Humanized CC chemokine receptor 4 (CCR4) antibodies and methods of use thereof
Inventors
Marasco, Wayne A. • Zhu, Quan • Chang, De-Kuan
Assignees
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Publication Number
US-12337034-B2
Publication Date
2025-06-24
Expiration Date
Abstract
The present invention provides humanized monoclonal antibodies, bi-specific antibodies, antibody conjugates, and fusion proteins that bind to the chemokine receptor CCR4. This antibody is derived from CCR4-IgG1 and recognizes the same epitope. This antibody contains either an IgG4 or a stabilized IgG4 in order to improve binding efficiency and reduce in vivo Fab arm exchange. Binding of the antibodies disclosed herein to CCR4 inhibits ligand-mediated activities and is used to treat symptoms of cancer.
Core Innovation
The invention relates to humanized anti-CCR4 monoclonal antibodies that bind the human CC chemokine receptor 4 (CCR4) and comprise an IgG4 heavy chain constant region. The antibodies are defined by specified heavy- and light-chain CDR amino acid sequences and include alternative heavy-chain CDR sets paired with alternative light-chain CDR sets. The antibody further comprises a bispecific antibody that immunospecifically binds to a second antigen.
The antibodies use an IgG4 Fc format designed to reduce in vivo Fab-arm exchange by employing a stabilized IgG4 hinge variant. The invention inhibits ligand-mediated CCR4 activity associated with CCR4/CCL17/CCL22 signaling. In this way, the invention modulates cancer immunity by blocking CCR4/CCL17/CCL22-driven Treg recruitment without depleting T-cell populations.
The invention further describes functional outcomes comparing IgG4 to IgG1 formats, including loss of depletion activity and inhibition of Treg chemoattraction in vitro and in vivo. The antibodies are associated with restoration or augmentation of effector T-cell responses, including increased proliferation and IFN-b3 with reduced Treg suppression. The document also describes reduced tumor size in xenograft models and provides therapeutic formats including bispecific antibody formats, antibody conjugates, and fusion proteins for CCR4-expressing cancers.
Claims Coverage
The document includes two independent claims (clm-00001 and clm-00026) with additional dependent claims refining the antibody and nucleic acid embodiments. The independent claim set defines an IgG4 humanized anti-CCR4 bispecific monoclonal antibody with specified CDR sequence sets and nucleic acids containing specific SEQ ID NO combinations, optionally including additional SEQ ID NOs.
Humanized IgG4 anti-CCR4 bispecific monoclonal antibody with defined CDR sequence sets
An isolated humanized monoclonal antibody that binds human CCR4 and has an IgG4 heavy chain constant region, where the antibody comprises specified heavy-chain CDR1/CDR2/CDR3 amino acid sequences and specified light-chain CDR1/CDR2/CDR3 amino acid sequences, and further comprises a bispecific antibody that immunospecifically binds to a second antigen.
Nucleic acid encoding defined sequence sets
A nucleic acid comprising the nucleic acid sequence of SEQ ID NO: 15 and SEQ ID NO: 17, or SEQ ID NO: 27 and SEQ ID NO: 29; wherein the nucleic acid further comprises SEQ ID NO: 5 or SEQ ID NO: 7.
Across the independent claims, the coverage centers on an IgG4 humanized anti-CCR4 bispecific monoclonal antibody with specified CDR sequences and on nucleic acids containing specified SEQ ID NO combinations that correspond to the antibody embodiments.
Stated Advantages
Reduces in vivo Fab-arm exchange by using a stabilized IgG4 hinge variant.
Inhibits ligand-mediated CCR4 activity.
Modulates cancer immunity by blocking CCR4/CCL17/CCL22-driven Treg recruitment without depleting T-cell populations.
IgG4 loss of depletion activity versus IgG1.
Inhibits Treg chemoattraction in vitro and in vivo (including dose dependence).
Restores or augments effector T-cell responses, including increased proliferation and IFN-b3 with reduced Treg suppression.
Reduces tumor size in xenograft models.
Documented Applications
Therapeutic use in CCR4-expressing cancers, including CTCL (mycosis fungoides/Sezary syndrome), primary cutaneous ALCL, ATLL, and solid tumors such as renal cell carcinoma.
Bispecific antibody formats and related therapeutic constructs targeting CCR4 together with a second antigen including CA-IX, ErbB2, HVEM, PD-L1, GITR, IL21/IL21R, CD160, TIM3, or LAG3, and related immunomodulatory use cases described in the document.
Methods described for inhibiting regulatory T-cell (Treg) migration in a subject by administering the CCR4-binding IgG4 bispecific antibody.
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