Polypeptide comprising aggrecan binding domain and carrying moiety
Inventors
Kitamura, Hidetomo • HOSHINO, Maiko • Sun, Yang • Kuramochi, Taichi • TU, Wenjie • Igawa, Tomoyuki • Hironiwa, Naoka • Noguchi, Yuki
Assignees
Chugai Pharmaceutical Co Ltd • Chugai Pharmabody Research Pte Ltd
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Publication Number
US-12077577-B2
Publication Date
2024-09-03
Expiration Date
Abstract
The present invention provides a polypeptide comprising an antigen binding domain which binds to an antigen present in cartilage tissue, and also provides use of the polypeptide. The polypeptide of the invention is useful for penetrating and/or retaining a desired substance in the cartilage tissue for a long period. The present invention further relates to a polypeptide comprising (i) an antigen binding domain which binds to a molecule in a cartilage tissue, and (ii) a carrying moiety having an inhibiting domain that inhibits the antigen binding activity of the antigen binding domain, and having a longer half-life than that of the antigen binding domain existing alone, and a pharmaceutical composition comprising the polypeptide. The present invention further relates to methods for producing and screening for the polypeptide.
Core Innovation
The invention provides an aggrecan-binding polypeptide in which an aggrecan-binding domain is linked by a peptide linker to a carrying moiety. The aggrecan-binding domain is defined by complementarity determining regions comprising specified VH and VL sequences associated with SEQ ID NO: 512/513, 514/515, 516/517, or 510/511, and the aggrecan-binding domain has a molecular weight of 120 kDa or smaller. The carrying moiety comprises an antibody constant region.
The peptide linker comprises a protease cleavage site, creating a protease-activated polypeptide in which antigen-binding activity is inhibited in circulation and restored after protease cleavage in disease tissue. The protease cleavage site is aligned with aggrecan protease biology and includes ADAMTS4, ADAMTS5, and MMP-13 cleavage sites.
The document further describes anti-Aggrecan antibody variants and derivatives, including IgG, Fab, F(ab’)2, Fab, and VHH formats. It also describes selection and screening of binding domains and fusion polypeptide libraries in which inhibitable antigen-binding activity is produced and restored upon cleavage by the chosen proteases.
Claims Coverage
The claim coverage includes two independent claim sets and two main inventive feature clusters. One cluster is a protease-cleavable aggrecan-binding polypeptide with a carrying moiety comprising an antibody constant region, and the other is an anti-Aggrecan antibody or antigen-binding domain defined by specified VH/VL complementarity determining regions.
Protease-cleavable aggrecan-binding polypeptide with limited domain size
A polypeptide comprising an aggrecan-binding domain linked by a peptide linker to a carrying moiety, wherein the aggrecan-binding domain has a molecular weight of 120 kDa or smaller and comprises complementarity determining regions of VH and VL sequences corresponding to SEQ ID NO: 512/513, 514/515, 516/517, or 510/511.
Protease cleavage in the linker and antibody-constant-region carrying moiety
The peptide linker comprises a protease cleavage site, and the carrying moiety comprises an antibody constant region.
CDR-defined anti-Aggrecan antibody or antigen-binding domain
An anti-Aggrecan antibody or antigen-binding domain thereof comprising the complementarity determining regions of VH and VL sequences corresponding to SEQ ID NO: 512/513, 514/515, 516/517, or 510/511.
Overall, the claim scope is anchored in aggrecan-binding specificity defined by discrete VH/VL complementarity determining region sequence sets, combined with a peptide linker containing a protease cleavage site and an antibody constant region carrying moiety.
Stated Advantages
Deep penetration and long retention in cartilage tissue.
Inhibition of antigen-binding activity in circulation to address adverse reactions.
Restoration of antigen-binding activity after protease cleavage in disease tissue.
Reduced antigen-binding domain size is used to address high-molecular-weight limitations of conventional antibodies.
Smaller formats such as Fab and VHH are described as providing cartilage penetration and retention advantages.
The protease-activated design concept is described as reducing systemic binding or exposure while enabling local antigen-binding activity release upon protease cleavage.
Documented Applications
Treatment of an aggrecan-associated disease or disorder by administering a therapeutically effective amount of the polypeptide or antibody as defined.
Reducing cartilage degradation in an individual with osteoarthritis by administering the polypeptide as defined.
Prevention or treatment of aggrecan-mediated disease or disorder and osteoarthritis.
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