binding domain includes complementarity determining regions CDR1, CDR2, and CDR3 defined by specific amino-acid sequence patterns and SEQ ID NOs, including position-wise amino-acid allowances and restrictions that certain positions are not simultaneously specific amino acids.
The serum albumin binding domain is also defined in embodiments by sequence-identity constraints relative to a wild-type anti-HSA sequence and by enumerated CDR variants using specified SEQ ID NOs. The described serum albumin binding includes binding to human, cynomolgus, and mouse serum albumin with stated Kd ranges and cross-reactivity ratios, and the disclosure states improved elimination half-time.
In additional embodiments, the multispecific protein incorporates a TCR-complex binding domain and a target antigen binding domain associated with a tumor antigen expressed on tumor cells. The disclosure further describes pharmaceutical compositions, vectors, host cells, and therapeutic indications connected to the multispecific protein, and includes stability and developability concepts such as thermal stability assessment, aggregation/dimer propensity at low pH, and a D62E substitution in CDR2 to reduce isomerization potential without loss of affinity.
Claims Coverage
The provided independent claims are directed to a multispecific protein architecture combining serum albumin binding, target antigen binding, and TCR-complex binding, with inventive definition of the serum albumin binding domain through specified CDR sequence patterning and/or specific CDR variant constraints (including SEQ ID NO-based definitions, identity constraints, and residue-substitution restrictions).
Multispecific protein with serum albumin, target antigen, and TCR-complex binding domains
A multispecific protein comprising a serum albumin binding domain, a target antigen binding domain, and a domain that binds to a protein within a T cell receptor complex (TCR), wherein the serum albumin binding domain comprises complementarity determining regions CDR1, CDR2, and CDR3 defined by the specified amino acid sequence patterns and a restriction that the listed positions are not simultaneously threonine, phenylalanine, serine, serine, serine, aspartic acid, aspartic acid, valine, serine, and arginine, respectively.
Serum albumin CDRs defined as wild-type anti-HSA with defined CDR residue substitutions
A multispecific protein wherein the serum albumin binding domain comprises complementarity determining regions CDR1, CDR2, and CDR3 within the sequence set forth as SEQ ID NO. 10 (wt anti-HSA), wherein one or more amino acid residues selected from specified amino acid positions 28, 29, 30, or 31 of CDR1; positions 56, 57, 62, or 64 of CDR2; and positions 103, and 104 of CDR3 are substituted with the specified allowed amino-acid substitutions.
Serum albumin CDRs with mutations relative to specified SEQ ID NOs and excluded mutation positions
A multispecific protein wherein the serum albumin protein comprises at least one mutation in CDR1, CDR2 or CDR3, wherein CDR1 has the sequence as set forth is SEQ ID NO:11, CDR2 has the sequence as set forth in SEQ ID NO:12, CDR3 has the sequence as set forth in SEQ ID NO:13, and wherein the at least one mutation is not in amino acid positions 1, 2, 7, 8, 9, or 10 of SEQ ID NO:11, positions 1, 3, 6, 10, or 11 of SEQ ID NO:12, or positions 1 or 2 of SEQ ID NO:13.
Across the independent claims, coverage centers on multispecific proteins that combine a serum albumin binding domain, a target antigen binding domain, and a TCR-complex binding domain, while the serum albumin binding domain is constrained through SEQ ID NO-defined CDR patterns and allowed substitution or mutation rules, including identity reference to wt anti-HSA and explicit exclusions of mutation positions.
Stated Advantages
Improved elimination half-time.
Documented Applications
Therapeutic indications for the multispecific protein are described.
Tumor antigen binding where the target antigen is expressed on tumor cells is described.
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