Inhibitors of aortic carboxypeptidase-like protein (ACLP)
Inventors
Layne, Matthew D. • TUMELTY, Kathleen E. • LAFYATIS, Robert
Assignees
Publication Number
US-12139542-B2
Publication Date
2024-11-12
Expiration Date
2035-05-27
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Abstract
The present invention generally relates to the field of treatment of fibroproliferative diseases and disorders and cancer. Embodiments of the present invention generally relate to compostions, methods and kits comprising an inhibitor of a portion of the N-terminal pro-fibrotic domain (PFD) of Aortic Carboxypeptidase-Like Protein (ACLP), and in some embodiments, in combination with an inhibitor of the discoidin (DS) domain of ACLP, for use in methods for the treatment of fibroproliferative diseases and cancer, and inhibition of ACLP-mediated activation of a member of the TGFβ receptor superfamily.
Core Innovation
The invention provides compositions, methods, and kits comprising an inhibitor of a portion of the N-terminal pro-fibrotic domain (PFD) of the Aortic Carboxypeptidase-Like Protein (ACLP), and in some embodiments, in combination with an inhibitor of the discoidin (DS) domain of ACLP, for use in methods for the treatment of fibroproliferative diseases and cancer. The inhibitors may be peptides or blocking antibodies generated against the N-terminal PFD and/or DS domain. Specifically, the PFD comprises a series of thrombospondin-like (Tsp) motifs, and inhibition of one or more of these motifs can inhibit TGFβ signaling.
The problem addressed by the invention is that effective therapies are lacking for fibroproliferative diseases such as systemic sclerosis, fibrosis, and certain cancers, due to incomplete understanding of the key molecules and pathways responsible for fibrosis and stromal activation. ACLP has been identified as highly expressed in fibrotic tissues and cancer stroma, correlating with poor outcomes and disease severity. However, which region of ACLP was responsible for mediating pro-fibrotic activity or TGFβRII signaling had not previously been determined.
This invention surprisingly discovered that the N-terminal pro-fibrotic domain (PFD) of ACLP, particularly the Tsp2 motif containing a unique 11-amino acid sequence repeated four times, is both necessary and sufficient for activating TGFβ signaling and stimulating myofibroblast differentiation and extracellular matrix production. Inhibition of the PFD, alone or in tandem with an inhibitor of the DS domain (which can potentiate TGFβ signaling in the presence of collagen), is capable of blocking ACLP-mediated pro-fibrotic and pro-cancerous activities. The disclosed inhibitors can be peptides, antibodies, or decoys designed to specifically disrupt these interactions.
The invention is particularly advantageous in that inhibitors targeting the unique PFD motifs of ACLP do not interfere with the beneficial functions of TGFβ or unrelated thrombospondin motifs, and act specifically at sites of injury, fibrosis, or cancer. Thus, this strategy offers a targeted approach to treat fibrosis and certain cancers by interrupting ACLP-specific molecular mechanisms that drive disease progression.
Claims Coverage
The independent claims define the inventive features directed to compositions and kits comprising specific peptides corresponding to defined regions of the ACLP protein: the N-terminal pro-fibrotic domain (PFD, including Tsp motifs such as SEQ ID NO: 3 and SEQ ID NO: 4) and the discoidin (DS) domain (amino acids 384-539 of SEQ ID NO: 1 or defined loop regions).
Admixture of specific ACLP PFD- and DS-domain peptides
An admixture comprising: - A first peptide containing at least 5 consecutive amino acids of SEQ ID NO: 3 or SEQ ID NO: 4 and having at least 85% identity to these sequences (corresponding to the Tsp motif(s) in the PFD of ACLP). - A second peptide comprising at least 5 consecutive amino acid residues of amino acids 384–539 of SEQ ID NO: 1 (covering the DS domain of ACLP), where the second peptide can include sequences from specific loop regions (e.g., MLRHGLG (SEQ ID NO: 12), QTGATEDDYYDGA (SEQ ID NO: 13), DARTQ (SEQ ID NO: 14), or RDSSIHDD (SEQ ID NO: 15)) or any of an enumerated set of short peptides from the DS domain (SEQ ID NO: 12–47). The claim further permits the first or second peptide, or both, to be fused to an Fc region comprising the amino acid sequence of SEQ ID NO: 48 or a variant with at least 85% identity.
Kit containing separate ACLP PFD- and DS-domain peptides
A kit comprising: - A first container with a first peptide comprising at least 5 consecutive amino acids of SEQ ID NO: 3 or SEQ ID NO: 4 and having at least 85% sequence identity to those sequences. - A second container with a second peptide comprising at least 5 consecutive amino acids of amino acids 384–539 of SEQ ID NO:1, which may include specific loop regions as described above or one or more peptides from SEQ ID NO: 12–47. Both peptides may optionally be fused to an Fc region (SEQ ID NO: 48 or fragment thereof), may be in lyophilized form, contain a detectable label, or be conjugated to an anti-cancer agent.
In summary, the claims protect admixtures and kits comprising defined peptides from distinct regions (PFD and DS) of the ACLP protein, encompassing specific sequence identities and optional modifications (such as Fc-fusion or labeling), for use in treating fibroproliferative diseases and cancers with a fibrotic core.
Stated Advantages
Inhibitors targeting the unique PFD motifs of ACLP do not interfere with beneficial TGFβ function or with other proteins containing thrombospondin motifs, providing specific inhibition of ACLP-related pathology.
The approach allows for targeted treatment at sites of injury, fibrosis, or cancer, resulting in minimal non-specific side effects or impact on normal tissues.
The specificity of the inhibitors to the unique Tsp motifs in the ACLP PFD allows for reduced or prevented fibrosis and effective treatment of fibrotic diseases and cancers, including those with a fibrotic core.
Combination of PFD and DS domain inhibitors provides a synergistic effect, enhancing inhibition of ACLP-mediated pro-fibrotic and pro-cancer activities, particularly in the presence of collagen.
Documented Applications
Treatment of fibroproliferative diseases and disorders, including systemic sclerosis (SSc), fibrosis, solid organ fibrosis, and scleroderma.
Treatment of fibrosis or fibroproliferative disorders of the lung, heart, liver, kidney, or vasculature.
Treatment of fibroproliferative disorders including membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, diabetic nephrology, or lupus nephritis.
Treatment of cancer, including solid cancers with a fibrotic core, cancers of epithelial origin, cancers undergoing epithelial to mesenchymal transition (EMT), and breast cancer (including Her2+ breast cancer) or sarcoma.
Methods to reduce cancer progression by administering inhibitors of the PFD of ACLP, alone or in combination with discoidin domain inhibitors.
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