Claims for Patent: 8,012,476

Summary for Patent: 8,012,476

Title:	Molecules with extended half-lives, compositions and uses thereof
Abstract:	The present invention provides molecules, including IgGs, non-IgG immunoglobulins, proteins and non-protein agents, that have increased in vivo half-lives due to the presence of an IgG constant domain, or a portion thereof that binds the FcRn, having one or more amino acid modifications that increase the affinity of the constant domain or fragment for FcRn. Such proteins and molecules with increased half-lives have the advantage that smaller amounts and or less frequent dosing is required in the therapeutic, prophylactic or diagnostic use of such molecules.
Inventor(s):	Dall\'Acqua; William (Gaithersburg, MD), Johnson; Leslie S. (Germantown, MD), Ward; Elizabeth Sally (Dallas, TX)
Assignee:	MedImmune, LLC (Gaithersburg, MD) Board of Regents, The University of Texas System (Austin, TX)
Application Number:	12/691,433
Patent Claims:	1. A modified IgG comprising an IgG constant domain, wherein the IgG constant domain comprises a human IgG CH3 domain in which there is an amino acid substitution at amino acid residues 433, 434 and 436 relative to a corresponding IgG comprising a wild-type human IgG CH3 domain, numbered according to the EU numbering index of Kabat, wherein the modified IgG has an increased half-life compared to the half-life of the corresponding IgG comprising the wild-type human IgG CH3 domain, and wherein the substitution at amino acid residue 433 is a substitution with a lysine, the substitution at amino acid residue 434 is a substitution with a phenylalanine, and the substitution at amino acid residue 436 is a substitution with a histidine. 2. The modified IgG of claim 1, wherein the IgG constant domain is a human IgG constant domain. 3. The modified IgG according to claim 2, further comprising one or more amino acid substitutions relative to the corresponding wild-type human IgG constant domain at one or more of amino acid residues 251, 253, 255, 285-290, 308-314, 385-389, 429-433, and 435, numbered according to the Kabat EU numbering index. 4. The modified IgG according to claim 3, wherein: the amino acid substitution at amino acid residue 251 is a substitution with arginine; the amino acid substitution at amino acid residue 255 is a substitution with leucine, glycine or isoleucine; the amino acid substitution at amino acid residue 308 is a substitution with a threonine or isoleucine; the amino acid substitution at amino acid residue 309 is a substitution with proline; the amino acid substitution at amino acid residue 311 is a substitution with serine, glutamic acid or leucine; the amino acid substitution at amino acid residue 312 is a substitution with alanine; the amino acid substitution at amino acid residue 314 is a substitution with alanine; the amino acid substitution at amino acid residue 385 is a substitution with arginine, aspartic acid, serine, threonine, histidine, lysine or alanine; the amino acid substitution at amino acid residue 386 is a substitution with threonine, proline, aspartic acid, serine, lysine, arginine, isoleucine or methionine; the amino acid substitution at amino acid residue 387 is a substitution with arginine, histidine, serine, threonine or alanine; the amino acid substitution at amino acid residue 389 is a substitution with proline, serine or arginine; and the amino acid substitution at amino acid residue 433 is a substitution with lysine, arginine, serine, isoleucine, proline or glutamine. 5. The modified IgG of claim 2, further comprising one or more amino acid substitutions relative to the corresponding wild-type human IgG constant domain at amino acid residues 252, 254 or 256, numbered according to the Kabat EU numbering index. 6. The modified IgG of claim 5, wherein: the amino acid substitution at amino acid residue 252 is a substitution with tyrosine, phenylalanine, serine, tryptophan or threonine; the amino acid substitution at amino acid residue 254 is a substitution with threonine, and the amino acid substitution at amino acid residue 256 is a substitution with serine, glutamic acid, arginine, glutamine, aspartic acid, alanine or asparagine. 7. The modified IgG of claim 2, further comprising an amino acid substitution relative to the corresponding wild-type human IgG constant domain at amino acid residue 314, numbered according to the Kabat EU numbering system. 8. The modified IgG according to claim 7, wherein the amino acid substitution at amino acid residue 314 is an alanine. 9. The modified IgG of claim 2, wherein the human IgG constant domain with the amino acid substitutions has a higher affinity for FcRn than a wild-type human IgG constant domain thereof. 10. The modified IgG of claim 9, wherein the human IgG constant domain with amino acid substitutions has a higher affinity for FcRn than a wild-type human IgG constant domain thereof at pH 6.0 than at pH 7.4. 11. The modified IgG of claim 2, wherein the modified IgG is a modified human IgG or a humanized IgG. 12. The modified IgG of claim 2, wherein the human IgG constant domain is the constant domain of IgG.sub.1, IgG.sub.2, IgG.sub.3 or IgG.sub.4. 13. The modified IgG of claim 12, wherein the human IgG constant domain is the constant domain of IgG.sub.1. 14. The modified IgG of claim 11, wherein the human IgG is IgG.sub.1, IgG.sub.2, IgG.sub.3 or IgG.sub.4. 15. The modified IgG of claim 1 or 2, which immunospecifically binds to a respiratory syncytial virus (RSV) antigen. 16. The modified IgG according to claim 15, which comprises: (a) a heavy chain variable domain and light chain variable domain of palivizumab (SEQ ID NOS.: 7 and 8, respectively); (b) a variable heavy (VH) complementarily determining region (CDR)1, VH CDR2, VH CDR3, variable light (VL) CDR1, VL CDR2 and VL CDR3 of palivizumab (SEQ ID NOS.: 1-6, respectively); (c) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of A4B4L1FR-S28R (SEQ ID NOS.:10, 19, 20, 39, 5, and 6, respectively); (d) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of AFFF (SEQ ID NOS.:10, 2, 12, 14, 15 and 16, respectively); (e) VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of p12f2 (SEQ ID NOS.:18, 19, 20, 22, 23 and 6, respectively); (f) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of p12f4 (SEQ ID NOS.:18, 25, 20, 22, 27 and 6, respectively); (g) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of p11d4 (SEQ ID NOS.:18, 25, 29, 31, 32 and 6, respectively); (h) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of Ale109 (SEQ ID NOS.:10, 25, 29, 22, 35 and 6, respectively); (i) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of A12a6 (SEQ ID NOS.:10, 37, 20, 39, 35 and 6, respectively); (j) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of A13c4 (SEQ ID NOS.:10, 41, 20, 22, 43, and 6, respectively); (k) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of A17d4 (SEQ ID NOS.:10, 45, 20, 47, 43, and 6, respectively); (l) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of A4B4 (SEQ ID NOS.:10, 19, 20, 39, 50, and 6, respectively); (m) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of A8C7 (SEQ ID NOS.:10, 45, 29, 31, 53, and 6, respectively); (n) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of 1.times.-493L1FR (SEQ ID NOS.:1, 2, 3, 14, 5 and 6, respectively); (o) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of 113-3F4 (SEQ ID NOS.:10, 2, 29, 14, 15 and 6, respectively); (p) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of M3H9 (SEQ ID NOS.:10, 2, 29, 14, 57 and 6, respectively); (q) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of Y10H6 (SEQ ID NOS.:10, 2, 29, 14, 59 and 6, respectively); (r) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of DG (SEQ ID NOS.:10, 2, 79, 14, 15 and 6, respectively); (s) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of AFFF(1) (SEQ ID NOS.:10, 2, 12, 14, 15 and 61, respectively); (t) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of 6H8 (SEQ ID NOS.:10, 2, 79, 14, 63 and 6, respectively); (u) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of L1-7E5 (SEQ ID NOS.:10, 2, 79, 39, 15 and 6, respectively); (v) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of L215B10 (SEQ ID NOS.:10, 2, 79, 14, 66 and 6, respectively); (w) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of A13A11 (SEQ ID NOS.:10, 19, 29, 31, 69 and 6, respectively); (x) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of A1H5 (SEQ ID NOS.:10, 25, 29, 72, 73 and 6, respectively); (y) a VH CDR1, V11 CDR2, V11 CDR3, VL CDR1, VL CDR2 and VL CDR3 of A4B4(1) (SEQ ID NOS.:10, 19, 20, 39, 75 and 6, respectively); or (z) a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of A4B4-F52S (SEQ ID NOS.:10, 19, 20, 39, 77 and 6, respectively). 17. The modified IgG of claim 1 or 2, wherein the modified IgG immunospecifically binds to HER2, tumor necrosis factor-alpha (TNF-.alpha.), transforming growth factor-.beta.(TGF-.beta.), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-8 (IL-8), CD2, CD3, CD4, CD11a, CD14, CD18, CD20, CD23, CD25, CD33, CD52, CD64, CD80, CD147, CD40 ligand (CD40L), vascular endothelial growth factor (VEGF), intracellular adhesion molecule-3 (ICAM-3), epithelial growth factor receptor (EGFR), .alpha..sub.v.beta..sub.3 integrin, .alpha..sub.4.beta..sub.7 integrin, human leukocyte antigen (HLA), complement factor 5 (C5), immunoglobulin E (IgE), glycoprotein II.sub.b/III.sub.a receptor, CA125, 17-IA cell surface antigen, Factor VII, GD3 epitope, human immunodeficiency glycoprotein 120 (HIV gp120), hepatitis B virus (HBV) or cytomegalovirus (CMV). 18. The modified IgG of claim 1 or 2 which is isolated. 19. A kit comprising the modified IgG of claim 1 or 2, in a container, and instructions for use. 20. An antibody conjugate comprising the modified IgG of claim 1 or 2, and a detectable substance or a therapeutic moiety. 21. An antibody conjugate comprising the modified IgG of claim 16 and a detectable substance or a therapeutic moiety. 22. A kit comprising the antibody conjugate according to claim 20, in a container, and instructions for use. 23. A kit comprising the antibody conjugate according to claim 21, in a container, and instructions for use. 24. A pharmaceutical composition comprising the modified IgG of claim 1 or 2, and a pharmaceutically acceptable carrier. 25. A pharmaceutical composition comprising the modified IgG of claim 15, and a pharmaceutically acceptable carrier. 26. A pharmaceutical composition comprising the modified IgG of claim 16, and a pharmaceutically acceptable carrier. 27. A pharmaceutical composition comprising the antibody conjugate of claim 20, and a pharmaceutically acceptable carrier. 28. A pharmaceutical composition comprising the antibody conjugate of claim 21, and a pharmaceutically acceptable carrier.

Details for Patent 8,012,476

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Swedish Orphan Biovitrum Ab (publ)	SYNAGIS	palivizumab	For Injection	103770	06/19/1998		2020-12-12
Swedish Orphan Biovitrum Ab (publ)	SYNAGIS	palivizumab	Injection	103770	07/23/2004		2020-12-12