TRAIL receptor-2 polypeptides and antibodies Number:7,521,048 from the United States Patent and Trademark Office (PTO) owispatent

Title: TRAIL receptor-2 polypeptides and antibodies

Abstract: Polypeptides are provided. Antibodies or antigen binding domains are provided which bind such polypeptides. Also provided are methods of obtaining an antibody that binds tumor necrosis factor (TNF)-related apoptosis-inducing ligand ("TRAIL") Receptor-2 (TR-2) comprising administering at least one of such polypeptides to an animal and obtaining an antibody that binds TR-2 from the animal. Antibodies reactive with TR-2 are provided. Also provided are cells producing antibodies reactive with TR-2, pharmaceutical compositions comprising antibodies reactive with TR-2, methods using antibodies reactive with TR-2, and kits comprising antibodies reactive with TR-2. Also provided are methods of decreasing or preventing binding of an antibody to TR-2 by administering such a polypeptide.

Patent Number: 7,521,048 Issued on 04/21/2009 to Gliniak,   et al.

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Inventors:	Gliniak; Brian (Seattle, WA), Yang; Xiao-Dong (Palo Alto, CA), Wong-Madden; Sharon (Bellevue, WA), Foltz; Ian (Burnaby, CA), Feng; Xiao (The Woodlands, TX), Fitch; Alison (Vancouver, CA), Foster; Stephen (Newbury Park, CA), Ketchem; Randal R. (Snohomish, WA)
Assignee:	Amgen Inc. (Thousand Oaks, CA)
Appl. No.:	11/512,051
Filed:	August 28, 2006

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Related U.S. Patent Documents

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	Application Number	Filing Date	Patent Number	Issue Date
	60713478	Aug., 2005
	60713433	Aug., 2005

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Current U.S. Class:	424/133.1 ; 530/388.22
Current International Class:	C12P 21/08 (20060101); A61K 39/00 (20060101)
Field of Search:	424/133.1

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References Cited [Referenced By]

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5627052	May 1997	Schrader
5763223	June 1998	Wiley et al.
6313269	November 2001	Deen et al.
6342363	January 2002	Ni et al.
6342369	January 2002	Ashkenazi
6417328	July 2002	Alnemri
6433147	August 2002	Ni et al.
6461823	October 2002	Ni et al.
6872568	March 2005	Ni et al.
2001/0010924	August 2001	Deen et al.
2002/0048785	April 2002	Holtzman
2002/0072091	June 2002	Ni et al.
2002/0098550	July 2002	Ni et al.
2002/0150985	October 2002	Adams et al.
2002/0161202	October 2002	Ashkenazi et al.
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2007/0004910	January 2007	Sexton et al.
2007/0217997	September 2007	Devy et al.

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	WO 99/09165		Feb., 1999		WO
	WO 99/11791		Mar., 1999		WO
	WO 99/12963		Mar., 1999		WO
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Primary Examiner: Blanchard; David J.
Assistant Examiner: Bristol; Lynn
Attorney, Agent or Firm: Scarr; Rebecca B. Ran; David B.

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Parent Case Text

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This application claims the benefit of U.S. Provisional Application No. 60/713,433, filed Aug. 31, 2005, and U.S. Provisional Application No. 60/713,478, filed Aug. 31, 2005. U.S. Provisional Application Nos. 60/713,433 and 60/713,478 are incorporated by reference herein in their entirety for any purpose.

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Claims

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We claim:

1. An isolated antibody comprising a heavy chain and a light chain that binds TRAIL Receptor-2 (TR-2), wherein the heavy chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 2, and the light chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 36.

2. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 4 and the light chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 38.

3. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 6 and the light chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 40.

4. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 8 and the light chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 42.

5. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 10 and the light chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 44.

6. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 12 and the light chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 46.

7. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 14 and the light chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 48.

8. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 16 and the light chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 50.

9. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 18 and the light chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 52.

10. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 20 and the light chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 54.

11. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 22 and the light chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 56.

12. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 24 and the light chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 58.

13. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 26 and the light chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 60.

14. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 28 and the light chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 62.

15. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 30 and the light chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 64.

16. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 32 and the light chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 66.

17. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 34 and the light chain comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 68.

18. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 2, and the light chain comprises the amino acid sequence of SEQ ID NO: 36.

19. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 4 and the light chain comprises the amino acid sequence of SEQ ID NO: 38.

20. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 6 and the light chain comprises the amino acid sequence of SEQ ID NO: 40.

21. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 8 and the light chain comprises the amino acid sequence of SEQ ID NO: 42.

22. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 10 and the light chain comprises the amino acid sequence of SEQ ID NO: 44.

23. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 12 and the light chain comprises the amino acid sequence of SEQ ID NO: 46.

24. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 14 and the light chain comprises the amino acid sequence of SEQ ID NO: 48.

25. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 16 and the light chain comprises the amino acid sequence of SEQ ID NO: 50.

26. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 18 and the light chain comprises the amino acid sequence of SEQ ID NO: 52.

27. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 20 and the light chain comprises the amino acid sequence of SEQ ID NO: 54.

28. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 22 and the light chain comprises the amino acid sequence of SEQ ID NO: 56.

29. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 24 and the light chain comprises the amino acid sequence of SEQ ID NO: 58.

30. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 26 and the light chain comprises the amino acid sequence of SEQ ID NO: 60.

31. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 28 and the light chain comprises the amino acid sequence of SEQ ID NO: 62.

32. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises amino acid sequence of SEQ ID NO: 30 and the light chain comprises amino acid sequence of SEQ ID NO: 64.

33. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 32 and the light chain comprises the amino acid sequence of SEQ ID NO: 66.

34. An isolated antibody comprising a heavy chain and a light chain that binds TR-2, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 34 and the light chain comprises the amino acid sequence of SEQ ID NO: 68.

35. The isolated antibody of any of claims 1, 2, 9, 10, 15, 16, 17, 18, 19, 26, 27, 32, 33, and 34, wherein the antibody is a fully human antibody.

36. The isolated antibody of any of claims 1, 2, 9, 10, 15, 16, 17, 18, 19, 26, 27, 32, 33, and 34, wherein the antibody is a Fab, a Fab', a F(ab')2, an Fv, or a single-chain Fv.

37. A pharmaceutical composition comprising the isolated antibody of any of claims 1, 2, 9, 10, 15, 16, 17, 18, 19, 26, 27, 32, 33, and 34 a pharmaceutically acceptable carrier.

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Description

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FIELD

Polypeptides are provided. Antibodies or antigen binding domains are provided which bind such polypeptides. Also provided are methods of obtaining an antibody that binds tumor necrosis factor (TNF)-related apoptosis-inducing ligand ("TRAIL") Receptor-2 (TR-2) comprising administering at least one of such polypeptides to an animal and obtaining an antibody that binds TR-2 from the animal. Antibodies reactive with TR-2 are provided. Also provided are cells producing antibodies reactive with TR-2, pharmaceutical compositions comprising antibodies reactive with TR-2, methods using antibodies reactive with TR-2, and kits comprising antibodies reactive with TR-2. Also provided are methods of decreasing or preventing binding of an antibody to TR-2 by administering such a polypeptide.

BACKGROUND

The interaction between TR-2 and its ligand, TRAIL, plays a role in the induction of apoptosis (see, for example, Almasan et al., Cytokine & Growth Factor Reviews 14: 337-348 (2003)). TRAIL, also known as Apo2 ligand, is a homomeric ligand that interacts with four members of the TNF-receptor superfamily (TRAIL receptors ("TR") 1 to 4), as well as with the related, soluble, opsteoprotegerin ("OPG") receptor. Binding of TRAIL to TR-1 or TR-2 at the surface of a cell triggers apoptosis of that cell. After initial binding of TRAIL to TR-1 or TR-2, intracellular proteins are recruited to the intracellular death domain of the receptor, forming a signaling complex. Certain intracellular caspases are recruited to the complex; where they autoactivate and in turn activate additional caspases and the intracellular apoptosis cascade. TR-3 and TR-4 and OPG lack the intracellular domain responsible for transmitting the apoptosis signal. Thus, binding of TRAIL to TR-3, TR-4, or OPG does not trigger apoptosis. TR-3 and TR-4 are also referred to as "decoy" receptors, and their overexpression has been shown to protect cells from apoptotic induction by TRAIL. TR-2 is expressed in a variety of cells, including liver, brain, breast, kidney, colon, lung, spleen, thymus, peripheral blood lymphocytes, prostate, testis, ovary, uterus, and various tissues along the gastro-intestinal tract. (See, for example, Walczak et al., EMBO J. 16: 5386-5397 (1997); Spierings et al., J. Histochem. Cytochem. 52: 821-831 (2004)). Though TRAIL and TRAIL receptors are widely expressed, they are most active in inducing apoptosis in transformed cells. (See, for example, Daigle et al., Swiss Med. Wkly. 131: 231-237 (2001)).

SUMMARY

In certain embodiments, an isolated polypeptide is provided comprising at least one complementarity determining region (CDR) selected from CDR1a, CDR2a, and CDR3a: wherein CDR1a comprises the amino acid sequence a b c d e f g h i j k l, wherein amino acid a is glycine, amino acid b is selected from glycine, tyrosine, or phenylalanine; amino acid c is selected from serine or threonine; amino acid d is selected from isoleucine or phenylalanine; amino acid e is selected from serine, threonine, or asparagine; amino acid f is selected from serine, aspartic acid, tyrosine, asparagine, threonine, or glycine; amino acid g is selected from glycine, aspartic acid, or tyrosine; amino acid h is selected from glycine, aspartic acid, tyrosine, asparagine, or serine; amino acid i is selected from tyrosine, isoleucine, histidine, methionine, or tryptophan; amino acid j is selected from asparagine, tyrosine, histidine, serine, or phenylalanine; amino acid k is tryptophan or is not present; and amino acid l is serine or is not present; wherein CDR2a comprises the amino acid sequence m n o p q r s t u v w x y z a' b' c', wherein amino acid m is selected from tryptophan, tyrosine, histidine, valine, glutamic acid, or serine; amino acid n is selected from methionine or isoleucine; amino acid o is selected from asparagine, tyrosine, serine, tryptophan, or histidine; amino acid p is selected from proline, tyrosine, serine, arginine, histidine, or asparagine; amino acid q is selected from asparagine, serine, or aspartic acid; amino acid r is selected from serine or glycine; amino acid s is selected from aspartic acid, serine, threonine, or arginine; amino acid t is selected from asparagine, threonine, alanine, isoleucine, or tyrosine; amino acid u is selected from threonine, tyrosine, leucine, lysine, asparagine, or isoleucine; amino acid v is selected from glycine, tyrosine, aspartic acid, or cysteine; amino acid w is selected from tyrosine or asparagine; amino acid x is selected from alanine or proline; amino acid y is selected from glutamine, serine, or aspartic acid; amino acid z is selected from lysine, leucine, or serine; amino acid a' is selected from phenylalanine, lysine, or valine; amino acid b' is selected from glutamine, serine, or lysine; and amino acid c' is glycine or is not present; wherein CDR3a comprises the amino acid sequence d' e' f' g' h' i' j' k' l' m' n' o' p' q' r' s' t' u' v' w', wherein amino acid d' is selected from tryptophan, aspartic acid, glycine, serine, or glutamic acid; amino acid e' is selected from asparagine, aspartic acid, glycine, arginine, serine, valine, or leucine; amino acid f' is selected from histidine, serine, alanine, tyrosine, proline, asparagine, glycine or threonine; amino acid g' is selected from tyrosine, serine, alanine, arginine, tryptophan, glycine or valine; amino acid h' is selected from glycine, alanine, serine, asparagine, methionine, tyrosine, tryptophan, cysteine, or aspartic acid; amino acid i' is selected from serine, tryptophan, glycine, phenylalanine, aspartic acid, tyrosine, or threonine; amino acid j' is selected from glycine, threonine, serine, leucine, valine, asparagine, tryptophan, or tyrosine; amino acid k' is selected from serine, phenylalanine, aspartic acid, tryptophan, glycine, or tyrosine, or is not present; amino acid l' is selected from histidine, aspartic acid, alanine, tryptophan, tyrosine, serine, phenylalanine, valine, or glycine, or is not present; amino acid m' is selected from phenylalanine, tyrosine, glutamic acid, proline, aspartic acid, cysteine, isoleucine, or methionine, or is not present; amino acid n' is selected from aspartic acid, phenylalanine, alanine, leucine, or serine, or is not present; amino acid o' is selected from tyrosine, leucine, aspartic acid, phenylalanine, proline, or valine, or is not present; amino acid p' is selected from leucine, aspartic acid, or tyrosine, or is not present; amino acid q' is selected from serine or tyrosine, or is not present; amino acid r' is tyrosine or is not present; amino acid s' is selected from glycine or tyrosine, or is not present; amino acid t' is selected from glycine or methionine, or is not present; amino acid u' is selected from methionine or aspartic acid, or is not present; amino acid v' is selected from aspartic acid or valine, or is not present; and amino acid w' is valine or is not present; and wherein the polypeptide, in association with an antibody light chain, binds TRAIL receptor-2 (TR-2).

In certain embodiments, an isolated polypeptide is provided comprising at least one complementarity determining region (CDR) selected from: amino acids 26 to 35 of SEQ ID NO: 2; amino acids 50 to 66 of SEQ ID NO: 2; amino acids 99 to 110 of SEQ ID NO: 2; amino acids 26 to 37 of SEQ ID NO: 4; amino acids 52 to 67 of SEQ ID NO: 4; amino acids 100 to 109 of SEQ ID NO: 4; amino acids 26 to 37 of SEQ ID NO: 6; amino acids 52 to 67 of SEQ ID NO: 6; amino acids 100 to 109 of SEQ ID NO: 6; amino acids 26 to 37 of SEQ ID NO: 8; amino acids 52 to 67 of SEQ ID NO: 8; amino acids 100 to 109 of SEQ ID NO: 8; amino acids 26 to 35 of SEQ ID NO: 10; amino acids 50 to 66 of SEQ ID NO: 10; amino acids 99 to 110 of SEQ ID NO: 10; amino acids 26 to 35 of SEQ ID NO: 12; amino acids 50 to 66 of SEQ ID NO: 12; amino acids 99 to 111 of SEQ ID NO: 12; amino acids 26 to 35 of SEQ ID NO: 14; amino acids 50 to 65 of SEQ ID NO: 14; amino acids 98 to 111 of SEQ ID NO: 14; amino acids 26 to 37 of SEQ ID NO: 16; amino acids 52 to 67 of SEQ ID NO: 16; amino acids 100 to 109 of SEQ ID NO: 16; amino acids 26 to 35 of SEQ ID NO: 18; amino acids 50 to 66 of SEQ ID NO: 18; amino acids 99 to 105 of SEQ ID NO: 18; amino acids 26 to 35 of SEQ ID NO: 20; amino acids 50 to 66 of SEQ ID NO: 20; amino acids 99 to 118 of SEQ ID NO: 20; amino acids 26 to 35 of SEQ ID NO: 22; amino acids 50 to 66 of SEQ ID NO: 22; amino acids 99 to 118 of SEQ ID NO: 22; amino acids 26 to 35 of SEQ ID NO: 24; amino acids 50 to 65 of SEQ ID NO: 24; amino acids 98 to 108 of SEQ ID NO: 24; amino acids 26 to 35 of SEQ ID NO: 26; amino acids 50 to 66 of SEQ ID NO: 26; amino acids 99 to 110 of SEQ ID NO: 26; amino acids 26 to 35 of SEQ ID NO: 28; amino acids 50 to 66 of SEQ ID NO: 28; amino acids 99 to 117 of SEQ ID NO: 28; amino acids 26 to 37 of SEQ ID NO: 30; amino acids 52 to 67 of SEQ ID NO: 30; amino acids 100 to 111 of SEQ ID NO: 30; amino acids 26 to 37 of SEQ ID NO: 32; amino acids 52 to 67 of SEQ ID NO: 32; amino acids 100 to 111 of SEQ ID NO: 32; amino acids 26 to 37 of SEQ ID NO: 34; amino acids 52 to 67 of SEQ ID NO: 34; and amino acids 100 to 111 of SEQ ID NO: 34; wherein the polypeptide, in association with an antibody light chain, binds TR-2.

In certain embodiments, an isolated polypeptide is provided comprising at least one complementarity determining region (CDR) selected from CDR1b, CDR2b, and CDR3b: wherein CDR1b comprises the amino acid sequence a1 b1 c1 d1 e1 f1 g1 h1 i1 j1 k1 l1 m1 n1 o1 p1 q1, wherein amino acid a1 is selected from arginine or lysine; amino acid b1 is selected from threonine, alanine, or serine; amino acid c1 is serine; amino acid d1 is glutamine; amino acid e1 is selected from serine or glycine; amino acid f1 is selected from isoleucine, leucine, or valine; amino acid g1 is selected from serine, leucine, or arginine; amino acid h1 is selected from threonine, serine, isoleucine, asparagine, arginine, histidine, or tyrosine; amino acid i1 is selected from tyrosine, arginine, tryptophan, aspartic acid, or serine; j1 is selected from leucine, isoleucine, asparagine, tyrosine, or serine; amino acid k1 is selected from asparagine, glycine, valine, alanine, or leucine; amino acid l1 is selected from tyrosine, alanine, or asparagine, or is not present; amino acid m1 is selected from asparagine or lysine, or is not present; amino acid n1 is selected from tyrosine, asparagine, or isoleucine, or is not present; amino acid o1 is selected from leucine or tyrosine, or is not present; amino acid p1 is selected from aspartic acid or leucine, or is not present; and amino acid q1 is selected from valine, alanine, or threonine, or is not present; wherein CDR2b comprises the amino acid sequence r1 s1 t1 u1 v1 w1 x1, wherein amino acid r1 is selected from alanine, aspartic acid, leucine, tryptophan, glycine, or valine; amino acid s1 is selected from threonine, valine, glycine, or alanine; amino acid t1 is serine; amino acid u1 is selected from serine, asparagine, or threonine; amino acid v1 is selected from leucine, phenylalanine, or arginine; amino acid w1 is selected from glutamine, alanine, or glutamic acid; and amino acid x1 is selected from serine, arginine, or threonine; wherein CDR3b comprises the amino acid sequence y1 z1 a1' b1' c1' d1' e1' f1' g1', wherein amino acid y1 is selected from glutamine, methionine, leucine, or histidine; amino acid z1 is selected from glutamine or lysine; amino acid a1' is selected from serine, threonine, alanine, histidine, tyrosine, or phenylalanine; amino acid b1' is selected from tyrosine, leucine, asparagine, or glycine; amino acid c1' is selected from serine, glutamine, isoleucine, or lysine; amino acid d1' is selected from threonine, phenylalanine, tyrosine, alanine, or serine; amino acid e1' is proline; amino acid f1' is selected from leucine, phenylalanine, tryptophan, serine, or arginine; and amino acid g1' is selected from threonine or serine; and wherein the polypeptide, in association with an antibody heavy chain, binds TR-2.

In certain embodiments, an isolated polypeptide is provided comprising at least one complementarity determining region (CDR) selected from: amino acids 24 to 34 of SEQ ID NO: 36; amino acids 50 to 56 of SEQ ID NO: 36; amino acids 89 to 97 of SEQ ID NO: 36; amino acids 24 to 34 of SEQ ID NO: 38; amino acids 50 to 56 of SEQ ID NO: 38; amino acids 89 to 97 of SEQ ID NO: 38; amino acids 24 to 34 of SEQ ID NO: 40; amino acids 50 to 56 of SEQ ID NO: 40; amino acids 89 to 97 of SEQ ID NO: 40; amino acids 24 to 34 of SEQ ID NO: 42; amino acids 50 to 56 of SEQ ID NO: 42; amino acids 89 to 97 of SEQ ID NO: 42; amino acids 24 to 34 of SEQ ID NO: 44; amino acids 50 to 56 of SEQ ID NO: 44; amino acids 89 to 97 of SEQ ID NO: 44; amino acids 24 to 34 of SEQ ID NO: 46; amino acids 50 to 56 of SEQ ID NO: 46; amino acids 89 to 97 of SEQ ID NO: 46; amino acids 24 to 40 of SEQ ID NO: 48; amino acids 56 to 62 of SEQ ID NO: 48; amino acids 95 to 103 of SEQ ID NO: 48; amino acids 24 to 39 of SEQ ID NO: 50; amino acids 55 to 61 of SEQ ID NO: 50; amino acids 94 to 102 of SEQ ID NO: 50; amino acids 24 to 40 of SEQ ID NO: 52; amino acids 56 to 62 of SEQ ID NO: 52; amino acids 95 to 103 of SEQ ID NO: 52; amino acids 24 to 34 of SEQ ID NO: 54; amino acids 50 to 56 of SEQ ID NO: 54; amino acids 89 to 97 of SEQ ID NO: 54; amino acids 24 to 34 of SEQ ID NO: 56, amino acids 50 to 56 of SEQ ID NO: 56; amino acids 89 to 97 of SEQ ID NO: 56; amino acids 24 to 40 of SEQ ID NO: 58; amino acids 56 to 62 of SEQ ID NO: 58; amino acids 95 to 103 of SEQ ID NO: 58; amino acids 24 to 34 of SEQ ID NO: 60; amino acids 50 to 56 of SEQ ID NO: 60; amino acids 89 to 97 of SEQ ID NO: 60; amino acids 24 to 34 of SEQ ID NO: 62; amino acids 50 to 56 of SEQ ID NO: 62; amino acids 89 to 97 of SEQ ID NO: 62; amino acids 24 to 35 of SEQ ID NO: 64; amino acids 51 to 57 of SEQ ID NO: 64; amino acids 90 to 88 of SEQ ID NO: 64; amino acids 24 to 34 of SEQ ID NO: 66; amino acids 50 to 57 of SEQ ID NO: 66; amino acids 89 to 97 of SEQ ID NO: 66; amino acids 24 to 34 of SEQ ID NO: 68; amino acids 50 to 56 of SEQ ID NO: 68; and amino acids 89 to 97 of SEQ ID NO: 68; wherein the polypeptide, in association with an antibody heavy chain, binds TR-2.

In certain embodiments, an isolated polynucleotide is provided comprising a sequence encoding a polypeptide comprising at least one complementarity determining region (CDR) selected from CDR1a, CDR2a, and CDR3a: wherein CDR1a comprises the amino acid sequence a b c d e f g h i j k l, wherein amino acid a is glycine, amino acid b is selected from glycine, tyrosine, or phenylalanine; amino acid c is selected from serine or threonine; amino acid d is selected from isoleucine or phenylalanine; amino acid e is selected from serine, threonine, or asparagine; amino acid f is selected from serine, aspartic acid, tyrosine, asparagine, threonine, or glycine; amino acid g is selected from glycine, aspartic acid, or tyrosine; amino acid h is selected from glycine, aspartic acid, tyrosine, asparagine, or serine; amino acid i is selected from tyrosine, isoleucine, histidine, methionine, or tryptophan; amino acid j is selected from asparagine, tyrosine, histidine, serine, or phenylalanine; amino acid k is tryptophan or is not present; and amino acid l is serine or is not present; wherein CDR2a comprises the amino acid sequence m n o p q r s t u v w x y z a' b' c', wherein amino acid m is selected from tryptophan, tyrosine, histidine, valine, glutamic acid, or serine; amino acid n is selected from methionine or isoleucine; amino acid o is selected from asparagine, tyrosine, serine, tryptophan, or histidine; amino acid p is selected from proline, tyrosine, serine, arginine, histidine, or asparagine; amino acid q is selected from asparagine, serine, or aspartic acid; amino acid r is selected from serine or glycine; amino acid s is selected from aspartic acid, serine, threonine, or arginine; amino acid t is selected from asparagine, threonine, alanine, isoleucine, or tyrosine; amino acid u is selected from threonine, tyrosine, leucine, lysine, asparagine, or isoleucine; amino acid v is selected from glycine, tyrosine, aspartic acid, or cysteine; amino acid w is selected from tyrosine or asparagine; amino acid x is selected from alanine or proline; amino acid y is selected from glutamine, serine, or aspartic acid; amino acid z is selected from lysine, leucine, or serine; amino acid a' is selected from phenylalanine, lysine, or valine; amino acid b' is selected from glutamine, serine, or lysine; and amino acid c' is glycine or is not present; wherein CDR3a comprises the amino acid sequence d' e' f' g' h' i' j' k' l' m' n' o' p' q' r' s' t' u' v' w', wherein amino acid d' is selected from tryptophan, aspartic acid, glycine, serine, or glutamic acid; amino acid e' is selected from asparagine, aspartic acid, glycine, arginine, serine, valine, or leucine; amino acid f' is selected from histidine, serine, alanine, tyrosine, proline, asparagine, glycine or threonine; amino acid g' is selected from tyrosine, serine, alanine, arginine, tryptophan, glycine or valine; amino acid h' is selected from glycine, alanine, serine, asparagine, methionine, tyrosine, tryptophan, cysteine, or aspartic acid; amino acid i' is selected from serine, tryptophan, glycine, phenylalanine, aspartic acid, tyrosine, or threonine; amino acid j' is selected from glycine, threonine, serine, leucine, valine, asparagine, tryptophan, or tyrosine; amino acid k' is selected from serine, phenylalanine, aspartic acid, tryptophan, glycine, or tyrosine, or is not present; amino acid l' is selected from histidine, aspartic acid, alanine, tryptophan, tyrosine, serine, phenylalanine, valine, or glycine, or is not present; amino acid m' is selected from phenylalanine, tyrosine, glutamic acid, proline, aspartic acid, cysteine, isoleucine, or methionine, or is not present; amino acid n' is selected from aspartic acid, phenylalanine, alanine, leucine, or serine, or is not present; amino acid o' is selected from tyrosine, leucine, aspartic acid, phenylalanine, proline, or valine, or is not present; amino acid p' is selected from leucine, aspartic acid, or tyrosine, or is not present; amino acid q' is selected from serine or tyrosine, or is not present; amino acid r' is tyrosine or is not present; amino acid s' is selected from glycine or tyrosine, or is not present; amino acid t' is selected from glycine or methionine, or is not present; amino acid u' is selected from methionine or aspartic acid, or is not present; amino acid v' is selected from aspartic acid or valine, or is not present; and amino acid w' is valine or is not present; and wherein the polypeptide, in association with an antibody light chain, binds TR-2.

In certain embodiments, an isolated polynucleotide is provided comprising a sequence encoding a polypeptide comprising at least one complementarity determining region (CDR) selected from CDR1b, CDR2b, and CDR3b: wherein CDR1b comprises the amino acid sequence a1 b1 c1 d1 e1 f1 g1 h1 i1 j1 k1 l1 m1 n1 o1 p1 q1, wherein amino acid a1 is selected from arginine or lysine; amino acid b1 is selected from threonine, alanine, or serine; amino acid c1 is serine; amino acid d1 is glutamine; amino acid e1 is selected from serine or glycine; amino acid f1 is selected from isoleucine, leucine, or valine; amino acid g1 is selected from serine, leucine, or arginine; amino acid h1 is selected from threonine, serine, isoleucine, asparagine, arginine, histidine, or tyrosine; amino acid i1 is selected from tyrosine, arginine, tryptophan, aspartic acid, or serine; j1 is selected from leucine, isoleucine, asparagine, tyrosine, or serine; amino acid k1 is selected from asparagine, glycine, valine, alanine, or leucine; amino acid l1 is selected from tyrosine, alanine, or asparagine, or is not present; amino acid m1 is selected from asparagine or lysine, or is not present; amino acid n1 is selected from tyrosine, asparagine, or isoleucine, or is not present; amino acid o1 is selected from leucine or tyrosine, or is not present; amino acid p1 is selected from aspartic acid or leucine, or is not present; and amino acid q1 is selected from valine, alanine, or threonine, or is not present; wherein CDR2b comprises the amino acid sequence r1 s1 t1 u1 v1 w1 x1, wherein amino acid r1 is selected from alanine, aspartic acid, leucine, tryptophan, glycine, or valine; amino acid s1 is selected from threonine, valine, glycine, or alanine; amino acid t1 is serine; amino acid u1 is selected from serine, asparagine, or threonine; amino acid v1 is selected from leucine, phenylalanine, or arginine; amino acid w1 is selected from glutamine, alanine, or glutamic acid; and amino acid x1 is selected from serine, arginine, or threonine; wherein CDR3b comprises the amino acid sequence y1 z1 a1' b1' c1' d1' e1' f1' g1', wherein amino acid y1 is selected from glutamine, methionine, leucine, or histidine; amino acid z1 is selected from glutamine or lysine; amino acid a1' is selected from serine, threonine, alanine, histidine, tyrosine, or phenylalanine; amino acid b1' is selected from tyrosine, leucine, asparagine, or glycine; amino acid c1' is selected from serine, glutamine, isoleucine, or lysine; amino acid d1' is selected from threonine, phenylalanine, tyrosine, alanine, or serine; amino acid e1' is proline; amino acid f1' is selected from leucine, phenylalanine, tryptophan, serine, or arginine; and amino acid g1' is selected from threonine or serine; and wherein the polypeptide, in association with an antibody heavy chain, binds TR-2.

In certain embodiments, an isolated anti-TR-2 antibody comprising a variable region and a constant region is provided, wherein the antibody comprises: (i) a first polypeptide comprising at least one complementarity determining region (CDR) selected from CDR1a, CDR2a, and CDR3a, wherein CDR1a comprises the amino acid sequence a b c d e f g h i j k l, wherein amino acid a is glycine, amino acid b is selected from glycine, tyrosine, or phenylalanine; amino acid c is selected from serine or threonine; amino acid d is selected from isoleucine or phenylalanine; amino acid e is selected from serine, threonine, or asparagine; amino acid f is selected from serine, aspartic acid, tyrosine, asparagine, threonine, or glycine; amino acid g is selected from glycine, aspartic acid, or tyrosine; amino acid h is selected from glycine, aspartic acid, tyrosine, asparagine, or serine; amino acid i is selected from tyrosine, isoleucine, histidine, methionine, or tryptophan; amino acid j is selected from asparagine, tyrosine, histidine, serine, or phenylalanine; amino acid k is tryptophan or is not present; and amino acid l is serine or is not present; wherein CDR2a comprises the amino acid sequence m n o p q r s t u v w x y z a' b' c', wherein amino acid m is selected from tryptophan, tyrosine, histidine, valine, glutamic acid, or serine; amino acid n is selected from methionine or isoleucine; amino acid o is selected from asparagine, tyrosine, serine, tryptophan, or histidine; amino acid p is selected from proline, tyrosine, serine, arginine, histidine, or asparagine; amino acid q is selected from asparagine, serine, or aspartic acid; amino acid r is selected from serine or glycine; amino acid s is selected from aspartic acid, serine, threonine, or arginine; amino acid t is selected from asparagine, threonine, alanine, isoleucine, or tyrosine; amino acid u is selected from threonine, tyrosine, leucine, lysine, asparagine, or isoleucine; amino acid v is selected from glycine, tyrosine, aspartic acid, or cysteine; amino acid w is selected from tyrosine or asparagine; amino acid x is selected from alanine or proline; amino acid y is selected from glutamine, serine, or aspartic acid; amino acid z is selected from lysine, leucine, or serine; amino acid a' is selected from phenylalanine, lysine, or valine; amino acid b' is selected from glutamine, serine, or lysine; and amino acid c' is glycine or is not present; wherein CDR3a comprises the amino acid sequence d' e' f' g' h' i' j' k' l' m' n' o' p' q' r' s' t' u' v' w', wherein amino acid d' is selected from tryptophan, aspartic acid, glycine, serine, or glutamic acid; amino acid e' is selected from asparagine, aspartic acid, glycine, arginine, serine, valine, or leucine; amino acid f' is selected from histidine, serine, alanine, tyrosine, proline, asparagine, glycine or threonine; amino acid g' is selected from tyrosine, serine, alanine, arginine, tryptophan, glycine or valine; amino acid h' is selected from glycine, alanine, serine, asparagine, methionine, tyrosine, tryptophan, cysteine, or aspartic acid; amino acid i' is selected from serine, tryptophan, glycine, phenylalanine, aspartic acid, tyrosine, or threonine; amino acid j' is selected from glycine, threonine, serine, leucine, valine, asparagine, tryptophan, or tyrosine; amino acid k' is selected from serine, phenylalanine, aspartic acid, tryptophan, glycine, or tyrosine, or is not present; amino acid l' is selected from histidine, aspartic acid, alanine, tryptophan, tyrosine, serine, phenylalanine, valine, or glycine, or is not present; amino acid m' is selected from phenylalanine, tyrosine, glutamic acid, proline, aspartic acid, cysteine, isoleucine, or methionine, or is not present; amino acid n' is selected from aspartic acid, phenylalanine, alanine, leucine, or serine, or is not present; amino acid o' is selected from tyrosine, leucine, aspartic acid, phenylalanine, proline, or valine, or is not present; amino acid p' is selected from leucine, aspartic acid, or tyrosine, or is not present; amino acid q' is selected from serine or tyrosine, or is not present; amino acid r' is tyrosine or is not present; amino acid s' is selected from glycine or tyrosine, or is not present; amino acid t' is selected from glycine or methionine, or is not present; amino acid u' is selected from methionine or aspartic acid, or is not present; amino acid v' is selected from aspartic acid or valine, or is not present; and amino acid w' is valine or is not present; and wherein the first polypeptide, in association with an antibody light chain, binds TR-2; and (ii) a second polypeptide comprising at least one complementarity determining region (CDR) selected from CDR1b, CDR2b, and CDR3b wherein CDR1b comprises the amino acid sequence a1 b1 c1 d1 e1 f1 g1 h1 i1 j1 k1 l1 ml n1 o1 p1 q1, wherein amino acid a1 is selected from arginine or lysine; amino acid b1 is selected from threonine, alanine, or serine; amino acid c1 is serine; amino acid d1 is glutamine; amino acid e1 is selected from serine or glycine; amino acid f1 is selected from isoleucine, leucine, or valine; amino acid g1 is selected from serine, leucine, or arginine; amino acid h1 is selected from threonine, serine, isoleucine, asparagine, arginine, histidine, or tyrosine; amino acid i1 is selected from tyrosine, arginine, tryptophan, aspartic acid, or serine; j1 is selected from leucine, isoleucine, asparagine, tyrosine, or serine; amino acid k1 is selected from asparagine, glycine, valine, alanine, or leucine; amino acid l1 is selected from tyrosine, alanine, or asparagine, or is not present; amino acid m1 is selected from asparagine or lysine, or is not present; amino acid n1 is selected from tyrosine, asparagine, or isoleucine, or is not present; amino acid o1 is selected from leucine or tyrosine, or is not present; amino acid p1 is selected from aspartic acid or leucine, or is not present; and amino acid q1 is selected from valine, alanine, or threonine, or is not present; wherein CDR2b comprises the amino acid sequence r1 s1 t1 u1 v1 w1 x1, wherein amino acid r1 is selected from alanine, aspartic acid, leucine, tryptophan, glycine, or valine; amino acid s1 is selected from threonine, valine, glycine, or alanine; amino acid t1 is serine; amino acid u1 is selected from serine, asparagine, or threonine; amino acid v1 is selected from leucine, phenylalanine, or arginine; amino acid w1 is selected from glutamine, alanine, or glutamic acid; and amino acid x1 is selected from serine, arginine, or threonine; wherein CDR3b comprises the amino acid sequence y1 z1 a1' b1' c1' d1' e1' f1' g1', wherein amino acid y1 is selected from glutamine, methionine, leucine, or histidine; amino acid z1 is selected from glutamine or lysine; amino acid a1' is selected from serine, threonine, alanine, histidine, tyrosine, or phenylalanine; amino acid b1' is selected from tyrosine, leucine, asparagine, or glycine; amino acid c1' is selected from serine, glutamine, isoleucine, or lysine; amino acid d1' is selected from threonine, phenylalanine, tyrosine, alanine, or serine; amino acid e1' is proline; amino acid f1' is selected from leucine, phenylalanine, tryptophan, serine, or arginine; and amino acid g1' is selected from threonine or serine; and wherein the second polypeptide, in association with an antibody heavy chain, binds TR-2.

In certain embodiments, an isolated anti-TR-2 antibody comprising a variable region and a constant region is provided, wherein the antibody comprises: a first polypeptide comprising complementarity determining regions (CDRs) as set forth in SEQ ID NO: 2 and a second polypeptide comprising CDRs as set forth in SEQ ID NO: 36; a first polypeptide comprising complementarity determining regions (CDRs) as set forth in SEQ ID NO: 4 and a second polypeptide comprising CDRs as set forth in SEQ ID NO: 38; a first polypeptide comprising complementarity determining regions (CDRs) as set forth in SEQ ID NO: 6 and a second polypeptide comprising CDRs as set forth in SEQ ID NO: 40; a first polypeptide comprising complementarity determining regions (CDRs) as set forth in SEQ ID NO: 8 and a second polypeptide comprising CDRs as set forth in SEQ ID NO: 42; a first polypeptide comprising complementarity determining regions (CDRs) as set forth in SEQ ID NO: 10 and a second polypeptide comprising CDRs as set forth in SEQ ID NO: 44; a first polypeptide comprising complementarity determining regions (CDRs) as set forth in SEQ ID NO: 12 and a second polypeptide comprising CDRs as set forth in SEQ ID NO: 46; a first polypeptide comprising complementarity determining regions (CDRs) as set forth in SEQ ID NO: 14 and a second polypeptide comprising CDRs as set forth in SEQ ID NO: 48; a first polypeptide comprising complementarity determining regions (CDRs) as set forth in SEQ ID NO: 16 and a second polypeptide comprising CDRs as set forth in SEQ ID NO: 50; a first polypeptide comprising complementarity determining regions (CDRs) as set forth in SEQ ID NO: 18 and a second polypeptide comprising CDRs as set forth in SEQ ID NO: 52; a first polypeptide comprising complementarity determining regions (CDRs) as set forth in SEQ ID NO: 20 and a second polypeptide comprising CDRs as set forth in SEQ ID NO: 54; a first polypeptide comprising complementarity determining regions (CDRs) as set forth in SEQ ID NO: 22 and a second polypeptide comprising CDRs as set forth in SEQ ID NO: 56; a first polypeptide comprising complementarity det