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Publication Number
US-12180295-B2
Publication Date
2024-12-31
Expiration Date
Abstract
The present invention relates to humanized antibodies against SIRPα that are suitable for use in anti-cancer therapy. The invention further relates to the use of the humanized anti-SIRPα antibodies in the treatment of human solid tumours and haematological malignancies, optionally in combination with further anti-cancer therapeutics.
Core Innovation
The invention relates to a humanized anti-SIRPα antibody, or an antigen-binding fragment thereof, comprising defined heavy chain complementarity determining regions and light chain complementarity determining regions. The antibody is characterized by specific HCDR/LCDR sequence assignments, including HCDR1 comprising SEQ ID NO:36, HCDR2 comprising SEQ ID NO:44, HCDR3 comprising SEQ ID NO:45, LCDR1 comprising SEQ ID NO:39, LCDR2 comprising SEQ ID NO:40, and LCDR3 comprising SEQ ID NO:41.
The disclosed antibodies are characterized by binding selectivity for human SIRPα variants, including SIRPαBIT, and low or no binding to SIRPγ and SIRPβ variants. The antibodies block the CD47-SIRPα interaction and antagonize SIRPαBIT/CD47-driven signaling, including SHP-1 recruitment signaling and SHP-1/SHP-2 signaling reduction.
The invention also addresses immune effector behavior through Fc-region engineering, with modified human IgG1 Fc regions containing specified amino acid substitutions at Eu-numbered positions. Reduced binding to activating human FcγR/FcαR is described in combination contexts to enhance ADCC/ADCP when used with therapeutic antibodies, while avoiding the Kurlander effect.
Claims Coverage
The claim coverage centers on a humanized anti-SIRPα antibody or antigen-binding fragment defined by a specific HCDR/LCDR sequence set. The inventive features also include binding and specificity properties, modified human IgG1 Fc region substitutions, a pharmaceutical composition, and cancer treatment co-administration with a therapeutic antibody. The claim set includes 6 inventive features.
Defined humanized antibody CDR sequence set
A humanized anti-SIRPα antibody or antigen-binding fragment thereof comprising HCDR1 SEQ ID NO:36, HCDR2 SEQ ID NO:44, HCDR3 SEQ ID NO:45, LCDR1 SEQ ID NO:39, LCDR2 SEQ ID NO:40, and LCDR3 SEQ ID NO:41.
Binding and specificity/immunogenicity properties
Affinity to human SIRPα variants and cynomolgus monkey SIRPα, lack of binding to human SIRPγ, and lack of immunogenicity measured by IL-2 ELISpot and/or T-cell proliferation assay.
Modified human IgG1 Fc region with specified substitutions
A humanized anti-SIRPα antibody comprising a modified human IgG1 Fc region containing amino acid substitutions at specified Eu-numbered positions of a wild-type human IgG1 Fc region.
Specific Fc substitution sets at designated positions
A humanized anti-SIRPα antibody that includes specific amino acid substitution sets at designated positions.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition comprising a humanized anti-SIRPα antibody or an antigen-binding fragment together with a pharmaceutically acceptable excipient.
Cancer treatment with co-administration with a therapeutic antibody
A cancer-treatment method in which an effective amount of a humanized anti-SIRPα antibody or its antigen-binding fragment is co-administered with a therapeutic antibody to a patient having a human solid tumour or a hematological malignancy.
Overall, the claim coverage is directed to a humanized anti-SIRPα antibody defined by a specific HCDR/LCDR sequence set, further specified by binding/selectivity and immunogenicity properties, optionally narrowed by specified human IgG1 Fc substitutions, and extended to pharmaceutical composition and cancer-treatment co-administration contexts.
Stated Advantages
High-affinity binding to human SIRPα and SIRPαBIT variants.
No or low binding to SIRPγ (CD3+ T-cells).
Ability to block CD47-SIRPα interaction and reduce SIRPα signaling, including SHP-1/SHP-2 signaling reduction.
Low immunogenicity.
Fc engineering reduces binding to activating human FcγR/FcαR to avoid the Kurlander effect while enhancing ADCC/ADCP when combined with therapeutic antibodies.
Blocking CD47 binding.
Antagonizing SIRPαBIT/CD47-driven signaling, including inhibition of SHP-1 recruitment signaling.
Enhancing functional ADCC, including increased neutrophil ADCC with cancer-targeting monoclonal antibodies.
Not immunogenic in immunogenicity testing described as IL-2 ELISpot and proliferation assays.
Documented Applications
Anti-cancer therapy for human solid tumors.
Anti-cancer therapy for hematological malignancies.
Combination treatment by co-administration with a therapeutic antibody.
Characterized use in binding and selectivity profiling to SIRPα variants and SIRPγ, including effects on human T-cell binding.
Characterized use in CD47 blocking and inhibition of SHP-1 recruitment signaling driven by SIRPαBIT/CD47.
Characterized use in functional ADCC enhancement together with cancer-targeting monoclonal antibodies.
Immunogenicity testing described as IL-2 ELISpot and T-cell proliferation assays.
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