Claims for Patent: 7,670,600

Summary for Patent: 7,670,600

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:	MedImmine, LLC (Gaithersburg, MD) Board of Regents, The University of Texas System (Austin, TX)
Application Number:	11/397,328
Patent Claims:	1. A modified IgG comprising a human IgG constant domain, wherein the human constant domain comprises an amino acid substitution at amino acid residue 428 relative to a wild-type human IgG constant 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 an IgG having the wild-type human IgG constant domain. 2. The modified IgG of claim 1, wherein the substitution at amino acid residue 428 is a substitution with threonine, leucine, phenylalanine or serine. 3. The moditied IgG according to claim 1 or 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 251-256, 285-290, 308-314, 385-389, and 429-436, 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 252 is a substitution with leucine, tyrosine, phenylalanine, serine, tryptophan or threonine; the amino acid substitution at amino acid residue 254 is a substitution with threonine; 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 256 is a substitution with phenylalanine, serine, arginine, glutamine, glutamic acid, aspartic acid, alanine or arginine; 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, proline, histidine, serine, threonine or alanine; the amino acid substitution at amino acid residue 389 is a substitution with proline or serine; the amino acid substitution at amino acid residue 433 is a substitution with lysine, arginine, serine, isoleucine, proline or glutamine; the amino acid substitution at amino acid residue 434 is a substitution with phenylalanine, tyrosine or histidine; and the amino acid substitution at amino acid residue 436 is a substitution with histidine, asparagine, arginine, threonine, lysine or methionine. 5. The modified IgG according to claim 1 or 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 Kabar EU numbering system. 6. The modified IgG according to claim 5, wherein the amino acid substitution at amino acid residue 314 is alanine. 7. The modified IgG according to claim 1 or 2, wherein the modified human IgG constant domain has a higher affinity for FcRn than a wild-type human IgG constant domain thereof. 8. The moditied IgG according to claim 7, wherein the modified human IgG constant domain has a higher affinity for FcRn than a wild-type human IgG constant domain thereof at pH 6.0 than at ph 7.4. 9. The modified IgG according to claim 1 or 2, wherein the modified IgG is a modified human IgG or a humanized IgG. 10. The modified IgG according to claim 9, wherein the modified IgG is a humanized anti-CD25monoclonal antibody, a humanized anti-.alpha..sub.v.beta..sub.3integrin antibody, or a humanized anti-CD3 antibody. 11. The modified IgG according to claim 1 or 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. 12. The modified IgG according to claim 11, wherein the human IgG constant domain is the constant domain of IgG.sub.1. 13. The modified IgG according to claim 9, wherein the human IgG is IgG.sub.1, IgG.sub.2, IgG.sub.3 or IgG.sub.4. 14. The modified UgG according to claim 1 or 2, which immunospecifically binds to a respiratory syncytial virus (RSV) antigen. 15. The modified IgG according to claim 14, which comprises; (a.) a heavy chain variable domain and a light chain variable domain of palivizumab (SEQ ID NOS.:7 and 8, respectively); (b.) a heavy chain variable domain and a light chain variable domain of A4B4L1FR-S28R (SEQ ID NOS.:48 and 11, respectively); (c.) a heavy chain variable domain and a light chain variable domain of AFFF (SEQ ID NOS.:9 and 13,. respectively); (d.) a heavy chain variable domain and a light chain variable domain of p12f2 (SEQ ID NOS.:17 and 21, respectively); (e.) a heavy chain variable domain and a light chain variable domain of p12f4 (SEQ ID NOS.:24 and 26, respectively); (f.) a heavy chain variable domain and a light chain variable domain of p11d4 (SEQ ID NOS.:28 and 30, respectively); (g.) a heavy chain variable domain and a light chain variable domain of Ale109 (SEQ ID NOS.:33 and 34, respectively); (h.) a heavy chain variable domain and a light chain variable domain of A12a6 (SEQ ID NOS.:36 and 38, respectively); (i.) a heavy chain variable domain and a light chain variable domain of A13c4 (SEQ ID NOS.:40 and 42, respectively); (j.) a heavy chain variable domain and a light chain variable domain of A17d4 (SEQ ID NOS.:44 and 46, respectively); (k.) a heavy chain variable domain and a light chain variable domain of A4B4 (SEQ ID NOS.:48 and 49, respectively); (l.) a heavy chain variable domain and a light chain variable domain of A8C7 (SEQ ID NOS.:51 and 52, respectively); (m.) a heavy chain variable domain and a light chain variable domain of 1X 493L1FR (SEQ ID NOS.:7 and 54,respectively); (n.) a heavy chain variable domain and a light chain variable domain of H3-3F4 (SEQ ID NOS.:55 and 56, respectively); (o.) a heavy chain variable domain and a light chain variable domain of M3H9 (SEQ ID NOS.:55 and 124, respectively); (p.) a heavy chain variable domain and a light chain variable domain of Y10H6 (SEQ ID NOS.:55 and 58, respectively); (q.) a heavy chain variable domain and a light chain variable domain of DG (SEQ ID NOS.:78 and 56, respectively); (r.) a heavy chain variable domain and a light chain variable domain of AFFF(1) (SEQ ID NOS.:9 and 60, respectively); (s.) a heavy chain variable domain and a light chain variable domain of 6H8 (SEQ ID NOS.:78 and 62, respectively); (t.) a heavy chain variable domain and a light chain variable domain of L1-7E5 (SEQ ID NOS.:78 and 64, respectively); (u.) a heavy chain variable domain and a light chain variable domain of L215B10 (SEQ ID NOS.:78 and 65, respectively); (v.) a heavy chain variable domain and a light chain variable domain of A13A11 (SEQ ID NOS.:67 and 68, respectively); (w.) a heavy chain variable domain and a light chain variable domain of A1H5 (SEQ ID NOS.:70 and 71, respectively); (x.) a heavy chain variable domain and a light chain variable domain of A4B4(1) (SEQ ID NOS.:48 and 74, respectively); or (y.) a heavy chain variable domain and a light chain variable domain of A4B4-F52S (SEQ ID NOS.:48 and 76, respectively). 16. The modified IgG according to claim 14, 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 CDRl, VL CDR2 and VL CDR3 of A4B4L1FR-S28R (SEQ ID NOS.: 10, 19, 20, 39, 5, and 6, respectively); (d) a VH CDRl, VH CDR2, VH CDR3, VL CDRl, 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 CDRl, VL CDR2 and VL CDR3 of p12t2 (SEQ ID NOS.:18, 19, 20, 22, 23 and 6, respectively); (f) a VH CDR1, VH CDR2, VH CDR3, VL CDRl, 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 p1 1d4 (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 Ale 109 (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.:l0, 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.:l0, 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 iX- 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 H3- 3F4 (SEQ ID NOS.: 10, 2, 29, 14, 15 and 6, respectively); (p) a VH CDRl, VH CDR2, VH CDR3, VL CDRl, 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 CDRI, 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 Li- 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 A13A1 1 (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, VH CDR2, VH 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. A pharmaceutical composition comprising the modified IgG according to claim 1 or 2, and a pharmaceutically acceptable carrier. 18. A kit comprising the modified IgG according to claim 1 or 2, in a container, and instructions for use. 19. An antibody conjugate comprising the modified IgG according to claim 1 or 2 and a detectable substance. 20. An antibody conjugate comprising the ruodilied IgG according to claim 1 or 2 and a therapeutic moiety. 21. A pharmaceutical composition comprising the antibody conjugate according to claim 19, and a pharmaceutically acceptable carrier. 22. A pharmaceutical composition comprising the antibody conjugate according to claim 20, and a pharmaceutically acceptable carrier. 23. A kit comprising the antibody conjugate according to claim 19, in a container, and instructions for use. 24. A kit comprising the antibody conjugate according to claim 20, in a container, and instructions for use. 25. A modified IgG comprising an IgG constant domain, wherein the IgG constant domain comprises a human CH3 domain in which there is an amino acid substitution at amino acid residue 428, numbered according to the EU numbering index of Kabat, wherein the modified IgG has an increased half-life compared to the half-life of an IgG comprising a corresponding IgG constant domain comprising a wild-txpe human CH3domain. 26. The modified IgG according to claim 25, wherein the amino acid substitution at amino acid residue 428 is a substitution with threonin, leucine, phenylalanine or serine.

Details for Patent 7,670,600

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