Tumor tissue-penetrating peptide specific to neuropilin and fusion protein having same peptide fused therein
Inventors
Kim, Yong Sung • Shin, Tae Hwan • KIM, Yae Jin • SUNG, Eun Sil
Assignees
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Publication Number
US-9975933-B2
Publication Date
2018-05-22
Expiration Date
Abstract
A tumor tissue-penetrating peptide specifically binding to neuropilin, or a fusion protein, a small molecule drug, a nanoparticle, or a liposome having the peptide fused therein is provided, as well as a method for preparing the same and a pharmaceutical composition comprising the same for treating, diagnosing, or preventing cancer or angiogenesis-related diseases. The tumor tissue-penetrating peptide is fused to the C-terminus of an anticancer antibody heavy-chain constant region (Fc) and the fused antibody specifically binds to neuropilin, and specifically accumulates in tumor tissue, widens intercellular gaps between tumor vascular endothelial cells, promotes extravasation, increases infiltration within tumor tissue, and shows a remarkably increased in vivo tumor-suppressing activity. Furthermore, the tumor tissue-penetrating peptide is fused into a fusion protein and inhibits the angiogenic function of neuropilin coreceptors resulting from targeting of neuropilin, and is expected to have an alleviating effect on angiogenesis-related diseases.
Core Innovation
The invention provides a tumor tissue-penetrating peptide that specifically binds neuropilin (NRP1/NRP2). The peptide is based on semaphorin-3A and semaphorin-3F-derived basic C-terminal sequences and is defined by amino acid sequences selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 4 and related sequence sets disclosed in the document.
Mutant affinity-enhanced peptide variants and linker-containing variants are fused to the C-terminus of an antibody Fc to create a bivalent Fc-TPP. The bivalent binding to neuropilin is stated to increase tumor accumulation and extravasation by widening endothelial intercellular gaps, and the fusion format is further stated to enhance tumor infiltration and inhibit neuropilin-mediated angiogenesis.
The document contrasts fusion constructs with single peptides, stating that single peptides alone do not induce the same signaling and/or permeability effects. Fusion constructs are exemplified as Fc-TPP and antibody fusion examples including Cetuximab-TPP and Trastuzumab-TPP, with reported preservation of antibody properties such as antigen binding and FcRn/FcγR binding.
Claims Coverage
The document contains two independent claims. One claim defines the neuropilin-binding tumor tissue-penetrating peptide by selected amino acid sequences, and the other claim defines a polynucleotide encoding selected peptide sequences.
Neuropilin-binding tumor tissue-penetrating peptide sequences
A tumor tissue-penetrating peptide specifically binding to neuropilin, represented by the amino acid sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 4.
Polynucleotide encoding selected peptide sequences
A polynucleotide coding a peptide represented by an amino acid sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 10.
Across the independent claims, the inventive scope centers on neuropilin-specific tumor tissue-penetrating peptides defined by SEQ ID sequence selections and polynucleotides encoding peptides represented by SEQ ID sequence selections.
Stated Advantages
Increased tumor accumulation and extravasation by widening endothelial intercellular gaps.
Enhanced tumor infiltration.
Inhibition of neuropilin-mediated angiogenesis.
Preservation of antibody properties, including antigen binding and FcRn/FcγR binding.
Single peptides alone do not induce the same signaling/permeability effects, supporting the advantage of the fusion constructs.
Enhanced in vivo infiltration and tumor suppression are reported in the document.
Documented Applications
Treating, preventing, or diagnosing cancer or angiogenesis-related diseases using a composition comprising the peptide of claim 1.
Diagnostic imaging using fluorescent labels.
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