Anti-SIRPα antibodies
Inventors
Verheijden, Gijsbertus Franciscus Maria • ROUWENDAL, Gerard • ARENDS, Roland Jan • van den Berg, Timo Kars • MATLUNG, Hanke Lottie • FRANKE, Katarina
Assignees
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Publication Number
US-11274159-B2
Publication Date
2022-03-15
Expiration Date
Abstract
The present invention relates to antibodies against SIRPα that are suitable for use in anti-cancer therapy. The invention further relates to the use of the anti-SIRPα antibodies in the treatment of human solid tumours and haematological malignancies, optionally in combination with other anti-cancer therapeutics. The anti-SIRPalpha antibodies described are more specific than known anti-SIRPalpha antibodies, whereas they show excellent affinity for both SIRPalpha1 and SIRPalphaBIT. In one embodiment the anti-SIRPalpha antibodies do not bind to SIRPgamma. In a second embodiment, the anti-SIRPalpha antibodies do not bind to SIRPgamma and do not bind to SIRPbeta1v1. In a third embodiment, the anti-SIRPalpha antibodies do not bind to SIRPgamma and do not bind to SIRPeta1v2. In a fourth embodiment, the anti-SIRPalpha antibodies do not bind to SIRPbeta1v1.
Core Innovation
The invention relates to anti-SIRPα antagonistic antibodies for anti-cancer therapy that comprise heavy chain and light chain variable region complementarity determining regions (CDRs) selected from specific combinations of CDR1, CDR2, and CDR3 amino acid sequences, with the CDRs determined according to Kabat numbering. The disclosed CDR combinations are defined by enumerated sequence identifiers corresponding to particular heavy-chain and light-chain CDR sequence pairings.
A central specificity feature is binding preference toward two predominant polymorphic variants, SIRPαBIT and SIRPα1, while avoiding binding to SIRPγ. In embodiments, additional avoidance is described for other SIRPα variants such as SIRPα1v1 or SIRPα1v2, linking the variable-region CDR selection to the stated variant specificity.
The invention further provides optional Fc engineering aimed at reducing binding to human activating Fc receptors. This is described as using specified IgG Fc amino-acid substitutions in a human IgG1 Fc region, with positions referenced in Eu numbering, and is connected to functional outcomes including increased ADCC/ADCP of co-administered therapeutic antibodies.
Claims Coverage
The independent claim contains one independently claim (clm-00001). It defines an anti-SIRPα antibody or antigen-binding fragment through Kabat-numbered heavy-chain and light-chain CDR selections from multiple enumerated SEQ ID NO pairings, specifying the allowed CDR1/CDR2/CDR3 sequence sets. Dependent coverage adds immunoglobulin format constraints, additional variable-region selection details, and specified human IgG1 Fc modifications, as well as formulation scope via pharmaceutical compositions with excipients.
Kabat-numbered paired CDR selection for anti-SIRPα binding
An anti-SIRPα antibody or antigen-binding fragment comprising heavy chain and light chain variable region CDRs selected from the group consisting of CDR1, CDR2 and CDR3 amino acid sequences of specified SEQ ID NO pairings, wherein the CDRs are determined according to Kabat numbering.
Chimeric, humanized, or human antibody framework limitation
The anti-SIRPα antibody is chimeric, humanized, or human.
Humanized antibody with selected HCVR/LCVR CDR sequence combinations
A humanized antibody includes HCVR and LCVR CDRs whose CDR1, CDR2, and CDR3 amino acid sequences are selected from specified SEQ ID NO combinations.
Modified human IgG1 Fc region with specified amino-acid substitutions
A modified anti-SIRPα antibody includes a modified human IgG1 Fc region with one or more specified amino acid substitutions at positions selected from L234, L235, G237, D265, D270, N297, A327, P328, and P329 (Eu numbering).
Specific Fc substitution combinations
An anti-SIRPα antibody includes specified amino acid substitution combinations comprising L234A and L235A, or L234E and L235A, or L234A, L235A and P329A, or L234A, L235A and P329G.
Pharmaceutical composition with pharmaceutically acceptable excipients
A pharmaceutical composition includes the anti-SIRPα antibody together with one or more pharmaceutically acceptable excipients.
Overall claim coverage is centered on Kabat-numbered CDR selection for anti-SIRPα antibodies using predefined SEQ ID NO CDR pairings, with dependent claim refinement covering antibody format, humanized variable-region constraints, and human IgG1 Fc modifications using defined substitution positions or substitution combinations. The dependent coverage also includes pharmaceutical compositions containing excipients.
Stated Advantages
Increased ADCC/ADCP of co-administered therapeutic antibodies.
Avoids binding to SIRPγ.
Documented Applications
Anti-cancer therapy, including solid tumors and hematological malignancies.
Use in solid tumors including AML, renal cell carcinoma, and melanoma.
Combination-treatment use with therapeutic antibodies, linked to increased ADCC/ADCP.
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