Trail r2-specific multimeric scaffolds
AssigneeMedImmune, LLC
InventorsManuel Baca, Thomas Thisted, Jeffrey Swers, David Tice
Life of this patent
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Abstract
The present invention provides Tenascin-3 FnIII domain-based multimeric scaffolds that specifically bind to TRAIL Receptor 2 (TRAIL R2), a cell membrane receptor involved in apoptosis. The invention further provides engineered variants with increased affinity for the target, increased stability, and reduced immunogenicity. Furthermore, the present invention is related to engineered multivalent scaffolds as prophylactic, diagnostic, or therapeutic agents, and their uses against diseases caused by cells expressing TRAIL R2, in particular to a therapeutic use against cancer.
Claims50
A TRAIL R2-specific recombinant multimeric scaffold comprising at least two Tn3 monomer scaffolds, wherein
- (a) each Tn3 monomer scaffold comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG,
- (b) the Tn3 monomer scaffolds are connected in tandem, and
- (c) the recombinant multimeric scaffold specifically binds to TRAIL R2.
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A TRAIL R2-specific recombinant multimeric scaffold comprising at least two Tn3 monomer scaffolds, wherein
- (a) each Tn3 monomer scaffold comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG,
- (b) the Tn3 monomer scaffolds are connected in tandem, and
- (c) the recombinant multimeric scaffold specifically binds to TRAIL R2;
- wherein at least two Tn3 monomer scaffolds comprise the amino acid sequence:
- IEV(XAB)nALITW(XBC)nCELX1YGI(XCD)nTTIX2L(XDE)nYSI(XEF)nYEVSLIC(XFG)nKX3TFTT
- wherein XAB, XBC, XCD, XDE, XEF, and XFG represent the amino acid residues present in the AB, BC, CD, DE, EF, and FG loops, respectively, wherein X1 represents amino acid residue A or T, wherein X2 represents amino acid residue D or G, wherein X3 represents amino acid E or G, and wherein the length of the loop n is an integer between 2 and 26.
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An isolated nucleic acid molecule encoding the multimeric scaffold comprising SEQ ID NO. 167.
Dependencies are inferred from the claim text.