Antitumor peptide derived from a complementarity determining region of a humanized monoclonal antibody to NaPi2B transporter
Inventors
Travassos, Luiz Rodolpho Raja Gabaglia
Assignees
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Publication Number
US-9193797-B2
Publication Date
2015-11-24
Expiration Date
Abstract
Described herein is novel isolated or synthetic peptides derived from a complementarity determining region hypervariable domain amino acid sequence of a humanized monoclonal antibody to NaPi2B transporter, as well as derivatives thereof, and a pharmaceutical composition and a method for inhibiting tumor growth or treating a tumor or cancer treating using the antitumor peptides and derivatives thereof.
Core Innovation
The invention relates to antitumor peptides derived from the complementarity determining region (CDR) H3 hypervariable region of the humanized NaPi2B-targeting monoclonal antibody RebMab200 (huMX35), including peptides identified by SEQ ID NOS and multiple derivative forms, such as D-amino acid substitutions, alanine-scan variants, and scramble controls. The described peptides show biological effects associated with antitumor activity, including increased tumor cell adhesion in a dose-dependent manner and inhibition of cell migration and invasion.
The document reports inhibition of invasion using Matrigel transwell invasion and includes evaluation of metastatic lung colonization in a murine melanoma model, with partial cell-line specificity. The invention also addresses stability and degradability of at least one peptide in plasma, with reported plasma half-life and degradation timeline.
The document further reports observations such as mild cytotoxicity in at least one leukemia cell line, inactivity against some tumor types, and in vivo observations including toxicity and hemolysis.
Claims Coverage
The independent claim defines a pharmaceutical composition that includes an antitumor peptide selected from a specified set of SEQ ID NOS together with a pharmaceutically acceptable carrier or diluent, i.e., two inventive aspects: the specific antitumor peptide set and formulation with a pharmaceutically acceptable carrier/diluent. Dependent claims further refine peptide structure for listed peptides and specify administration forms and carrier/excipient component categories.
Selected antitumor peptide set with pharmaceutically acceptable carrier
A pharmaceutical composition comprising an antitumor peptide selected from the group consisting of SEQ ID NOS: 3, 8, 9, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, and 33, and a pharmaceutically acceptable carrier or diluent.
Cyclic peptide structural constraint for SEQ ID NO: 8
An isolated or synthetic antitumor peptide where the peptide of SEQ ID NO: 8 is cyclic.
Specified administration dosage-form types
A pharmaceutical composition formulated in one of several administration forms including solid and non-solid dosage forms.
Parenteral, intradermal, or subcutaneous formulation with sterile diluents and functional additives
A pharmaceutical composition for parenteral, intradermal, or subcutaneous administration that includes sterile diluents and additional components including an antibacterial agent, an antioxidant, a chelating agent, and a buffering agent.
Injection/intravenous formulation with selected carrier and fluidity/isotonicity/antimicrobial additive categories
A pharmaceutical injection/intravenous composition that includes a selected carrier and additives for maintaining fluidity coating, providing antibacterial/antifungal activity, and ensuring isotonicity.
Oral formulation with inert diluents/edible carriers and extensive excipient set including biodegradable polymer
A pharmaceutical composition for oral administration that includes inert diluents or edible carriers and formulation excipients including binders, excipients, sugars, gums, disintegrants, lubricants, glidants, sweetening and flavoring agents, and a biodegradable polymer.
Overall, the claim coverage centers on pharmaceutical compositions that use an explicitly listed set of antitumor peptides combined with a pharmaceutically acceptable carrier or diluent, with dependent refinements covering specific structural constraints for SEQ ID NO: 8 and formulation details across multiple administration routes and dosage forms.
Stated Advantages
Increases tumor cell adhesion in a dose-dependent manner.
Inhibits cell migration and invasion.
Protects against metastatic lung colonization in a murine melanoma model.
Provides plasma stability/degradation characteristics for at least one peptide, including reported half-life and degradation by a defined timepoint.
Provides pharmaceutical composition and administration framework using pharmaceutically acceptable carriers, diluents, and dosage forms for treating cancer.
Documented Applications
Using the peptides to protect against metastatic lung colonization in a murine melanoma model.
Using the peptides to inhibit tumor growth or treat cancer via administration of an effective amount.
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