FCRN antagonist with improved half-life and method of use

Abstract

An Fc fusion molecule that binds to FcRn (FcRn) having an improved half-life and a method of using the same are described herein.

Description

Technology Field

[0001] Cross-reference regarding related applications

[0002] This application claims priority and interest to U.S. Provisional Application No. 63 / 702,533 filed October 2, 2024 and U.S. Provisional Application No. 63 / 590,691 filed October 16, 2023, the disclosures of each of which are incorporated herein by reference in their entirety. Background Technology

[0003] Immunoglobulin gamma (IgG) antibodies play a key role in the pathology of numerous disorders, such as autoimmune and inflammatory diseases. IgG generally has a longer half-life than other plasma proteins, partly because the Fc domain of IgG binds to the Fc receptor, FcRn. Although FcRn was originally characterized as a neonatal transport receptor for maternal IgG, it also functions to protect IgG from degradation in adults. FcRn binds to pinocytotic IgG and protects it from transport to degradable lysosomes by recirculating the IgG back into the extracellular compartment, where the IgG is released from FcRn and can resume its biological function.

[0004] Therapeutics targeting FcRn generally function to inhibit IgG recycling by binding to the domain responsible for the recycling of these molecules. Consequently, IgG-based FcRn antagonists have significantly shorter half-lives than other therapies due to the lack of a recycling mechanism. Thus, there is a need for improved FcRn antagonists with longer half-lives.

[0005] The present invention provides an Fc fusion molecule that binds to a newborn Fc receptor (FcRn), comprising, in particular, a modified Fc fragment fused to a half-life extension domain. The present invention is based in part on the unexpected finding that the Fc fusion molecule described herein reduces the concentration of IgG by at least 75% within 5 days.

[0006] In one embodiment, the present invention provides an Fc fusion molecule that binds to a newborn Fc receptor (FcRn), comprising: an Fc fragment comprising amino acid substitutions (i) N434Y and (ii) H433R or H433K compared to the amino acid sequence presented in SEQ ID NO. 56 from the N-terminus to the C-terminus; a linker; and an albumin or albumin-binding domain.

[0007] In one embodiment, the present invention provides an Fc fusion molecule that binds to a newborn Fc receptor (FcRn), comprising: an Fc fragment comprising amino acid substitutions (i) N434Y and (ii) H433R or H433K compared to the amino acid sequence presented in SEQ ID NO. 56 from the C-terminus to the N-terminus; a linker; and an albumin or albumin-binding domain.

[0008] In one embodiment, the present invention provides an Fc fusion molecule that binds to a newborn Fc receptor (FcRn), comprising: an Fc fragment comprising amino acid substitutions N434Y and H433R compared to the amino acid sequence presented in SEQ ID NO. 56, particularly from the N-terminus to the C-terminus; a linker; and an albumin or albumin-binding domain.

[0009] In one embodiment, the present invention provides an Fc fusion molecule that binds to a newborn Fc receptor (FcRn), comprising: an Fc fragment comprising amino acid substitutions N434Y and H433R compared to the amino acid sequence presented in SEQ ID NO. 56, particularly from the C-terminus to the N-terminus; a linker; and an albumin or albumin-binding domain.

[0010] In one embodiment, the present invention provides an Fc fusion molecule that binds to a newborn Fc receptor (FcRn), comprising: an Fc fragment comprising amino acid substitutions N434Y and H433K compared to the amino acid sequence presented in SEQ ID NO. 56, particularly from the N-terminus to the C-terminus; a linker; and an albumin or albumin-binding domain.

[0011] In one embodiment, the present invention provides an Fc fusion molecule that binds to a newborn Fc receptor (FcRn), comprising: an Fc fragment comprising amino acid substitutions N434Y and H433K compared to the amino acid sequence presented in SEQ ID NO. 56, particularly from the C-terminus to the N-terminus; a linker; and an albumin or albumin-binding domain.

[0012] In one embodiment, the present invention provides an Fc fusion molecule that binds to a newborn Fc receptor (FcRn), comprising: an Fc fragment comprising amino acid substitutions M428L and N434F compared to the amino acid sequence presented in SEQ ID NO. 56, particularly from the N-terminus to the C-terminus; a linker; and an albumin or albumin-binding domain.

[0013] In one embodiment, the present invention provides an Fc fusion molecule that binds to a newborn Fc receptor (FcRn), comprising: an Fc fragment comprising amino acid substitutions M428L and N434F compared to the amino acid sequence presented in SEQ ID NO. 56, particularly from the C-terminus to the N-terminus; a linker; and an albumin or albumin-binding domain.

[0014] In some embodiments, the Fc fragment further comprises amino acid substitutions of M252Y, S254T, and T256E. In some embodiments, the Fc fragment further comprises amino acid substitutions of H433R or H433K. In some embodiments, the Fc fragment comprises amino acid substitutions of M428L, N434F, M252Y, S254T, T256E, and H433R. In some embodiments, the Fc fragment comprises amino acid substitutions of M428L, N434F, M252Y, S254T, T256E, and H433K.

[0015] In one embodiment, the present invention provides an Fc fusion molecule that binds to a newborn Fc receptor (FcRn), comprising: an Fc fragment comprising amino acid substitutions H433R and N434F, in particular from the N-terminus to the C-terminus compared to the amino acid sequence presented in SEQ ID NO. 56; a linker; and an albumin or albumin-binding domain.

[0016] In one embodiment, the present invention provides an Fc fusion molecule that binds to a newborn Fc receptor (FcRn), comprising: an Fc fragment comprising amino acid substitutions H433R and N434F, particularly compared to the amino acid sequence presented in SEQ ID NO. 56 from the C-terminus to the N-terminus; a linker; and an albumin or albumin-binding domain.

[0017] In some embodiments, the Fc fragment further includes amino acid substitutions of M252Y, S254T, and T256E.

[0018] In some embodiments, the Fc fragment further includes an amino acid substitution of M428L.

[0019] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to any one of SEQ ID NOs 1 to 9 or 57 to 67. In some embodiments, the Fc fragment comprises an amino acid sequence that is identical to any one of SEQ ID NOs 1 to 9 or 57 to 67.

[0020] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 1. In some embodiments, the Fc fragment comprises an amino acid sequence identical to SEQ ID NO. 1. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 1. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 1. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 1. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 1. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 1. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 1. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 1. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 1.

[0021] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 2. In some embodiments, the Fc fragment comprises an amino acid sequence identical to SEQ ID NO. 2. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 2. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 2. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 2. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 2. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 2. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 2. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 2. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 2.

[0022] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 3. In some embodiments, the Fc fragment comprises an amino acid sequence identical to SEQ ID NO. 3. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 3. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 3. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 3. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 3. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 3. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 3. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 3. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 3.

[0023] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 4. In some embodiments, the Fc fragment comprises an amino acid sequence identical to SEQ ID NO. 4. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 4. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 4. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 4. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 4. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 4. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 4. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 4. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 4.

[0024] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 5. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 5. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 5. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 5. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 5. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 5. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 5. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 5. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 5.

[0025] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 6. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 6. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 6. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 6. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 6. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 6. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 6. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 6. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 6.

[0026] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 7. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 7. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 7. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 7. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 7. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 7. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 7. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 7. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 7.

[0027] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 8. In some embodiments, the Fc fragment comprises an amino acid sequence identical to SEQ ID NO. 8. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 8. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 8. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 8. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 8. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 8. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 8. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 8. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 8.

[0028] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 9. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 9. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 9. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 9. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 9. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 9. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 9. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 9. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 9.

[0029] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 57. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 57. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 57. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 57. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 57. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 57. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 57. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 57. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 57.

[0030] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 58. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 58. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 58. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 58. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 58. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 58. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 58. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 58. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 58.

[0031] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 59. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 59. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 59. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 59. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 59. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 59. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 59. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 59. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 59.

[0032] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 60. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 60. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 60. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 60. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 60. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 60. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 60. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 60. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 60.

[0033] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 61. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 61. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 61. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 61. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 61. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 61. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 61. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 61. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 61.

[0034] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 62. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 62. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 62. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 62. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 62. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 62. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 62. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 62. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 62.

[0035] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 63. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 63. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 63. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 63. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 63. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 63. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 63. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 63. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 63.

[0036] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 64. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 64. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 64. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 64. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 64. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 64. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 64. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 64. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 64.

[0037] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 65. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 65. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 65. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 65. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 65. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 65. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 65. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 65. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 65.

[0038] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 66. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 66. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 66. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 66. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 66. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 66. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 66. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 66. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 66.

[0039] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 67. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 67. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 67. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 67. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 67. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 67. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 67. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 67. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 67.

[0040] In some embodiments, the Fc fragment comprises an amino acid sequence identical to any one of SEQ ID NOs 1 to 9 or 57 to 67.

[0041] In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 1. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 2. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 3. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 4. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 5.

[0042] In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 6. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 7. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 8. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 9.

[0043] In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 57. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 58. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 59. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 60. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 61. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 62.

[0044] In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 63. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 64. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 65. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 66. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 67.

[0045] In some embodiments, the Fc fusion molecule comprises albumin. In some embodiments, the albumin comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 10. In some embodiments, the albumin comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 10. In some embodiments, the albumin comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 10. In some embodiments, the albumin comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 10. In some embodiments, the albumin comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 10. In some embodiments, the albumin comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 10. In some embodiments, albumin comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 10. In some embodiments, albumin comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 10. In some embodiments, albumin comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 10.

[0046] In some embodiments, the Fc fusion molecule comprises an albumin binding domain. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 11. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 11. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 11. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 11. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 11. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 11. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 11. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 11. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 11.

[0047] In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 12. In some embodiments, the albumin binding domain comprises an amino acid sequence identical to SEQ ID NO. 12. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 12. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 12. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 12. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 12. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 12. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 12. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 12. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 12.

[0048] In some embodiments, the linker comprises glycine and serine. In some embodiments, the linker comprises one or more repeat units of GGGGS (SEQ No. 13). In some embodiments, the linker comprises at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight repeat units of GGGGS (SEQ No. 13).

[0049] In some embodiments, the linker comprises at least two repeat units of GGGGS (SEQ No. 13). In some embodiments, the linker comprises at least three repeat units of GGGGS (SEQ No. 13). In some embodiments, the linker comprises at least four repeat units of GGGGS (SEQ No. 13). In some embodiments, the linker comprises at least five repeat units of GGGGS (SEQ No. 13). In some embodiments, the linker comprises at least six repeat units of GGGGS (SEQ No. 13). In some embodiments, the linker comprises at least seven repeat units of GGGGS (SEQ No. 13). In some embodiments, the linker comprises at least eight repeat units of GGGGS (SEQ No. 13).

[0050] In some embodiments, the linker comprises two repeat units of GGGGS (SEQ No. 13). In some embodiments, the linker comprises three repeat units of GGGGS (SEQ No. 13). In some embodiments, the linker comprises four repeat units of GGGGS (SEQ No. 13). In some embodiments, the linker comprises five repeat units of GGGGS (SEQ No. 13). In some embodiments, the linker comprises six repeat units of GGGGS (SEQ No. 13). In some embodiments, the linker comprises seven repeat units of GGGGS (SEQ No. 13). In some embodiments, the linker comprises eight repeat units of GGGGS (SEQ No. 13).

[0051] In some embodiments, the linker comprises a sequence according to any one of SEQ ID NOs 13 to 15. In some embodiments, the linker comprises a sequence according to SEQ ID NO. 13. In some embodiments, the linker comprises a sequence according to SEQ ID NO. 14. In some embodiments, the linker comprises a sequence according to SEQ ID NO. 15.

[0052] In some embodiments, the Fc fragment is derived from the IgG1, IgG2, or IgG4 immunoglobulin domain. In some embodiments, the Fc fragment is derived from the IgG1 immunoglobulin domain. In some embodiments, the Fc fragment is derived from the IgG2 immunoglobulin domain. In some embodiments, the Fc fragment is derived from the IgG4 immunoglobulin domain.

[0053] In some embodiments, the Fc fusion molecule comprises an Fc fragment, a linker, and albumin or an albumin binding domain from the N-terminus to the C-terminus. In some embodiments, the Fc fusion molecule comprises an Fc fragment, a linker, and albumin from the N-terminus to the C-terminus. In some embodiments, the Fc fusion molecule comprises an Fc fragment, a linker, and an albumin binding domain from the N-terminus to the C-terminus.

[0054] In some embodiments, the Fc fusion molecule comprises an Fc fragment, a linker, and albumin or an albumin binding domain from the C-terminus to the N-terminus. In some embodiments, the Fc fusion molecule comprises an Fc fragment, a linker, and albumin from the C-terminus to the N-terminus. In some embodiments, the Fc fusion molecule comprises an Fc fragment, a linker, and an albumin binding domain from the C-terminus to the N-terminus.

[0055] In one embodiment, the present invention provides an Fc fusion molecule that binds to FcRn, particularly comprising an amino acid sequence identical to at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of any one of SEQ ID NOs 16 to 55. In one embodiment, the present invention provides an Fc fusion molecule that binds to FcRn, particularly comprising an amino acid sequence identical to at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of any one of SEQ ID NOs 16 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to any one of SEQ ID NOs 28 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 16. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 17. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 18. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 19.In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 20.

[0056] In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 21. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 22. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 23. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 24. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 25.

[0057] In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 26. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 27. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 28. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 29. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 30.

[0058] In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 31. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 32. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 33. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 34. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 35.

[0059] In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 36. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 37. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 38. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 39. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 40.

[0060] In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 41. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 42. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 43. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 44. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 45.

[0061] In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 46. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 47. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 48. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 49. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 50.

[0062] In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 51. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 52. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 53. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 54. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 55.

[0063] In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 68. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 69. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 70. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 71. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 72. In some embodiments, the Fc fusion molecule comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 73.

[0064] In one embodiment, the present invention provides an Fc fusion molecule that binds to FcRn, particularly comprising an amino acid sequence identical to any one of SEQ ID NOs 16 to 55. In one embodiment, the present invention provides an Fc fusion molecule that binds to FcRn, particularly comprising an amino acid sequence identical to any one of SEQ ID NOs 16 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule comprises an amino acid sequence identical to any one of SEQ ID NOs 28 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule comprises an amino acid sequence identical to SEQ ID NO. 16. In some embodiments, the Fc fusion molecule comprises an amino acid sequence identical to SEQ ID NO. 17. In some embodiments, the Fc fusion molecule comprises an amino acid sequence identical to SEQ ID NO. 18. In some embodiments, the Fc fusion molecule comprises an amino acid sequence identical to SEQ ID NO. 19. In some embodiments, the Fc fusion molecule comprises an amino acid sequence identical to SEQ ID NO. 20.

[0065] In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 21. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 22. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 23. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 24. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 25.

[0066] In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 26. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 27. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 28. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 29. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 30.

[0067] In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 31. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 32. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 33. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 34. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 35.

[0068] In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 36. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 37. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 38. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 39. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 40.

[0069] In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 41. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 42. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 43. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 44. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 45.

[0070] In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 46. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 47. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 48. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 49. In some embodiments, the Fc fusion molecule comprises the same amino acid sequence as SEQ ID NO. 50.

[0071] In some embodiments, the Fc fusion molecule comprises an amino acid sequence identical to SEQ ID NO. 51. In some embodiments, the Fc fusion molecule comprises an amino acid sequence identical to SEQ ID NO. 52. In some embodiments, the Fc fusion molecule comprises an amino acid sequence identical to SEQ ID NO. 53. In some embodiments, the Fc fusion molecule comprises an amino acid sequence identical to SEQ ID NO. 54. In some embodiments, the Fc fusion molecule comprises an amino acid sequence identical to SEQ ID NO. 55.

[0072] In some embodiments, the Fc fusion molecule comprises an amino acid sequence identical to SEQ ID NO. 68. In some embodiments, the Fc fusion molecule comprises an amino acid sequence identical to SEQ ID NO. 69. In some embodiments, the Fc fusion molecule comprises an amino acid sequence identical to SEQ ID NO. 70. In some embodiments, the Fc fusion molecule comprises an amino acid sequence identical to SEQ ID NO. 71. In some embodiments, the Fc fusion molecule comprises an amino acid sequence identical to SEQ ID NO. 72. In some embodiments, the Fc fusion molecule comprises an amino acid sequence identical to SEQ ID NO. 73.

[0073] In some embodiments, the Fc fusion molecule further comprises a second Fc fragment. In some embodiments, the second Fc fragment is the Fc fragment described herein.

[0074] In some embodiments, the second Fc fragment comprises the same amino acid substitution as the first Fc fragment. In some embodiments, the first Fc fragment and the second Fc fragment are further modified to promote heteromerization. In some embodiments, the first Fc fragment and the second Fc fragment further comprise one or more amino acid substitutions selected from Y349C, S354C, T366S, T366W, T366Y, L368A, Y407T, and Y407V.

[0075] In some embodiments, the first Fc fragment further comprises the amino acid substitutions Y349C, T366S, L368A, and Y407V, and the second Fc fragment further comprises the amino acid substitutions S354C and T366W. In some embodiments, the second Fc fragment further comprises the amino acid substitutions Y349C, T366S, L368A, and Y407V, and the first Fc fragment further comprises the amino acid substitutions S354C and T366W. In some embodiments, the first Fc fragment further comprises the amino acid substitutions T366S, L368A, and Y407V, and the second Fc fragment further comprises the amino acid substitution T266W. In some embodiments, the second Fc fragment further comprises the amino acid substitutions T366S, L368A, and Y407V, and the first Fc fragment further comprises the amino acid substitution T266W.

[0076] In some embodiments, the second Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to any one of SEQ ID NOs 1 to 9. In some embodiments, the second Fc fragment comprises an amino acid sequence identical to any one of SEQ ID NOs 1 to 9.

[0077] In certain embodiments, an Fc fusion molecule that binds to a newborn Fc receptor (FcRn), comprising N-terminus to C-terminus or C-terminus to N-terminus, is described herein: a) an Fc fragment comprising a sequence having at least 80% sequence identity with any one of SEQ ID NOs 1 to 9; b) a linker; and c) an albumin or albumin binding domain comprising a sequence having at least 80% sequence identity with any one of SEQ ID NOs 10 to 12. In some embodiments, the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 1, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 10. In some embodiments, the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 1, the linker comprises a sequence according to SEQ ID NO. 14, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 10. In some embodiments, the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 1, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11. In some embodiments, the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 1, the linker comprises a sequence according to SEQ ID NO. 15, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11.In some embodiments, the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 4 or SEQ ID NO. 5, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11. In some embodiments, the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 4 or SEQ ID NO. 5, the linker comprises a sequence according to SEQ ID NO. 15, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11. In some embodiments, the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 3, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 10. In some embodiments, the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 3, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 12. In some embodiments, the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 3, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11. In some embodiments, the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 3, the linker comprises a sequence according to SEQ ID NO. 15, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 12.In some embodiments, the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 3, the linker comprises a sequence according to SEQ ID NO. 15, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11. In some embodiments, the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 6 or SEQ ID NO. 7, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 12. In some embodiments, the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 6 or SEQ ID NO. 7, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11. In some embodiments, the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 6 or SEQ ID NO. 7, the linker comprises a sequence according to SEQ ID NO. 15, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 12. In some embodiments, the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 6 or SEQ ID NO. 7, the linker comprises a sequence according to SEQ ID NO. 15, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11. In some embodiments, the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 2, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 10.In some embodiments, the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 8 or SEQ ID NO. 9, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11. In some embodiments, the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 8 or SEQ ID NO. 9, the linker comprises a sequence according to SEQ ID NO. 15, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11. In some embodiments, the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 2, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11. In some embodiments, the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 2, the linker comprises a sequence according to SEQ ID NO. 15, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11. In some embodiments, the Fc fusion molecule further comprises a second Fc fragment having at least 80% sequence identity with any one of the amino acid sequences of SEQ ID NOs 1 to 9.

[0078] In certain embodiments, an Fc fusion molecule that binds to a neonatal Fc receptor (FcRn) is described herein, comprising a sequence having at least 80% sequence identity with any one of SEQ ID NOs 16 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule is about 1 x 10⁻⁶ at pH 6.0 or pH 7.4 as measured by surface plasmon resonance (SPR). -8 K less than or equal to MD It binds to FcRn. In some embodiments, the Fc fusion molecule has a half-life that is at least twice as long as that of an Fc fusion molecule that does not contain albumin or an albumin binding domain. In some embodiments, the Fc fusion molecule has a half-life that is at least twice as long as that of an Fc fragment. In some embodiments, the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence of any one of SEQ ID NOs 10 to 12.

[0079] In some embodiments, the Fc fusion molecule reduces IgG levels to less than 60%, less than 50%, less than 40%, less than 30%, or less than 25%. In some embodiments, the Fc fusion molecule reduces IgG levels to less than 60%. In some embodiments, the Fc fusion molecule reduces IgG levels to less than 50%. In some embodiments, the Fc fusion molecule reduces IgG levels to less than 40%. In some embodiments, the Fc fusion molecule reduces IgG levels to less than 30%. In some embodiments, the Fc fusion molecule reduces IgG levels to less than 25%.

[0080] In certain embodiments, a pharmaceutical composition comprising the Fc fusion molecule and a pharmaceutically acceptable carrier described herein is described herein.

[0081] In certain embodiments, a method for treating a disease or disorder in a patient requiring treatment of the disease or disorder is described herein, said method comprising the step of administering to the patient an effective amount of the Fc fusion molecule described herein or the pharmaceutical composition described herein. In some embodiments, the disease or disorder is an autoimmune disease. In some embodiments, the disease or disorder is generalized myasthenia gravis (gMG), chronic inflammatory demyelinating polyneuropathy, myositis, autoimmune encephalitis, myelin oligodendrocyte glycoprotein antibody disorder (MOG antibody disorder), membranous nephropathy, lupus nephritis, thyroid eye disease, warm autoimmune hemolytic anemia, fetal and neonatal hemolytic disease, idiopathic thrombocytopenic purpura, primary Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, bullous pemphigus, pemphigus foliaceus, pemphigus vulgaris, or cutaneous lupus erythematosus. In some embodiments, the method reduces disease severity in a patient, and disease severity is evaluated by the gMG disease severity result scale.

[0082] In a specific embodiment, a method for treating a pathology associated with elevated levels of IgG in a patient requiring treatment for a pathology associated with elevated levels of IgG is described herein, said method comprising the step of administering to the patient a therapeutically effective amount of the isolated Fc fragment described herein or the pharmaceutical composition described herein.

[0083] In certain embodiments, a method for reducing the biological activity of IgG in a patient requiring a reduction in the biological activity of IgG is described herein, said method comprising the step of administering to the patient a therapeutically effective amount of the Fc fusion molecule described herein or the pharmaceutical composition described herein. In some embodiments, the disease is an autoimmune disease.

[0084] In a specific embodiment, a method for preventing a disorder in a patient requiring prevention of a disorder is described herein, said method comprising the step of administering to the patient a therapeutically effective amount of the Fc fusion molecule described herein or the pharmaceutical composition described herein; the disorder is an unwanted side effect of the therapeutic antibody.

[0085] In one embodiment, the present invention provides a method for reducing the biological activity of IgG, particularly in a patient who requires a reduction in the biological activity of IgG, said method comprising the step of administering to the patient a therapeutically effective amount of the Fc fusion molecule described herein or the pharmaceutical composition described herein.

[0086] In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 60%, less than 50%, less than 40%, less than 30%, or less than 25% for at least 5, 7, 10, 15, or 20 days after administration.

[0087] In some embodiments, administration of the Fc fusion molecule reduces the IgG level to less than 60%. In some embodiments, administration of the Fc fusion molecule reduces the IgG level to less than 50%. In some embodiments, administration of the Fc fusion molecule reduces the IgG level to less than 40%. In some embodiments, administration of the Fc fusion molecule reduces the IgG level to less than 30%. In some embodiments, administration of the Fc fusion molecule reduces the IgG level to less than 25%.

[0088] In some embodiments, IgG levels decrease for at least 5 days after administration. In some embodiments, IgG levels decrease for at least 7 days after administration. In some embodiments, IgG levels decrease for at least 10 days after administration. In some embodiments, IgG levels decrease for at least 15 days after administration. In some embodiments, IgG levels decrease for at least 20 days after administration.

[0089] In some embodiments, IgG levels are reduced compared to baseline. In some embodiments, baseline is the IgG level in the patient before administration. In some embodiments, baseline is the IgG level in a comparable patient without administration of the Fc fusion molecule described herein. Brief explanation of the drawing

[0090] The novelty of the present disclosure is particularly evident in the appended claims. A better understanding of the characteristics and advantages of the present disclosure will be obtained by referring to the following detailed description and the accompanying drawings, which present exemplary embodiments in which the principles of the present disclosure are utilized. FIGS. 1a to 1d This illustrates an exemplary form of a divalent and monovalent Fc fusion molecule. Fig. 1a Figure 1 illustrates an exemplary divalent Fc fusion molecule comprising an N-terminal albumin or albumin binding domain (ABD), a linker, and a C-terminal Fc domain (Form 1). Fig. 1b Figure 2 illustrates an exemplary divalent Fc fusion molecule comprising an N-terminal Fc domain, a linker, and a C-terminal albumin or albumin binding domain (ABD) (Form 2). Fig. 1c Figure 3 illustrates an exemplary monovalent Fc fusion molecule comprising an N-terminal albumin or albumin binding domain (ABD), a linker, and a C-terminal Fc domain (Form 3). Fig. 1d An exemplary monovalent Fc fusion molecule comprising a C-terminal Fc domain, a linker, and an N-terminal albumin or albumin binding domain (ABD) is illustrated (Form 4). FIGS. 2a to 2d SPR kinetics analysis of a divalent Fc fusion molecule against human serum albumin (HSA) is illustrated. Fig. 2a is A sensorogram of the HSA titration for Fc fusion molecule 5 immobilized on a CM5 chip at pH 7.4 is shown. Fig. 2b Figure 6 shows the sensorgram of the HSA titration for Fc fusion molecule 5 immobilized on a CM5 chip at pH 6.0. Fig. 2cFigure 7.4 shows the sensorgram of the HSA titration for Fc fusion molecule 6 immobilized on a CM5 chip at pH 7.4. Fig. 2d Figure 6 shows the sensogram of the HSA titration for Fc fusion molecule 6 immobilized on a CM5 chip at pH 6.0. The dark gray and light gray lines represent the data and fit, respectively. FIGS. 3a to 3d SPR kinetics analysis of a divalent Fc fusion molecule for human FCRN (huFCRN) is illustrated. Fig. 3a is A sensorogram of the huFCRN titration for Fc fusion molecule 5 immobilized on a CM5 chip at pH 7.4 is shown. Fig. 3b Figure 6.0 shows the sensogram of the huFCRN titration for Fc fusion molecule 5 immobilized on a CM5 chip at pH 6.0. Fig. 3c Figure 7.4 shows the sensogram of the huFCRN titration for Fc fusion molecule 6 immobilized on a CM5 chip at pH 7.4. Fig. 3d Figure 6 shows the sensogram of the huFCRN titration for Fc fusion molecule 6 immobilized on a CM5 chip at pH 6.0. FIGS. 4a to 4d SPR kinetics analysis of a monovalent Fc fusion molecule against human serum albumin (HSA) is illustrated. Fig. 4a A sensorogram of the HSA titration for Fc fusion molecule 11 immobilized on a CM5 chip at pH 7.4 is shown. Fig. 4b Figure 6.0 shows the sensorgram of the HSA titration for Fc fusion molecule 11 immobilized on a CM5 chip at pH 6.0. Fig. 4c Figure 12 illustrates the sensorgram of the HSA titration for the Fc fusion molecule immobilized on the CM5 chip at pH 7.4. Fig. 4d Figure 6.0 shows the sensorgram of the HSA titration for Fc fusion molecule 12 immobilized on a CM5 chip at pH 6.0. FIGS. 5a to 5d SPR kinetics analysis of a monovalent Fc fusion molecule for human FCRN (huFCRN) is illustrated. Fig. 5a isA sensorogram of the huFCRN titration for Fc fusion molecule 11 immobilized on a CM5 chip at pH 7.4 is shown. Fig. 5b Figure 6.0 shows the sensorgram of the huFCRN titration for Fc fusion molecule 11 immobilized on a CM5 chip at pH 6.0. Fig. 5c Figure 12 illustrates the huFCRN titration for Fc fusion molecule immobilized on a CM5 chip at pH 7.4. Fig. 5d Figure 6.0 shows the sensogram of the huFCRN titration for Fc fusion molecule 12 immobilized on a CM5 chip at pH 6.0. Fig. 6 is Illustrate an overview of pharmacokinetic studies performed in mice. FIGS. 7a to 7e Data on pharmacokinetic (PK) and pharmacodynamic (PD) profiles for various Fc fusion molecules, including the PD effect of Fc fusion molecules as determined by human IVIG tracer reduction, are presented. FIGS. 7c to 7e ). Fig. 8 is An exemplary graph illustrating the degradation of FcRn-GFP in HEK cells in the presence of an exemplary Fc fusion molecule is shown. Specific details for implementing the invention

[0091] definition

[0092] Unless otherwise defined, all technical terms, notations, and other scientific terms used herein are intended to have the meanings generally understood by those skilled in the art. In some cases, terms having a generally understood meaning are defined herein for clarity and / or ease of reference, and the inclusion of such definitions should not be interpreted as indicating a difference from what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and are commonly used by those skilled in the art using conventional methodologies, such as the widely used molecular cloning methodologies described in, for example, the literature [Sambrook et al., Molecular Cloning: A Laboratory Manual 4th ed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY]. Where appropriate, procedures involving the use of commercially available kits and reagents are generally performed according to the protocols and conditions defined by the manufacturer, unless otherwise noted.

[0093] Any numerical value used in this application is intended to include any variation within the standard deviation or normal variation recognized by those skilled in the art.

[0094] Unless otherwise specified, the term 'antibody' as used herein refers to an intact antibody, an antigen-binding fragment, or an intact antibody including an Fc fragment that has been modified, manipulated, or chemically conjugated ( for example , intact monoclonal antibody) or a fragment thereof, for example, the Fc fragment of an antibody ( for example , Fc fragment of a monoclonal antibody), or antigen-binding fragment of an antibody ( for exampleIt is understood to mean the antigen-binding fragment of a monoclonal antibody. Generally, an antibody is a multimeric protein containing four polypeptide chains. Two polypeptide chains are called the immunoglobulin heavy chain (H chain), and two polypeptide chains are called the immunoglobulin light chain (L chain). The immunoglobulin heavy chain and light chain may be connected by inter-chain disulfide bonds. The immunoglobulin heavy chain may be connected by inter-chain disulfide bonds. The light chain consists of one variable region (VL) and one constant region (CL). The heavy chain consists of one variable region (VH) and at least three constant regions (CH1, CH2, and CH3). The variable region determines the binding specificity of the antibody. Each variable region possesses three supervariable regions known as complementarity determining regions (CDR) flanked with four relatively conserved regions known as framework regions (FR). The degrees of FR and CDR have been defined (references [Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242]; and references [Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917]). The three CDRs, designated as CDR1, CDR2, and CDR3, contribute to antibody binding specificity. Naturally occurring antibodies have been used as starting materials for engineered antibodies, such as chimeric antibodies and humanized antibodies. Examples of antibody-based antigen-binding fragments include Fab, Fab', (Fab')2, Fv, and single-chain antibodies ( for example Includes , scFv), minibodies, and diabodies. Examples of modified or engineered antibodies are chimeric antibodies, humanized antibodies, and multispecific antibodies ( for exampleIncludes , bispecific antibodies. An example of a chemically conjugated antibody is an antibody conjugated to a toxin moiety.

[0095] The 'Fc polypeptide' of dimeric Fc used herein refers to two polypeptides forming a dimeric Fc domain, in other words , refers to one of the polypeptides comprising a C-terminal constant region of an immunoglobulin heavy chain capable of stable self-assembly. For example, the Fc polypeptide of dimeric IgG Fc comprises IgG CH2 and IgG CH3 constant domain sequences. Fc can be of the IgA, IgD, IgE, IgG, and IgM classes. These classes are also designated as α, δ, ε, γ, and μ, respectively. Some of these are subclasses (isotypes), for example It can be further divided into IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0096] The terms 'Fc receptor' or 'FcR' are used to describe receptors that bind to the Fc region of antibodies. For example, an FcR may be a natural sequence human FcR. Generally, FcRs bind to IgG antibodies (gamma receptors) and include the FcγRI, FcγRII, and FcγRIII subclasses of receptors, which include allelic variants and, alternatively, spliced ​​forms of these receptors. The FcγRII receptor includes FcγRIIA ("activating receptor") and FcγRIIB ("inhibitory receptor"), which have similar amino acid sequences that differ mainly within their cytoplasmic domains. Other isoforms of immunoglobulins may also be bound by specific FcRs ( for example , literature[Janeway et al. , Immuno BiologySee : the immune system in health and disease, (Elsevier Science Ltd., NY) (4th ed., 1999)]). The activating receptor FcγRIIA contains an immune receptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. The inhibitory receptor FcγRIIB contains an immune receptor tyrosine system inhibitory motif (ITIM) in its cytoplasmic domain (reference [Da ron, Annu. Rev. Immunol Reviewed in . 15:203-234 (1997)]). FcR is [Ravetch and Kinet, Annu. Rev . Immunol 9:457-92 (1991)]; literature[Capel et al. , Immunomethods 4:25-34 (1994)]; and literature[de Haas et al. This is reviewed in [J. Lab. Clin. Med. 126:330-41 (1995)]. Other FcRs, including those identified in the future, are included in the term 'FcR' herein. The term also includes the neonatal receptor, FcRn, which is responsible for transmitting maternal IgG to the fetus (reference [Guyer et al. , J. Immunol . 117:587 (1976)]; and literature[Kim et al. , J. Immunol . 24:249 (1994)]).

[0097] The terms ‘receptor’, ‘individual’, ‘subject’, ‘host’, and ‘patient’ are used interchangeably herein and, in some embodiments, refer to any mammalian subject, in particular, for whom diagnosis, treatment, or therapy is desired. For therapeutic purposes, ‘mammal’ refers to any animal classified as a mammal, including humans, livestock and farm animals, and laboratory, zoo, sports, or pet animals, such as dogs, horses, cats, cattle, sheep, goats, pigs, mice, rats, rabbits, guinea pigs, monkeys, etc. In some embodiments, the mammal is a human. None of these terms require the supervision of a medical professional.

[0098] As used herein, the term 'effective amount' refers to a compound sufficient to achieve a beneficial or desired result ( for example , refers to the amount of the compound of this disclosure). The effective amount may be administered in one or more doses, applications, or dosages and is not intended to be limited to a specific formulation or route of administration. As used herein, the term 'therapeutic' refers to any effect, for example It includes reducing, decreasing, controlling, improving, or eliminating pathological conditions, diseases, disabilities, etc., thereby causing improvement or improving their symptoms.

[0099] As used herein, the term 'pharmaceutical composition' refers to a combination of an active agent and an inert or active carrier, and this refers to a composition In vivo or In vitro It is made particularly suitable for diagnostic or therapeutic use.

[0100] As used herein, the term 'pharmaceuticalally acceptable carrier' refers to any standard pharmaceutical carrier, e.g., phosphate-buffered saline solution, water, emulsion ( for example It refers to , oil / water or water / oil emulsions), and various types of wetting agents. The composition may also include stabilizers and preservatives. Examples of carriers, stabilizers, and adjuvants include for example, refer to the literature [Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975)].

[0101] The singular form used herein includes multiple referents unless otherwise specified.

[0102] The aspects and embodiments of the invention described herein are understood to include 'comprising,' 'constituting,' and 'essentially constituting' the aspects and embodiments.

[0103] In all compositions described herein and in all methods using compositions described herein, the composition may include the listed components or steps, or may be 'essentially composed' of the listed components or steps. When a composition is described as being 'essentially composed' of the listed components, the composition contains the listed components and may contain other components that do not substantially affect the condition being treated, but does not contain any other components that substantially affect the condition being treated in addition to these explicitly listed components; or, if the composition contains additional components that substantially affect the condition being treated in addition to those listed, the composition does not contain additional components in a concentration or amount sufficient to substantially affect the condition being treated. When a method is described as being 'essentially composed' of the listed steps, the method includes the listed steps and may include other steps that do not substantially affect the condition being treated, but the method does not include any other steps that substantially affect the condition being treated in addition to these explicitly listed steps. As a non-limiting specific example, when a composition is described as 'essentially composed' of components, the composition may further contain any amount of pharmaceutically acceptable carriers, vehicles, or diluents and other such components that do not substantially affect the condition being treated.

[0104] The term 'about' indicates and includes the specified value and the range of values ​​greater than and less than said value. In certain embodiments, the term 'about' indicates a specified value ± 10%, ± 5%, or ± 1%. In certain embodiments, if appropriate, the term 'about' indicates a specified value(s) ± one standard deviation of said value(s).

[0105] When used sequentially, the term 'optional' means including one or all of the enumerated combinations, and considers all sub-combinations.

[0106] The term 'amino acid' refers to 20 common naturally occurring amino acids. Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine ​​(Cys; C); glutamic acid (Glu; E), glutamine (Gln; Q), glycine (Gly; G); histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V).

[0107] The term 'affinity' refers to the strength of the total sum of non-covalent interactions between a single bond site of a molecule (e.g., Fc fragment) and its bond partner (e.g., FcRn). Unless otherwise specified, as used herein, 'affinity' refers to the intrinsic bond affinity reflecting the 1:1 interaction between the members of a bond pair (e.g., Fc fragment and FcRn). Affinity is K D It is indirectly proportional to.

[0108] As used herein, the term 'kd' (sec-1) refers to the dissociation rate constant of a specific antibody-antigen or protein-protein interaction. This value is also referred to as the koff value.

[0109] The term 'ka' (M⁻¹X⁻¹) as used herein refers to the rate constant of a specific antibody-antigen interaction or protein-protein association. This value is also referred to as the kon value.

[0110] The terms 'KD' or 'K' used at this institution D (M) refers to the dissociation equilibrium constant of a specific antibody-antigen or protein-protein interaction. KD = kd / ka. In some embodiments, the affinity of a protein is described in terms of KD for the interaction between such protein and its binding partner. For clarity, as is known in the art, a smaller KD value indicates a greater affinity interaction, while a larger KD value indicates a lower affinity interaction.

[0111] The terms 'measurable KD' or 'measurable K' used herein D ' is less than 1M, less than 0.1M, less than 0.01M, less than 0.001M, 1 x 10 -4 Less than M, 1 x 10 -5 Less than M, or 1 x 10 -6 It refers to a KD value less than M.

[0112] As used herein, the term 'KA' (M-1) refers to the association equilibrium constant of a specific antibody-antigen or protein-protein interaction. KA = ka / kd

[0113] 'Percent (%) identity' refers to the degree to which two sequences (nucleotides or amino acids) have identical residues at the same position when aligned. For example, 'the amino acid sequence is X% identical to sequence number Y' refers to the % identity of the amino acid sequence with respect to sequence number Y, explaining that X% of the residues in the amino acid sequence are identical to the residues in the sequence disclosed at sequence number Y. Generally, computer programs are used for these calculations. Exemplary programs for comparing and aligning sequence pairs include ALIGN (Myers and Miller, 1988), FASTA (Pearson and Lipman, 1988; Pearson, 1990), and BLAST with gaps (Altschul et al., 1997), BLASTP, BLASTN, or GCG (Devereux et al., 1984).

[0114] Fc fusion molecule

[0115] In certain embodiments, an Fc fusion molecule that binds to a newborn Fc receptor (FcRn) is described herein.

[0116] Fc short story

[0117] In certain embodiments, an Fc fusion molecule that binds to a newborn Fc receptor (FcRn), comprising an Fc fragment, is described herein. In some embodiments, the Fc fusion molecule comprises an Fc fragment comprising a sequence having at least 80% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 1 to 9 or 57 to 67. In some embodiments, the Fc fusion molecule comprises an Fc fragment comprising a sequence having at least 85% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 1 to 9 or 57 to 67. In some embodiments, the Fc fusion molecule comprises an Fc fragment comprising a sequence having at least 90% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 1 to 9 or 57 to 67. In some embodiments, the Fc fusion molecule comprises an Fc fragment comprising a sequence having at least 95% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 1 to 9 or 57 to 67. In some embodiments, the Fc fusion molecule comprises an Fc fragment having at least 96% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 1 to 9 or 57 to 67. In some embodiments, the Fc fusion molecule comprises an Fc fragment having at least 97% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 1 to 9 or 57 to 67. In some embodiments, the Fc fusion molecule comprises an Fc fragment having at least 98% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 1 to 9 or 57 to 67. In some embodiments, the Fc fusion molecule comprises an Fc fragment having at least 99% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 1 to 9 or 57 to 67. In some embodiments, the Fc fusion molecule comprises an Fc fragment having a sequence according to any one of SEQ ID NOs 1 to 9 or 57 to 67.The amino acid sequence of an exemplary Fc fragment is shown in Table 1a.

[0118]

[0119]

[0120]

[0121] In some embodiments, the Fc fusion molecule comprises a modified Fc or an Fc fragment containing one or more modifications. In some embodiments, the Fc fragment is an IgG subclass IgG1, IgG2, or IgG4. In some embodiments, one or more modifications are located on the Fc from IgG1 (e.g., human IgG1 (hIgG1)). In some embodiments, one or more modifications are located on the Fc from IgG4 (e.g., human IgG4 (hIgG4)). In some embodiments, one or more modifications are located on the Fc from IgG2. In some embodiments, one or more modifications promote the selective binding of the Fc gamma receptor.

[0122] In some embodiments, the Fc fragment is modified using knobs-into-holes, strand-exchange engineered domains (SEED), or stereoconstruction techniques. In some embodiments, the Fc fragment is modified to promote Fc heteromers. In some embodiments, the Fc fragment comprises a variant (e.g., a knobs-into-hole variant). In some embodiments, the Fc fragment comprises a variant of the amino acid sequence presented in SEQ ID NO. 56, wherein the variant comprises at least one amino acid substitution selected from Y349C, S354C, T366S, T366W, L368A, Y407V, M428L, H433K, N434F, and N434Y. In some embodiments, the Fc fragment comprises a variant of the amino acid sequence presented in SEQ ID NO. 56, and the variant comprises at least one amino acid substitution selected from Y349C, S354C, T366S, T366W, T366Y, L368A, Y407T, Y407V, M428L, H433K, N434F, and N434Y.

[0123] In some embodiments, the Fc fragment binds to a neonatal Fc receptor (FcRn) from humans, cyano, mice, or rats. In some embodiments, the Fc fragment comprises a variant of the amino acid sequence presented in SEQ ID NO. 56, wherein the variant comprises at least one amino acid substitution selected from M428L, H433R, and N434Y. In some embodiments, the isolated Fc fragment comprises additional amino acid substitutions at one or more of amino acid positions 252, 254, and 256 of SEQ ID NO. 56. In some embodiments, the additional amino acid substitutions are M252Y, S254T, and / or T256E.

[0124] In some embodiments, the Fc fragment comprises a variant of the amino acid sequence presented in SEQ ID NO. 56, and the variant comprises an amino acid substitution at position 428. In some embodiments, the amino acid substitution is M428L. In some embodiments, the Fc fragment comprises additional amino acid substitutions at one or more of the amino acid positions 252, 254, 256, 433, and 434 of SEQ ID NO. 56. In some embodiments, the additional amino acid substitutions are M252Y, S254T, T256E, H433K, H433R, N434F, and / or N434Y.

[0125] In some embodiments, the Fc fragment comprises a variant of the amino acid sequence presented in SEQ ID NO. 56, and the variant comprises the amino acid substitution H433R. In some embodiments, additional amino acid substitutions appear at one or more of amino acid positions 252, 254, 256, 428, and 434 of SEQ ID NO. 56. In some embodiments, one or more additional amino acid substitutions are M252Y, S254T, T256E, M428L, N434F, and / or N434Y.

[0126] In some embodiments, the Fc fragment comprises a variant of the amino acid sequence presented in SEQ ID NO. 56, and the variant comprises the amino acid substitution N434Y. In some embodiments, the Fc fragment comprises additional amino acid substitutions at one or more of amino acid positions 252, 254, 256, 428, and 433 of SEQ ID NO. 56. In some embodiments, the amino acid substitutions are M252Y, S254T, T256E, M428L, H433K, and / or H433R.

[0127] In some embodiments, the Fc fragment comprises a variant of the amino acid sequence presented in SEQ ID NO. 56, wherein the variant comprises an amino acid substitution H433K and additional amino acid substitutions at one or more of amino acid positions 252, 254, 256, 428, and 434. In some embodiments, the additional amino acid substitutions are M252Y, S254T, T256E, M428L, N434F, and / or N434Y.

[0128] In some embodiments, the Fc fragment comprises a variant of the amino acid sequence presented in SEQ ID NO. 56, and the variant comprises amino acid substitutions (i) N434Y and (ii) H433R or H433K. In some embodiments, the variant further comprises amino acid substitutions of M252Y, S254T, and T256E. In some embodiments, the variant further comprises an amino acid substitution of M428L. In some embodiments, the variant comprises amino acid substitutions of M252Y, S254T, T256E, M428L, H433K, and N434Y. In some embodiments, the variant comprises amino acid substitutions of M252Y, S254T, T256E, H433K, and N434Y.

[0129] In some embodiments, the Fc fragment comprises a variant of the amino acid sequence presented in SEQ ID NO. 56, and the variant comprises the amino acid substitutions N434Y and H433R. In some embodiments, the variant further comprises the amino acid substitutions M252Y, S254T, and T256E. In some embodiments, the variant further comprises the amino acid substitution M428L. In some embodiments, the variant comprises the amino acid substitutions M252Y, S254T, T256E, H433R, and N434Y.

[0130] In some embodiments, the Fc variant comprises a variant of the amino acid sequence presented in SEQ ID NO. 56, and the variant comprises the amino acid substitutions N434Y and H433K. In some embodiments, the variant further comprises the amino acid substitutions M252Y, S254T, and T256E. In some embodiments, the variant further comprises the amino acid substitution M428L.

[0131] In some embodiments, the Fc fragment comprises a variant of the amino acid sequence presented in SEQ ID NO. 56, and the variant comprises amino acid substitutions of M428L and N434F. In some embodiments, the variant further comprises amino acid substitutions of M252Y, S254T, and T256E. In some embodiments, the variant further comprises amino acid substitutions of H433R or H433K. In some embodiments, the variant comprises amino acid substitutions of M428L, N434F, M252Y, S254T, T256E, and H433R. In some embodiments, the variant comprises amino acid substitutions of M428L, N434F, M252Y, S254T, T256E, and H433K. In some embodiments, the variant comprises amino acid substitutions of M428L, N434F, M252Y, S254T, and T256E.

[0132] In some embodiments, the Fc fragment comprises a variant of the amino acid sequence presented in SEQ ID NO. 56, and the variant comprises amino acid substitutions of H433R and N434F. In some embodiments, the variant further comprises amino acid substitutions of M252Y, S254T, and T256E. In some embodiments, the variant further comprises an amino acid substitution of M428L. In some embodiments, the variant comprises amino acid substitutions of M252Y, S254T, T256E, H433R, and N434F.

[0133] Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region follows the EU numbering system, also known as the EU index, as described in the literature [Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991]. As used herein, the 'Fc polypeptide' of dimeric Fc refers to one of two polypeptides forming the dimeric Fc domain, namely, a polypeptide containing the C-terminal constant region of an immunoglobulin heavy chain capable of stable self-association. For example, the Fc polypeptide of dimeric IgG Fc comprises the IgG CH2 and IgG CH3 constant domain sequences. In certain embodiments, the Fc fragment disclosed herein comprises the C-terminal 226 amino acids of the complete human IgG Fc region. Fc may be of class IgG and may be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, and IgG4. In certain embodiments, the Fc fragment described herein is of the IgG1 subclass. In certain embodiments, the Fc fragment described herein is a variant of the human IgG1Fc region presented in SEQ ID NO. 1. In certain embodiments, the Fc fragment described herein is of the IgG2 subclass. In certain embodiments, the Fc fragment described herein is of the IgG4 subclass.

[0134] The term 'Fc receptor' or 'FcR' is used to describe receptors that bind to the Fc region of antibodies. For example, an FcR may be a natural sequence human FcR. Generally, FcRs bind to IgG antibodies (gamma receptors) and include the FcγRI, FcγRII, and FcγRIII subclasses of receptors, which include allelic variants and, alternatively, spliced ​​forms of these receptors. FcγRII receptors include FcγRIIA ('activating receptor') and FcγRIIB ('inhibiting receptor'), which have similar amino acid sequences that differ primarily within their cytoplasmic domains. Other isoforms of immunoglobulins may also be bound by specific FcRs (e.g., see Janeway et al., Immuno Biology: the immune system in health and disease, (Elsevier Science Ltd., NY) (4th ed., 1999)). The above terms also include the neonatal receptor, FcRn, which is responsible for delivering maternal IgG to the fetus (reference [Guyer et al., J. Immunol. 117:587 (1976)]; and reference [Kim et al., J. Immunol. 24:249 (1994)]). The Fc fragment described herein selectively binds to FcRn. In certain embodiments, the Fc fragment selectively binds to mammalian FcRn, including cyano, rat, and / or mouse FcRn.

[0135] The activating receptor FcγRIIA contains an immune receptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibition of receptor FcγRIIB contains an immune receptor tyrosine-based inhibition motif ('ITIM') in its cytoplasmic domain (Reference [M. Da (Reviewed in [Ravetch and Kinet, Annu. Rev. Immunol. 15:203-234 (1997)]). FcRs are reviewed in the literature [Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991)]; literature [Capel et al., Immunomethods 4:25-34 (1994)]; and literature [de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995)]. Other FcRs, including those identified in the future, are included in the term 'FcR' herein.

[0136] Modifications in the CH2 domain can affect the binding of FcR to Fc. Numerous amino acid modifications in the Fc region to selectively alter the affinity of Fc for different Fc gamma receptors are known in the art.

[0137] Exemplary mutations that alter the binding of FcR to Fc are listed below:

[0138] S298A / E333A / K334A, S298A / E333A / K334A / K326A (Lu Y, Vernes JM, Chiang N, et al. J Immunol Methods. 2011 Feb 28;365(1-2):132-41]);

[0139] F243L / R292P / Y300L / V305I / P396L, F243L / R292P / Y300L / L235V / P396L (Stavenhagen JB, Gorlatov S, Tuaillon N, et al. Cancer Res. 2007 Sep 15;67(18):8882-90; Nordstrom JL, Gorlatov S, Zhang W, et al. Breast Cancer Res 2011 Nov 30;13(6):R123]);

[0140] F243L(Reference [Stewart R, Thom G, Levens M, et al. Protein Eng Des Sel. 2011 Sep;24(9):671-8]), S298A / E333A / K334A(Reference [Shields RL, Namenuk AK, Hong K, et al. J Biol Chem. 2001 Mar 2;276(9):6591-604]);

[0141] S239D / I332E / A330L, S239D / I332E (Lazar GA, Dang W, Karki S, et al. Proc Natl Acad Sci US A. 2006 Mar 14;103(11):4005-10);

[0142] S239D / S267E, S267E / L328F(Reference[Chu SY, Vostiar I, Karki S, et al. Mol Immunol. 2008 Sep;45(15):3926-33]);

[0143] S239D / D265S / S298A / I332E, S239E / S298A / K326A / A327H, G237F / S298A / A330L / I332E, S239D / I332E / S298A, S239D / K326E / A330L / I332E / S298A, G236A / S239D / D270L / I332E, S239E / S267E / H268D, L234F / S267E / N325L, G237F / V266L / S267D and other mutations listed in WO2011 / 120134 and WO2011 / 120135 as incorporated herein. Therapeutic antibody manipulation (The literature [William R. Strohl and Lila M. Strohl, Woodhead Publishing series in Biomedicine No 11, ISBN 1 907568 37 9, Oct 2012]) lists mutations in Chapter 283.

[0144] In some embodiments, the Fc fragment comprises one or more variations selected from the group consisting of: S298A, E333A, K334A, K326A, F243L, R292P, Y300L, V305I, P396L, F243L, R292P, Y300L, L235V, P396L, F243L, S239D, I332E, A330L, S267E, L328F, D265S, S239E, K326A, A327H, G237F, K326E, G236A, D270L, H268D, S324T, L234F, N325L, V266L, and S267D. In some embodiments, one or more variations are selected from the group consisting of S228P, M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, and N434W.

[0145] In some embodiments, the Fc fragment comprises a specific combination of amino acid substitutions selected from the group consisting of: L234A / L235A; V234A / G237A; L235A / G237A / E318A; S228P / L236E; H268Q / V309L / A330S / A331S; C220S / C226S / C229S / P238S; C226S / C229S / E3233P / L235V / L235A; L234F / L235E / P331S; C226S / P230S; L234A / G237A; L234A / L235A / G237A; Q311R / M428L; and L234A / L235A / P329G.

[0146] In some embodiments, the Fc fragment comprises an additional amino acid residue at the N-terminus or C-terminus. In some embodiments, the Fc fragment provided herein comprises a C-terminal lysine residue. In some embodiments, the Fc fragment has an additional 1, 2, 3, 4, or 5 amino acid residues at the N-terminus and / or C-terminus.

[0147] In some embodiments, the Fc fragment described herein comprises at least one galactose residue in an oligosaccharide attached to the Fc region. Such antibody variants may have improved CDC function.

[0148] In some embodiments, the Fc fragment described herein includes one or more modifications that improve or reduce C1q bonding and / or CDC.

[0149] In some embodiments, the Fc fragment comprises one or more amino acid substitutions, and one or more substitutions result in a decrease in one or more of ADCC activity, ADCP activity, or CDC activity compared to Fc without one or more substitutions.

[0150] In some embodiments, the Fc fragment is generated by a recombinant cell engineered to express a desired constant domain.

[0151] In some embodiments, the Fc fragment disclosed herein is a variant of SEQ ID NO. 56 (e.g., comprising one or more amino acid substitutions in comparison therewith), and one or more substitutions are K measurable at pH 7.4 in comparison to the Fc fragment of SEQ ID NO. 56. D It causes and does not bind detectably to FcRn at pH 7.4 without one or more substitutions.

[0152] In a specific embodiment, the half-life of the Fc fragment at pH 6.0 is increased compared to the Fc fragment containing the wild-type Fc region due to one or more amino acid substitutions.

[0153] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 1. In some embodiments, the Fc fragment comprises an amino acid sequence identical to SEQ ID NO. 1. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 1. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 1. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 1. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 1. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 1. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 1. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 1. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 1.

[0154] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 2. In some embodiments, the Fc fragment comprises an amino acid sequence identical to SEQ ID NO. 2. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 2. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 2. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 2. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 2. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 2. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 2. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 2. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 2.

[0155] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 3. In some embodiments, the Fc fragment comprises an amino acid sequence identical to SEQ ID NO. 3. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 3. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 3. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 3. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 3. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 3. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 3. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 3. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 3.

[0156] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 4. In some embodiments, the Fc fragment comprises an amino acid sequence identical to SEQ ID NO. 4. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 4. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 4. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 4. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 4. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 4. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 4. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 4. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 4.

[0157] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 5. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 5. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 5. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 5. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 5. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 5. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 5. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 5. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 5.

[0158] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 6. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 6. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 6. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 6. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 6. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 6. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 6. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 6. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 6.

[0159] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 7. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 7. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 7. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 7. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 7. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 7. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 7. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 7. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 7.

[0160] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 8. In some embodiments, the Fc fragment comprises an amino acid sequence identical to SEQ ID NO. 8. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 8. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 8. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 8. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 8. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 8. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 8. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 8. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 8.

[0161] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 9. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 9. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 9. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 9. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 9. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 9. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 9. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 9. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 9.

[0162] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 57. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 57. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 57. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 57. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 57. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 57. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 57. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 57. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 57.

[0163] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 58. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 58. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 58. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 58. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 58. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 58. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 58. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 58. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 58.

[0164] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 59. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 59. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 59. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 59. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 59. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 59. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 59. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 59. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 59.

[0165] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 60. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 60. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 60. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 60. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 60. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 60. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 60. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 60. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 60.

[0166] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 61. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 61. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 61. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 61. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 61. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 61. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 61. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 61. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 61.

[0167] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 62. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 62. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 62. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 62. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 62. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 62. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 62. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 62. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 62.

[0168] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 63. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 63. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 63. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 63. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 63. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 63. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 63. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 63. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 63.

[0169] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 64. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 64. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 64. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 64. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 64. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 64. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 64. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 64. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 64.

[0170] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 65. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 65. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 65. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 65. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 65. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 65. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 65. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 65. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 65.

[0171] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 66. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 66. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 66. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 66. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 66. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 66. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 66. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 66. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 66.

[0172] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO. 67. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 67. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 67. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 67. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 67. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 67. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 67. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 67. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 67.

[0173] In some embodiments, the Fc fragment comprises an amino acid sequence identical to any one of SEQ ID NOs 1 to 9 or 57 to 67.

[0174] In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 1. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 2. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 3. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 4. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 5.

[0175] In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 6. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 7. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 8. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 9.

[0176] In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 57. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 58. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 59. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 60. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 61. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 62.

[0177] In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 63. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 64. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 65. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 66. In some embodiments, the Fc fragment comprises the same amino acid sequence as SEQ ID NO. 67.

[0178] Linker

[0179] A linker sequence can be provided to the Fc fusion molecule described herein to separate different components (e.g., albumin or albumin binding domain, Fc fragment).

[0180] In some embodiments, the linker is a peptide linker. In some embodiments, the peptide linker includes a hinge region or a part thereof. In some embodiments, the hinge region is derived from an IgG hinge region. In some embodiments, the hinge region is derived from a human IgG hinge region.

[0181] In some embodiments, the peptide linker is a flexible peptide linker. In some embodiments, the peptide linker is a rigid peptide linker. In some embodiments, the peptide linker is a cleavable peptide linker. In some embodiments, the linker is repeated once. In some embodiments, the linker is repeated more than once.

[0182] In some embodiments, the linker comprises at least 5 to about 50 amino acids. In some embodiments, the linker comprises about 5 to about 50 amino acids, about 5 to about 45 amino acids, about 5 to about 40 amino acids, about 5 to about 35 amino acids, about 5 to about 30 amino acids, about 5 to about 25 amino acids, about 5 to about 20 amino acids, about 5 to about 15 amino acids, about 5 to about 10 amino acids, about 10 to about 50 amino acids, about 15 to about 50 amino acids, about 20 to about 50 amino acids, about 25 to about 50 amino acids, about 30 to about 50 amino acids, about 35 to about 50 amino acids, about 40 to about 50 amino acids, or about 45 to about 50 amino acids.

[0183] In some embodiments, the linker comprises a sequence according to any one of SEQ ID NOs 13 to 15. In some embodiments, the linker comprises a sequence according to any one of SEQ ID NOs 13 to 15 or 74 to 75. In some embodiments, the linker comprises a sequence according to SEQ ID NO. 13. In some embodiments, the linker comprises a sequence according to SEQ ID NO. 14. In some embodiments, the linker comprises a sequence according to SEQ ID NO. 15.

[0184] In some embodiments, the linker comprises a sequence according to any one of SEQ ID NOs 74 to 75. In some embodiments, the linker comprises a sequence according to SEQ ID NO. 74. In some embodiments, the linker comprises a sequence according to SEQ ID NO. 75.

[0185] In some embodiments, the linker is (GS) n , (G2S) n , (G3S) n , (G4S) n , and (G) n The sequence comprises a sequence selected from the group consisting of, wherein n is an integer from 2 to 20. In some embodiments, n is an integer from 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, 4 to 20, 6 to 20, 6 to 8, 8 to 20, 10 to 20, 12 to 20, 14 to 20, 16 to 20, or 18 to 20. In some embodiments, n is an integer of 6 or more. In some embodiments, n is an integer of 8 or more. In some embodiments, n is 6. In some embodiments, n is 8.

[0186] In some embodiments, the linker is (G4S) n Includes, where n is an integer from 2 to 20. In some embodiments, n is an integer from 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, 4 to 20, 6 to 20, 6 to 8, 8 to 20, 10 to 20, 12 to 20, 14 to 20, 16 to 20, or 18 to 20. In some embodiments, n is an integer of 6 or more. In some embodiments, n is an integer of 8 or more. In some embodiments, n is 6. In some embodiments, n is 8.

[0187] In some embodiments, the linker includes (G4S)1. In some embodiments, the linker includes (G4S)2. In some embodiments, the linker includes (G4S)3. In some embodiments, the linker includes (G4S)4. In some embodiments, the linker includes (G4S)5. In some embodiments, the linker includes (G4S)6. In some embodiments, the linker includes (G4S)7. In some embodiments, the linker includes (G4S)8.

[0188] In some embodiments, the linker comprises a sequence of GGGGG. In some embodiments, the linker comprises a sequence of (GGGGG)n, where n is an integer from 2 to 6.

[0189] In some embodiments, the linker comprises a sequence selected from GGSGGD or GGSGGE. In some embodiments, the linker is (GGSGGD)n or (GGSGGE) n It includes a sequence selected from a group consisting of, and n is an integer from 2 to 6.

[0190] In some embodiments, the linker comprises a sequence selected from the group consisting of GGGSGSGGGGS and GGGGGPGGGGP. In some embodiments, the linker is (GGGSGSGGGGS) n and (GGGGGPGGGGP) n It includes a sequence selected from a group consisting of, and n is an integer from 1 to 3.

[0191] In some embodiments, the linker includes a sequence selected from the group consisting of GGGGGG and GGGGGGGG.

[0192] In some embodiments, the linker comprises a sequence selected from the group consisting of (GX)n, (GGX)n, (GGGX)n, (GGGGX)n, and (GzX)n, where z is 1 to 20 and n is at least 8. In some embodiments, z is 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, 4 to 20, 6 to 20, 8 to 20, 10 to 20, 12 to 20, 14 to 20, 16 to 20, or 18 to 20. In some embodiments, X is serine, aspartic acid, glutamic acid, threonine, or proline.

[0193] In some embodiments, the linker is Table 1b It includes an amino acid sequence selected from.

[0194]

[0195] Half-life extension domain

[0196] In some embodiments, the Fc fusion molecule comprises an Fc fragment and a half-life extension domain. In some embodiments, the Fc fusion molecule comprises an Fc fragment, a linker, and a half-life extension domain.

[0197] In some embodiments, the half-life extension domain comprises albumin. In some embodiments, the half-life extension moiety comprises human serum albumin. In some embodiments, the half-life extension domain comprises a protein or a fragment thereof that binds to albumin. In some embodiments, the half-life extension domain comprises a protein or a fragment thereof that binds to human serum albumin (HSA).

[0198] In some embodiments, the half-life extension domain comprises an anti-HAS antibody or a fragment thereof. In some embodiments, the half-life extension domain comprises anti-HSA Fab. In some embodiments, the half-life extension domain comprises anti-HSA Fab'. In some embodiments, the half-life extension domain comprises anti-HSA F(ab)'2. In some embodiments, the half-life extension domain comprises an anti-HSA variable fragment (Fv). In some embodiments, the half-life extension domain comprises an anti-HSA single-domain antibody (sdAb). In some embodiments, the half-life extension domain comprises anti-HSA VHH. In some embodiments, the half-life extension domain comprises anti-HSA VNAR. In some embodiments, the half-life extension domain comprises an anti-HSA single-chain variable fragment (scFv). In some embodiments, the half-life extension domain comprises anti-HSA single-chain Fab (scFab).

[0199] In some embodiments, the half-life extension domain comprises one or more lipids. The lipids may comprise various lengths, chemicals, linkers, and conjugates that are obvious to those skilled in the art. In some embodiments, the reactive extension domain comprises a saturated fatty acid. In some embodiments, the saturated fatty acid is linked to the Fc fragment through its carboxylate group. In some embodiments, the saturated fatty acid is C 6-18 Saturated fatty acids (e.g., C6, C 12 , C 16 , or C 18 It includes a saturated fatty acid. In some embodiments, the half-life extension domain includes a saturated fatty acid. In some embodiments, the saturated fatty acid is linked to the Fc fragment through its carboxylate group. In some embodiments, the saturated fatty acid is C 6-18 Saturated lipids (e.g., C6, C 12 , C 16 , or C 18 It contains saturated fatty acids.

[0200] In some embodiments, the half-life extending domain comprises one or more polyethylene glycols (PEG). The PEG may comprise various lengths, various molecular weights, and various linkers that are obvious to those skilled in the art. In some embodiments, the PEG is monodisperse. In some embodiments, the monodisperse PEG comprises 12 to 48 ethylene glycol repeats ( for example , having 12 to 24 repeats, 12 to 36 repeats, 24 to 48 repeats, 24 to 36 repeats, or 36 to 48 repeats). In some embodiments, the PEG is polydisperse. In some embodiments, the polydisperse PEG is 500 to 50,000 daltons ( for example , 500-1,000 Da, 500-5,000 Da, 500-20,000 Da, 500-40,000 Da, 1,000-5,000 Da, 1,000-20,000 Da, 1,000-40,000 Da, 1,000-50,000 Da, 5,000-10,000 Da, 5,000-20,000 Da, 5,000-40,000 Da, 5,000-50,000 Da, 10,000-20,000 Da, 10,000-40,000 Da, 10,000-50,000 Da, 20,000-40,000 Da, or It has a molecular weight of 20,000-50,000 Da. In some embodiments, the molecular weight of the polydisperse PEG is 0.5 kDa, 1 kDa, 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, or 50 kDa.

[0201] In some embodiments, the half-life extension domain comprises a polydisperse PEG having a molecular weight of 1 kDa. In some embodiments, the half-life extension domain comprises a polydisperse PEG having a molecular weight of 5 kDa. In some embodiments, the half-life extension domain comprises a polydisperse PEG having a molecular weight of 10 kDa. In some embodiments, the half-life extension domain comprises a polydisperse PEG having a molecular weight of 15 kDa. In some embodiments, the half-life extension domain comprises a polydisperse PEG having a molecular weight of 20 kDa. In some embodiments, the half-life extension domain comprises a polydisperse PEG having a molecular weight of 25 kDa. In some embodiments, the half-life extension domain comprises a polydisperse PEG having a molecular weight of 30 kDa. In some embodiments, the half-life extension domain comprises a polydisperse PEG having a molecular weight of 35 kDa. In some embodiments, the half-life extension domain comprises polydisperse PEG having a molecular weight of 40 kDa. In some embodiments, the half-life extension domain comprises polydisperse PEG having a molecular weight of 50 kDa.

[0202] In some embodiments, the half-life extension domain comprises a reactive extension polypeptide. The half-life extension polypeptide may comprise various lengths, chemicals, linkers, and conjugates that are obvious to those skilled in the art. In some embodiments, the half-life extension polypeptide comprises repeated units of Pro-Ala-Ser (PAS). In some embodiments, the half-life extension polypeptide comprises 50 to 500 repeated PAS units ( for example It includes 50 to 100 PAS units, 50 to 200 PAS units, 100 to 200 PAS units, 100 to 500 PAS units, or 200 to 500 PAS units.

[0203] In some embodiments, the half-life extending polypeptide comprises XTEN polypeptide. XTEN is described in US20150037359A1, the contents of which are incorporated herein by reference in their entirety.

[0204] antigen binding domain

[0205] In some embodiments, the Fc fusion molecule comprises an Fc fragment and an antigen-binding domain. In some embodiments, the Fc fusion molecule comprises an Fc fragment, a linker, and an antigen-binding domain.

[0206] In some embodiments, the antigen-binding domain comprises Fab, Fab', F(ab)2, variable fragment (Fv), single-domain antibody (sdAb), VHH, VNAR, single-chain variable fragment (scFv), or single-chain Fab (scFab). In some embodiments, the antigen-binding domain comprises Fab. In some embodiments, the antigen-binding domain comprises Fab'. In some embodiments, the antigen-binding domain comprises F(ab)'2. In some embodiments, the antigen-binding domain comprises Fv. In some embodiments, the antigen-binding domain comprises a light-chain variable domain. In some embodiments, the antigen-binding domain comprises a heavy-chain variable domain. In some embodiments, the antigen-binding domain comprises sdAb. In some embodiments, the antigen-binding domain comprises VHH. In some embodiments, the antigen-binding domain comprises VNAR. In some embodiments, the antigen-binding domain comprises scFv. In some embodiments, the antigen-binding domain comprises scFab.

[0207] In some embodiments, the antigen-binding domain is monospecific. In some embodiments, the antigen-binding domain is bispecific. In some embodiments, the antigen-binding domain is multispecific.

[0208] In some embodiments, the antigen-binding domain targets a non-human antigen. In some embodiments, the non-human antigen is a protein or fragment that is not normally expressed in humans but can be found in humans. In some embodiments, the non-human antigen comprises a protein or a fragment thereof expressed by a pathogen. In some embodiments, the non-human antigen is a bacterial antigen. In some embodiments, the non-human antigen is a viral antigen.

[0209] In some embodiments, the antigen binding domain targets a human antigen. In some embodiments, the human antigen is associated with an autoimmune disease. In some embodiments, the human antigen is IgG1. In some embodiments, the human antigen is IgE. In some embodiments, the human antigen is IgM. In some embodiments, the human antigen is IgA. In some embodiments, the human antigen is IgD.

[0210] In some embodiments, the human antigen is human serum albumin.

[0211] Albumin and albumin binding domain

[0212] An Fc fusion molecule comprising albumin or an albumin binding domain is provided herein.

[0213] In some embodiments, the Fc fusion molecule comprises an Fc fragment and albumin. In one embodiment, the albumin is human serum albumin. In some embodiments, the albumin comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 10. In some embodiments, the albumin comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 10. In some embodiments, the albumin comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 10. In some embodiments, the albumin comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 10. In some embodiments, the albumin comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 10. In some embodiments, the albumin comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 10. In some embodiments, the albumin comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 10. In some embodiments, the albumin comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 10. In some embodiments, albumin contains the same amino acid sequence as SEQ ID NO. 10.

[0214] In some embodiments, the Fc fusion molecule comprises an Fc fragment and an albumin-binding domain. In some embodiments, the albumin-binding domain binds to human serum albumin. In some embodiments, the albumin-binding domain comprises the albumin-binding domain described in WO2012175400A1, the contents of which are incorporated herein by reference in their entirety.

[0215] In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 11. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 11. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 11. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 11. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 11. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 11. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 11. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 11. In some embodiments, the albumin binding domain comprises an amino acid sequence identical to SEQ ID NO. 11.

[0216] In some embodiments, the albumin binding domain comprises an amino acid substitution of F32A for SEQ ID NO. 11. In some embodiments, the albumin binding domain comprises the amino acid sequence of SEQ ID NO. 76.

[0217] In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 80% identical to SEQ ID NO. 12. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 85% identical to SEQ ID NO. 12. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 90% identical to SEQ ID NO. 12. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 95% identical to SEQ ID NO. 12. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 96% identical to SEQ ID NO. 12. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 97% identical to SEQ ID NO. 12. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 98% identical to SEQ ID NO. 12. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least 99% identical to SEQ ID NO. 12. In some embodiments, the albumin binding domain comprises an amino acid sequence identical to SEQ ID NO. 12.

[0218] In some embodiments, the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 10 to 12. In some embodiments, the albumin or albumin binding domain comprises a sequence having at least 85% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 10 to 12. In some embodiments, the albumin or albumin binding domain comprises a sequence having at least 90% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 10 to 12. In some embodiments, the albumin or albumin binding domain comprises a sequence having at least 95% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 10 to 12. In some embodiments, the albumin or albumin binding domain comprises a sequence having at least 96% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 10 to 12. In some embodiments, the albumin or albumin binding domain comprises a sequence having at least 97% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 10 to 12. In some embodiments, the albumin or albumin binding domain comprises a sequence having at least 98% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 10 to 12. In some embodiments, the albumin or albumin binding domain comprises a sequence having at least 99% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 10 to 12. In some embodiments, the albumin or albumin binding domain comprises a sequence according to any one of SEQ ID NOs 10 to 12.

[0219] An exemplary amino acid sequence of albumin or an albumin-binding domain is Table 1c It appears in.

[0220]

[0221] Fc fusion molecular form

[0222] In some embodiments, the Fc fusion molecule described herein comprises an Fc fragment and a second domain. In some embodiments, the Fc fusion molecule comprises an Fc fragment, a linker, and a second domain. In some embodiments, the Fc fusion molecule Fig. 1 Includes the format listed in.

[0223] In some embodiments, the Fc fusion molecule comprises an Fc fragment, a linker, and an antigen-binding domain from the N-terminus to the C-terminus. In some embodiments, the Fc fusion molecule forms a homodimer. In some embodiments, the Fc fusion molecule forms a heterodimer with a second Fc fragment. In some embodiments, the Fc fusion molecule forms a heterodimer with a second Fc fusion molecule comprising a second Fc fragment, a second linker, and a second antigen-binding domain from the N-terminus to the C-terminus. In some embodiments, the first antigen-binding domain and the second antigen-binding domain are identical.

[0224] In some embodiments, the Fc fusion molecule comprises an Fc fragment, a linker, and a half-life extension domain from the N-terminus to the C-terminus. In some embodiments, the Fc fusion molecule forms a homomer. In some embodiments, the Fc fusion molecule forms a heteromer with a second Fc fragment. In some embodiments, the Fc fusion molecule forms a heteromer with a second Fc fusion molecule comprising a second Fc fragment, a second linker, and a second half-life extension domain from the N-terminus to the C-terminus. In some embodiments, the first half-life extension domain and the second half-life extension domain are identical.

[0225] In some embodiments, the Fc fusion molecule comprises an Fc fragment, a linker, and albumin from the N-terminus to the C-terminus. In some embodiments, the Fc fusion molecule forms a homomer. In some embodiments, the Fc fusion molecule forms a heteromer with a second Fc fragment. In some embodiments, the Fc fusion molecule forms a heteromer with a second Fc fusion molecule comprising a second Fc fragment, a second linker, and a second albumin from the N-terminus to the C-terminus. In some embodiments, the first albumin and the second albumin are identical.

[0226] In some embodiments, the Fc fusion molecule comprises an Fc fragment, a linker, and an albumin binding domain from the N-terminus to the C-terminus. In some embodiments, the Fc fusion molecule forms a homomer. In some embodiments, the Fc fusion molecule forms a heteromer with a second Fc fragment. In some embodiments, the Fc fusion molecule forms a heteromer with a second Fc fusion molecule comprising a second Fc fragment, a second linker, and a second albumin binding domain from the N-terminus to the C-terminus. In some embodiments, the first albumin binding domain and the second albumin binding domain are identical.

[0227] In some embodiments, the Fc fusion molecule comprises an Fc fragment, a linker, and an antigen-binding domain from the C-terminus to the N-terminus. In some embodiments, the Fc fusion molecule forms a homodimer. In some embodiments, the Fc fusion molecule forms a heterodimer with a second Fc fragment. In some embodiments, the Fc fusion molecule forms a heterodimer with a second Fc fusion molecule comprising a second Fc fragment, a second linker, and a second antigen-binding domain from the C-terminus to the N-terminus. In some embodiments, the first antigen-binding domain and the second antigen-binding domain are identical.

[0228] In some embodiments, the Fc fusion molecule comprises an Fc fragment, a linker, and a half-life extension domain from the C-terminus to the N-terminus. In some embodiments, the Fc fusion molecule forms a homomer. In some embodiments, the Fc fusion molecule forms a heteromer with a second Fc fragment. In some embodiments, the Fc fusion molecule forms a heteromer with a second Fc fusion molecule comprising a second Fc fragment, a second linker, and a second half-life extension domain from the C-terminus to the N-terminus. In some embodiments, the first half-life extension domain and the second half-life extension domain are identical.

[0229] In some embodiments, the Fc fusion molecule comprises an Fc fragment, a linker, and albumin from the C-terminus to the N-terminus. In some embodiments, the Fc fusion molecule forms a homomer. In some embodiments, the Fc fusion molecule forms a heteromer with a second Fc fragment. In some embodiments, the Fc fusion molecule forms a heteromer with a second Fc fusion molecule comprising a second Fc fragment, a second linker, and a second albumin from the C-terminus to the N-terminus. In some embodiments, the first albumin and the second albumin are identical.

[0230] In some embodiments, the Fc fusion molecule comprises an Fc fragment, a linker, and an albumin binding domain from the C-terminus to the N-terminus. In some embodiments, the Fc fusion molecule forms a homomer. In some embodiments, the Fc fusion molecule forms a heteromer with a second Fc fragment. In some embodiments, the Fc fusion molecule forms a heteromer with a second Fc fusion molecule comprising a second Fc fragment, a second linker, and a second albumin binding domain from the C-terminus to the N-terminus. In some embodiments, the first albumin binding domain and the second albumin binding domain are identical. In one aspect, the present invention provides a divalent Fc fusion molecule particularly comprising two polypeptides, each polypeptide comprising a half-life extension domain at the N-terminus of the Fc fragment.

[0231] In one embodiment, the present invention provides a divalent Fc fusion molecule particularly comprising two polypeptides, each polypeptide comprising an anti-HSA VHH fused to the N-terminus of an Fc fragment.

[0232] In one embodiment, the present invention provides a divalent Fc fusion molecule particularly comprising two polypeptides, each polypeptide comprising an albumin binding domain fused to the N-terminus of an Fc fragment.

[0233] In one embodiment, the present invention provides a divalent Fc fusion molecule particularly comprising two polypeptides, each polypeptide comprising albumin fused to the N-terminus of an Fc fragment.

[0234] In one embodiment, the present invention provides a divalent Fc fusion molecule particularly comprising two polypeptides, each polypeptide comprising a half-life extension domain fused to the C-terminus of an Fc fragment.

[0235] In one embodiment, the present invention provides a divalent Fc fusion molecule particularly comprising two polypeptides, each polypeptide comprising an anti-HSA VHH fused to the C-terminus of an Fc fragment.

[0236] In one embodiment, the present invention provides a divalent Fc fusion molecule particularly comprising two polypeptides, each polypeptide comprising an albumin binding domain fused to the C-terminus of an Fc fragment.

[0237] In one embodiment, the present invention provides a divalent Fc fusion molecule particularly comprising two polypeptides, each polypeptide comprising albumin fused to the C-terminus of an Fc fragment.

[0238] In one embodiment, the present invention provides a monovalent Fc fusion molecule particularly comprising two polypeptides, wherein the first polypeptide comprises a half-life extension domain fused to the N-terminus of the first Fc fragment, and the second polypeptide comprises the second Fc fragment.

[0239] In one embodiment, the present invention provides a monovalent Fc fusion molecule particularly comprising two polypeptides, wherein the first polypeptide comprises an anti-HSA VHH fused to the N-terminus of the first Fc fragment, and the second polypeptide comprises the second Fc fragment.

[0240] In one embodiment, the present invention provides a monovalent Fc fusion molecule particularly comprising two polypeptides, wherein the first polypeptide comprises an albumin binding domain fused to the N-terminus of the first Fc fragment, and the second polypeptide comprises the second Fc fragment.

[0241] In one embodiment, the present invention provides a monovalent Fc fusion molecule particularly comprising two polypeptides, wherein the first polypeptide comprises albumin fused to the N-terminus of the first Fc fragment, and the second polypeptide comprises the second Fc fragment.

[0242] In one embodiment, the present invention provides a monovalent Fc fusion molecule particularly comprising two polypeptides, wherein the first polypeptide comprises a half-life extension domain fused to the C-terminus of the first Fc fragment, and the second polypeptide comprises the second Fc fragment.

[0243] In one embodiment, the present invention provides a monovalent Fc fusion molecule particularly comprising two polypeptides, wherein the first polypeptide comprises an anti-HSA VHH fused to the C-terminus of the first Fc fragment, and the second polypeptide comprises the second Fc fragment.

[0244] In one embodiment, the present invention provides a monovalent Fc fusion molecule particularly comprising two polypeptides, wherein the first polypeptide comprises an albumin binding domain fused to the C-terminus of the first Fc fragment, and the second polypeptide comprises the second Fc fragment.

[0245] In one embodiment, the present invention provides a monovalent Fc fusion molecule particularly comprising two polypeptides, wherein the first polypeptide comprises albumin fused to the C-terminus of the first Fc fragment, and the second polypeptide comprises the second Fc fragment.

[0246] In one embodiment, the present invention provides a monovalent Fc fusion molecule particularly comprising two polypeptides, wherein the first polypeptide comprises anti-HSA VHH at the C-terminus of the first Fc fragment, and the second polypeptide comprises the second Fc fragment, and the first Fc fragment and the second Fc fragment comprise M252Y, S254T, T256E, H433K, and N434Y compared to the amino acid sequences presented in SEQ ID NO. 56.

[0247] In one embodiment, the present invention provides a monovalent Fc fusion molecule particularly comprising two polypeptides, wherein the first polypeptide comprises an anti-HSA VHH fused to the N-terminus of the first Fc fragment, and the second polypeptide comprises the second Fc fragment, and the first Fc fragment and the second Fc fragment comprise M252Y, S254T, T256E, H433K, and N434Y compared to the amino acid sequences presented in SEQ ID NO. 56.

[0248] In one embodiment, the present invention provides a monovalent Fc fusion molecule particularly comprising two polypeptides, wherein the first polypeptide comprises an anti-HSA VHH fused to the C-terminus of the first Fc fragment, and the second polypeptide comprises the second Fc fragment, and the first Fc fragment and the second Fc fragment comprise M252Y, S254T, T256E, M428L, H433K, and N434F compared to the amino acid sequences presented in SEQ ID NO. 56.

[0249] In one embodiment, the present invention provides a monovalent Fc fusion molecule particularly comprising two polypeptides, wherein the first polypeptide comprises an anti-HSA VHH fused to the N-terminus of the first Fc fragment, and the second polypeptide comprises the second Fc fragment, and the first Fc fragment and the second Fc fragment comprise M252Y, S254T, T256E, M428L, H433K, and N434F compared to the amino acid sequences presented in SEQ ID NO. 56.

[0250] In some embodiments, the first Fc fragment and the second Fc fragment are identical. In some embodiments, the second Fc fragment and the second Fc fragment are further modified to promote heteromerization.

[0251] In some embodiments, the first Fc fragment and the second Fc fragment further comprise one or more amino acid substitutions selected from Y349C, S354C, T366S, T366W, T366Y, L368A, Y407T, and Y407V. In some embodiments, the first Fc fragment further comprises the amino acid substitutions Y349C, T366S, L368A, and Y407V, and the second Fc fragment further comprises the amino acid substitutions S354C and T366W. In some embodiments, the second Fc fragment further comprises the amino acid substitutions Y349C, T366S, L368A, and Y407V, and the first Fc fragment further comprises the amino acid substitutions S354C and T366W. In some embodiments, the first Fc fragment further comprises the amino acid substitutions T366S, L368A, and Y407V, and the second Fc fragment further comprises the amino acid substitution T266W. In some embodiments, the second Fc fragment further comprises the amino acid substitutions T366S, L368A, and Y407V, and the first Fc fragment further comprises the amino acid substitution T266W.

[0252] Fc fusion molecules are provided herein. The amino acid sequences of exemplary Fc fusion molecules and their components (e.g., albumin or albumin-binding domain, Fc fragment, linker) are Table 1d It is provided in.

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281] In certain embodiments, an Fc fusion molecule that binds to a newborn Fc receptor (FcRn) is further described herein, comprising a sequence having at least 80% sequence identity with any one of SEQ ID NOs 16 to 55. In some embodiments, the Fc fusion molecule comprises a sequence having at least 85% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 16 to 55. In some embodiments, the Fc fusion molecule comprises a sequence having at least 90% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 16 to 55. In some embodiments, the Fc fusion molecule comprises a sequence having at least 95% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 16 to 55. In some embodiments, the Fc fusion molecule comprises a sequence having at least 96% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 16 to 55. In some embodiments, the Fc fusion molecule comprises a sequence having at least 97% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 16 to 55. In some embodiments, the Fc fusion molecule comprises a sequence having at least 98% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 16 to 55. In some embodiments, the Fc fusion molecule comprises a sequence having at least 99% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 16 to 55. In some embodiments, the Fc fusion molecule comprises a sequence according to any one of SEQ ID NOs 16 to 55.

[0282] In some embodiments, the Fc fusion molecule comprises a sequence having at least 80% sequence identity with any one of SEQ ID NOs 16 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 85% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 16 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 90% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 16 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 95% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 16 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 96% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 16 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 97% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 16 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 98% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 16 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 99% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 16 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence according to any one of SEQ ID NOs 16 to 55 or 68 to 73.

[0283] In some embodiments, the Fc fusion molecule comprises a sequence having at least 80% sequence identity with any one of SEQ ID NOs 28 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 85% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 28 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 90% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 28 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 95% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 28 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 96% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 28 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 97% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 28 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 98% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 28 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 99% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 28 to 55 or 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence according to any one of SEQ ID NOs 28 to 55 or 68 to 73.

[0284] In some embodiments, the Fc fusion molecule comprises a sequence having at least 80% sequence identity with any one of SEQ ID NOs 28 to 45. In some embodiments, the Fc fusion molecule comprises a sequence having at least 85% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 28 to 45. In some embodiments, the Fc fusion molecule comprises a sequence having at least 90% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 28 to 45. In some embodiments, the Fc fusion molecule comprises a sequence having at least 95% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 28 to 45. In some embodiments, the Fc fusion molecule comprises a sequence having at least 96% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 28 to 45. In some embodiments, the Fc fusion molecule comprises a sequence having at least 97% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 28 to 45. In some embodiments, the Fc fusion molecule comprises a sequence having at least 98% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 28 to 45. In some embodiments, the Fc fusion molecule comprises a sequence having at least 99% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 28 to 45. In some embodiments, the Fc fusion molecule comprises a sequence according to any one of SEQ ID NOs 28 to 45.

[0285] In some embodiments, the Fc fusion molecule comprises a sequence having at least 80% sequence identity with any one of SEQ ID NOs 46 to 55. In some embodiments, the Fc fusion molecule comprises a sequence having at least 85% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 46 to 55. In some embodiments, the Fc fusion molecule comprises a sequence having at least 90% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 46 to 55. In some embodiments, the Fc fusion molecule comprises a sequence having at least 95% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 46 to 55. In some embodiments, the Fc fusion molecule comprises a sequence having at least 96% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 46 to 55. In some embodiments, the Fc fusion molecule comprises a sequence having at least 97% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 46 to 55. In some embodiments, the Fc fusion molecule comprises a sequence having at least 98% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 46 to 55. In some embodiments, the Fc fusion molecule comprises a sequence having at least 99% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 46 to 55. In some embodiments, the Fc fusion molecule comprises a sequence according to any one of SEQ ID NOs 46 to 55.

[0286] In some embodiments, the Fc fusion molecule comprises a sequence having at least 80% sequence identity with any one of SEQ ID NOs 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 85% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 90% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 95% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 96% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 97% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 98% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence having at least 99% sequence identity with an amino acid sequence according to any one of SEQ ID NOs 68 to 73. In some embodiments, the Fc fusion molecule comprises a sequence according to any one of SEQ ID NOs 68 to 73.

[0287] In some embodiments, the Fc fusion molecule described herein has an extended half-life (i.e., serum half-life). In some embodiments, the Fc fusion molecule described herein has a half-life of at least about 14, 28, 42, 56, 70, 84, 96 weeks, or more than 96 weeks. In some embodiments, the Fc fusion molecule described herein comprises a half-life in the range of about 14 to about 96 days, about 14 to about 84 days, about 14 to about 70 days, about 14 to about 56 days, about 14 to about 42 days, about 14 to about 28 days, about 28 to about 96 days, about 28 to about 84 days, about 28 to about 70 days, about 28 to about 56 days, about 28 to about 42 days, about 42 to about 96 days, about 42 to about 84 days, about 42 to about 70 days, or about 42 to about 56 days. In some embodiments, the Fc fusion molecule described herein comprises a half-life in the range of about 42 to about 56 days. In some embodiments, the Fc fusion molecule described herein has a half-life of at least about 50 days. In some embodiments, the Fc fusion molecule described herein has a half-life of about 50 days. Methods for measuring half-life are known in the art. In some embodiments, the half-life is measured in non-human primates. In some embodiments, the half-life is measured in humans.

[0288] In some embodiments, the Fc fusion molecule described herein has a half-life that is at least 20% longer than that of the comparative molecule. In some embodiments, the comparative molecule is an Fc fusion molecule that does not contain albumin or an albumin-binding domain. In some embodiments, the albumin or albumin-binding domain comprises a sequence having at least 80% sequence identity (e.g., 80%, 85%, 90%, 95%, 97%, 99%, 100%) with respect to the amino acid sequence according to any one of SEQ ID NOs 10 to 12. In some embodiments, the half-life of the Fc fusion molecule described herein is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% longer than that of the comparative molecule. In some embodiments, the half-life of the Fc fusion molecule described herein is at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, or at least 10 times longer than the half-life of the comparative molecule.

[0289] In some embodiments, the Fc fusion molecule reduces IgG levels to less than 60%, less than 50%, less than 40%, less than 30%, or less than 25%. In some embodiments, the Fc fusion molecule reduces IgG levels to less than 60%. In some embodiments, the Fc fusion molecule reduces IgG levels to less than 50%. In some embodiments, the Fc fusion molecule reduces IgG levels to less than 40%. In some embodiments, the Fc fusion molecule reduces IgG levels to less than 30%. In some embodiments, the Fc fusion molecule reduces IgG levels to less than 25%.

[0290] combination

[0291] The affinity of molecule X for its partner Y is the dissociation equilibrium constant (K DIt may be represented as ). The kinetic components contributing to the dissociation equilibrium constant are described in greater detail below. Affinity may be measured by general methods known in the art, including those described herein, such as surface plasmon resonance (SPR) techniques (e.g., BIACORE®) or biolayer interferometry (e.g., FORTEBIO®).

[0292] In the binding of an Fc fusion molecule to a target molecule, the terms 'bind', 'specific binding', 'specifically bind', 'specifically bind', 'specifically bind', 'selectively bind', and 'selective' to a specific antigen (e.g., a polypeptide target such as FcRn) imply a binding that is measurably different from non-specific or non-selective interactions (e.g., with a non-target molecule). Specific binding may be measured, for example, by measuring binding to a target molecule (e.g., FcRn) and comparing it to binding to a non-target molecule. Specific binding may also be determined by competition with a control molecule mimicking the target molecule. In such cases, if the binding of the Fc fusion molecule to the target molecule is competitively inhibited by the control molecule, specific binding occurs. In some embodiments, the affinity of the Fc fusion molecule to the non-target molecule is less than about 50% of the affinity for FcRn (i.e., K for FcRn). D is K for non-targets D(2 times lower than). In some embodiments, the affinity of the Fc fusion molecule to the non-target molecule is less than about 40% of the affinity for FcRn. In some embodiments, the affinity of the Fc fusion molecule to the non-target molecule is less than about 30% of the affinity for FcRn. In some embodiments, the affinity of the Fc fusion molecule to the non-target molecule is less than about 20% of the affinity for FcRn. In some embodiments, the affinity of the Fc fusion molecule to the non-target molecule is less than about 10% of the affinity for FcRn. In some embodiments, the affinity of the Fc fusion molecule to the non-target molecule is less than about 1% of the affinity for FcRn. In some embodiments, the affinity of the Fc fusion molecule to the non-target molecule is less than about 0.1% of the affinity for FcRn.

[0293] In some embodiments, the Fc fusion molecule is 1 x 10⁶ measured by ELISA or SPR or other suitable method known in the art at pH 6.0 or pH 7.4. -8 , 1.1 x 10 -8 , 1.2 x 10 -8 , 1.3 x 10 -8 , 1.4 x 10 -8 , 1.5 x 10 -8 , 1.6 x 10 -8 , 1.7 x 10 -8 , 1.8 x 10 -8 , 1.9 x 10 -8 , 1.95 x 10 -8 , 2 x 10 -8 , 2.5 x 10 -8 , 3 x 10 -8 , 3.5 x 10 -8 , 4 x 10 -8 , 4.5 x 10 -8 , 5 x 10 -8 , 6 x 10 -8 , 7 x 10 -8 , 8 x 10 -8 , 9 x 10 -8 , 1 x 10-9 , 1.1 x 10 -9 , 1.2 x 10 -9 , 1.3 x 10 -9 , 1.4 x 10 -9 , 1.5 x 10 -9 , 1.6 x 10 -9 , 1.7 x 10 -9 , 1.8 x 10 -9 , 1.9 x 10 -9 , 1.95 x 10 -9 , 2 x 10 -9 , 2.5 x 10 -9 , 3 x 10 -9 , 3.5 x 10 -9 , 4 x 10 -9 , 4.5 x 10 -9 , 5 x 10 -9 , 6 x 10 -9 , 7 x 10 -9 , 8 x 10 -9 , 9 x 10 -9 , 1 x 10 -10 , 1.1 x 10 -10 , 1.2 x 10 -10 , 1.3 x 10 -10 , 1.4 x 10 -10 , 1.5 x 10 -10 , 1.6 x 10 -10 , 1.7 x 10 -10 , 1.8 x 10 -10 , 1.9 x 10 -10 , 1.95 x 10 -10 , 2 x 10 -10 , 2.5 x 10 -10 , 3 x 10 -10 , 3.5 x 10 -10 , 4 x 10 -10 , 4.5 x 10 -10 , 5 x 10 -10 , 6 x 10 -10 , 7 x 10 -10 , 8 x 10 -10 , 또는 9 x 10 -10 M 이하의 K DIt binds to FcRn.

[0294] In some embodiments, the Fc fusion molecule is about 1.0–1.1 x 10⁻⁶ as measured by ELISA or SPR or other suitable methods known in the art at pH 6.0 or pH 7.4. -8 M, 1.1-1.2 x 10 -8 M, 1.2-1.3 x 10 -8 M, 1.3-1.4 x 10 -8 M, 1.4-1.5 x 10 -8 M, 1.5-1.6 x 10 -8 M, 1.6-1.7 x 10 -8 M, 1.7-1.8 x 10 -8 M, 1.8-1.9 x 10 -8 M, 1.9-2 x 10 -8 M, 1-2 x 10 -8 M, 1-5 x 10 -8 M, 2-7 x 10 -8 M, 3-8 x 10 -8 M, 3-5 x 10 -8 M, 4-6 x 10 -8 M, 5-7 x 10 -8 M, 6-8 x 10 -8 M, 7-9 x 10 -8 M, 7-9.9 x 10 -8 M, 5-9.9 x 10 -8 M, 1.0-1.1 x 10 -9 M, 1.1-1.2 x 10 -9 M, 1.2-1.3 x 10 -9 M, 1.3-1.4 x 10 -9 M, 1.4-1.5 x 10 -9 M, 1.5-1.6 x 10 -9 M, 1.6-1.7 x 10 -9 M, 1.7-1.8 x 10 -9 M, 1.8-1.9 x 10 -9 M, 1.9-2 x 10 -9 M, 1-2 x 10 -9 M, 1-5 x 10 -9M, 2-7 x 10 -9 M, 3-8 x 10 -9 M, 3-5 x 10 -9 M, 4-6 x 10 -9 M, 5-7 x 10 -9 M, 6-8 x 10 -9 M, 7-9 x 10 -9 M, 7-9.9 x 10 -9 M, or 5-9.9 x 10⁻⁶ -9 It binds to FcRn as M. In some embodiments, the Fc fusion molecule is about 1 x 10⁻⁶ as measured by ELISA, SPR, or other suitable methods known in the art at pH 6.0 or pH 7.4. -8 M or less, or about 1 x 10 -9 K less than or equal to M D It binds to FnRn.

[0295] In some embodiments, the Fc fusion molecule is about 1 x 10⁻⁶ as measured by ELISA or SPR or other suitable methods known in the art at pH 6.0 or pH 7.4. -8 , 1.1 x 10 -8 , 1.2 x 10 -8 , 1.3 x 10 -8 , 1.4 x 10 -8 , 1.5 x 10 -8 , 1.6 x 10 -8 , 1.7 x 10 -8 , 1.8 x 10 -8 , 1.9 x 10 -8 , 1.95 x 10 -8 , 2 x 10 -8 , 2.5 x 10 -8 , 3 x 10 -8 , 3.5 x 10 -8 , 4 x 10 -8 , 4.5 x 10 -8 , 5 x 10 -8 , 6 x 10 -8 , 7 x 10 -8 , 8 x 10 -8 , 9 x 10 -8, 1 x 10 -9 , 1.1 x 10 -9 , 1.2 x 10 -9 , 1.3 x 10 -9 , 1.4 x 10 -9 , 1.5 x 10 -9 , 1.6 x 10 -9 , 1.7 x 10 -9 , 1.8 x 10 -9 , 1.9 x 10 -9 , 1.95 x 10 -9 , 2 x 10 -9 , 2.5 x 10 -9 , 3 x 10 -9 , 3.5 x 10 -9 , 4 x 10 -9 , 4.5 x 10 -9 , 5 x 10 -9 , 6 x 10 -9 , 7 x 10 -9 , 8 x 10 -9 , 9 x 10 -9 , 1 x 10 -10 , 1.1 x 10 -10 , 1.2 x 10 -10 , 1.3 x 10 -10 , 1.4 x 10 -10 , 1.5 x 10 -10 , 1.6 x 10 -10 , 1.7 x 10 -10 , 1.8 x 10 -10 , 1.9 x 10 -10 , 1.95 x 10 -10 , 2 x 10 -10 , 2.5 x 10 -10 , 3 x 10 -10 , 3.5 x 10 -10 , 4 x 10 -10 , 4.5 x 10 -10 , 5 x 10 -10 , 6 x 10 -10 , 7 x 10 -10 , 8 x 10 -10 , 또는 9 x 10 -10 M 이하의 K DIt binds to albumin (e.g., human serum albumin).

[0296] In some embodiments, the Fc fusion molecule is about 1.0–1.1 x 10⁻⁶ as measured by ELISA or SPR or other suitable methods known in the art at pH 6.0 or pH 7.4. -8 M, 1.1-1.2 x 10 -8 M, 1.2-1.3 x 10 -8 M, 1.3-1.4 x 10 -8 M, 1.4-1.5 x 10 -8 M, 1.5-1.6 x 10 -8 M, 1.6-1.7 x 10 -8 M, 1.7-1.8 x 10 -8 M, 1.8-1.9 x 10 -8 M, 1.9-2 x 10 -8 M, 1-2 x 10 -8 M, 1-5 x 10 -8 M, 2-7 x 10 -8 M, 3-8 x 10 -8 M, 3-5 x 10 -8 M, 4-6 x 10 -8 M, 5-7 x 10 -8 M, 6-8 x 10 -8 M, 7-9 x 10 -8 M, 7-9.9 x 10 -8 M, 5-9.9 x 10 -8 M, 1.0-1.1 x 10 -9 M, 1.1-1.2 x 10 -9 M, 1.2-1.3 x 10 -9 M, 1.3-1.4 x 10 -9 M, 1.4-1.5 x 10 -9 M, 1.5-1.6 x 10 -9 M, 1.6-1.7 x 10 -9 M, 1.7-1.8 x 10 -9 M, 1.8-1.9 x 10 -9 M, 1.9-2 x 10 -9 M, 1-2 x 10 -9 M, 1-5 x 10-9 M, 2-7 x 10 -9 M, 3-8 x 10 -9 M, 3-5 x 10 -9 M, 4-6 x 10 -9 M, 5-7 x 10 -9 M, 6-8 x 10 -9 M, 7-9 x 10 -9 M, 7-9.9 x 10 -9 M, or 5-9.9 x 10⁻⁶ -9 M binds to albumin (e.g., human serum albumin). In some embodiments, the Fc fusion molecule is about 1 x 10⁶ as measured by ELISA or SPR or other suitable methods known in the art at pH 6.0 or pH 7.4. -8 M or less, or about 1 x 10 -9 K less than or equal to M D It binds to albumin.

[0297] Pharmaceutical composition

[0298] The present disclosure also features a pharmaceutical composition containing a therapeutically effective amount of the Fc fusion molecule described herein. The composition may be formulated for use in various drug delivery systems. One or more physiologically acceptable excipients or carriers may also be included in the composition for appropriate formulation. A formulation suitable for use in the present disclosure is found in the literature [Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17th ed., 1985]. For a brief review of methods for drug delivery, for example , refer to the literature [Langer (Science 249:1527-1533, 1990)].

[0299] In some embodiments, the pharmaceutical composition may contain a formulation material to modify, maintain, or preserve, for example, pH, osmotic pressure, viscosity, transparency, color, isotonicity, odor, sterility, stability, solubility or release rate, or absorption or penetration of the composition. In these embodiments, suitable formulation materials are amino acids (e.g., glycine, glutamine, asparagine, arginine, or lysine); antimicrobial agents; antioxidants (e.g., ascorbic acid, sodium sulfite, or sodium bisulfite); buffers (e.g., borates, bicarbonates, Tris-HCl, citrates, phosphates, or other organic acids); bulking agents (e.g., mannitol or glycine); chelating agents (e.g., ethylenediaminetetraacetic acid (EDTA)); Complexing agents (e.g., caffeine, polyvinylpyrrolidone, beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (e.g., glucose, mannose, or dextrin); proteins (e.g., serum albumin, gelatin, or immunoglobulin); coloring agents, flavoring agents, and diluents; emulsifiers; hydrophilic polymers (e.g., polyvinylpyrrolidone); low molecular weight polypeptides; salt-forming counterions (e.g., sodium); preservatives (e.g., benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide); solvents (e.g., glycerin, propylene glycol, or polyethylene glycol); Sugar alcohols (e.g., mannitol or sorbitol); suspending agents; surfactants or wetting agents (e.g., Pluronics, PEG, polysorbates, e.g., polysorbate 20, polysorbate, Triton, tromethamine, lecithin, cholesterol, tiloxapal); stability enhancers (e.g., sucrose or sorbitol); isotonic enhancers (e.g., alkali metal halides, preferably sodium chloride or potassium chloride, mannitol sorbitol); delivery vehicles; diluents; excipients and / or pharmaceutical adjuvants, but are not limited thereto (Literature [ Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990)].

[0300] In some embodiments, the pharmaceutical composition does not contain citrate.

[0301] In some embodiments, the pharmaceutical composition comprises nanoparticles, for example, It may contain polymeric nanoparticles, liposomes, or micelles.

[0302] In some embodiments, the pharmaceutical composition may contain a sustained or controlled delivery formulation. Techniques for formulating sustained or controlled delivery means, such as liposome carriers, bio-erosive microparticles or porous beads, and depot injections are also known to those skilled in the art. Sustained-release formulations are formed articles, for example In the form of films or microcapsules for example It may include porous polymeric microparticles or a semipermeable polymer matrix. The sustained-release matrix may include polyester, hydrogel, polylactide, a copolymer of L-glutamic acid and gamma ethyl-L-glutamate, poly(2-hydroxyethyl-phosphoric acid), ethylene vinyl acetate, or poly-D(-)-3-hydroxybutyric acid. The sustained-release composition may also include liposomes that can be prepared by any of the methods known in the art.

[0303] Pharmaceutical compositions containing the Fc fusion molecules disclosed herein may be provided in the form of dosing units and may be prepared by any suitable method. Pharmaceutical compositions are formulated to be compatible with their intended routes of administration. Examples of routes of administration include intravenous (IV), intradermal, inhalation, transdermal, topical, transmucosal, intrathecal, and rectal administration. In some embodiments, the Fc fusion molecules disclosed herein are administered intravenously or subcutaneously. In some embodiments, the Fc fusion molecules disclosed herein are administered intravenously. In some embodiments, the Fc fusion molecules disclosed herein are administered subcutaneously.

[0304] Useful formulations can be manufactured by methods known in the pharmaceutical field. For example, literature [ Remington's Pharmaceutical Sciences Refer to , 18th ed. (Mack Publishing Company, 1990). Formulations suitable for parenteral administration comprise a sterile diluent, e.g., water for injection, saline solution, fixative oil, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvent; an antimicrobial agent, e.g., benzyl alcohol or methyl paraben; an antioxidant, e.g., ascorbic acid or sodium bisulfite; a chelating agent, e.g., EDTA; a buffer, e.g., acetate, citrate, or phosphate; and an isotonic modifier, e.g., sodium chloride or dextrose. In some embodiments, formulations for parenteral administration are citrate-free.

[0305] For intravenous or subcutaneous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ, USA), or phosphate-buffered saline (PBS). The carrier must be stable under manufacturing and storage conditions and must be preserved against microorganisms. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof.

[0306] Intravenous or subcutaneous drug delivery formulations may be held in a syringe, pen, or bag. In some embodiments, the bag is connected to a channel including a tube and / or needle. In some embodiments, the formulation is a lyophilized formulation or a liquid formulation.

[0307] These compositions may be sterilized by conventional sterilization techniques or sterile filtered. The resulting aqueous solution may be packaged for use as is or freeze-dried, and the freeze-dried formulation is combined with a sterile aqueous carrier before administration.

[0308] A polyol capable of acting as an isotonic agent and stabilizing the Fc fusion molecule may also be included in the formulation. The polyol is added to the formulation in an amount that may vary for the desired isotonicity of the formulation. In some embodiments, the aqueous formulation is isotonic. The amount of polyol added may also vary depending on the molecular weight of the polyol. For example, a smaller amount of monosaccharide (e.g., trehalose) compared to disaccharides (e.g., trehalose) for example , mannitol) is added. In some embodiments, the polyol used in the formulation as an isotonic agent is mannitol.

[0309] Detergents or surfactants may also be added to the formulation. An exemplary detergent is a nonionic detergent, such as polysorbate ( for example , polysorbate 20, 80, etc.) or poloxamer ( for example It includes poloxamer 188). The amount of detergent added is added to reduce aggregation of the formulated Fc fusion molecules and / or minimize the formation of particulates within the formulation and / or reduce adsorption. In some embodiments, the formulation includes a surfactant that is a polysorbate. In some embodiments, the formulation may contain detergent polysorbate 80 or Tween 80. Tween 80 is a term used to describe polyoxyethylene (20) sorbitan monooleate (see reference [Fiedler, Lexikon der Hifsstoffe, Editio Cantor Verlag Aulendorf, 4th edi., 1996]).

[0310] In embodiments, the protein product of the present disclosure is formulated as a liquid formulation. In some embodiments, the liquid formulation is prepared by combining it with a sugar at a stabilizing level. In some embodiments, the liquid formulation is prepared in an aqueous carrier. In some embodiments, the stabilizer is added in an amount less than that which may result in a viscosity undesirable or unsuitable for intravenous administration. In some embodiments, the sugar is a disaccharide, for example, is sucrose. In some embodiments, the liquid formulation may also include one or more of a buffer, a surfactant, and a preservative.

[0311] In some embodiments, the pH of the liquid formulation is set by the addition of a pharmaceutically acceptable acid and / or base. In some embodiments, the pharmaceutically acceptable acid is hydrochloric acid. In some embodiments, the base is sodium hydroxide.

[0312] The aqueous carriers of interest to this invention are pharmaceutically acceptable (safe and non-toxic for administration to humans) and are useful for liquid formulations. Exemplary carriers include sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), and pH buffer solution ( for example It includes phosphate-buffered saline), sterile saline solution, Ringer's solution, or dextrose solution.

[0313] Preservatives may be optionally added to the formulations of the present invention to reduce bacterial activity. The addition of preservatives may, for example, facilitate the manufacture of multi-use (multi-dose) formulations.

[0314] Fc fusion molecules can be freeze-dried to produce freeze-dried formulations containing proteins and cryoprotectants. The cryoprotectant is a sugar, for example , may be a disaccharide. In some embodiments, the cryoprotectant is sucrose or maltose. The lyophilized formulation may also include one or more of a buffer, a surfactant, a bulking agent, and / or a preservative.

[0315] The amount of sucrose or maltose useful for stabilizing the lyophilized medicine may be at least a weight ratio of protein to sucrose or maltose of 1:2. In some embodiments, the weight ratio of protein to sucrose or maltose is 1:2 to 1:5. In some embodiments, the pH of the formulation prior to lyophilization is set by the addition of a pharmaceutically acceptable acid and / or base. In some embodiments, the pharmaceutically acceptable acid is hydrochloric acid. .In some embodiments, the pharmaceutically acceptable base is sodium hydroxide.

[0316] The patient's dosage may be adjusted based on the patient's approximate body weight or surface area. Other factors in determining the appropriate dosage may include the disease or condition to be treated or prevented, the severity of the disease, the route of administration, and the patient's age, sex, and medical condition. Further details of the calculations required to determine the appropriate therapeutic dosage are routinely performed by those skilled in the art, particularly in consideration of the dosage information and assays disclosed herein. The dosage may also be determined through the use of known assays to determine the dosage, in conjunction with appropriate dosage response data. The dosage for individual patients may be adjusted while monitoring the progression of the disease. The blood levels of the patient's targetable construct or complex may be measured to determine whether the dosage needs to be adjusted to reach or maintain an effective concentration. Pharmacogenomics may be used to determine which targetable construct and / or complex and their dosage are most likely to be effective for a given individual (Reference [Schmitz et al. , Clinica Chimica Acta 308: 43-53, 2001]; Literature[Steimer et al. , Clinica Chimica Acta 308: 33-41, 2001]).

[0317] How to use

[0318] In some embodiments, the present application provides a method of contacting FcRn with the Fc fusion molecule described herein. In some embodiments, FcRn is expressed on a cell surface.

[0319] In some embodiments, the present application provides a method of using the Fc fusion molecule described herein for the treatment of a disorder or disease in a patient requiring treatment of the disorder or disease. In some embodiments, the present application provides a method of using the Fc fusion molecule described herein to reduce IgG levels in a patient requiring reduction of IgG levels. In some embodiments, a method of treatment in a patient requiring treatment is provided herein, said method comprising the step of administering a therapeutically effective amount of the Fc fusion molecule described herein or a pharmaceutical composition comprising the Fc fusion molecule to the patient requiring treatment.

[0320] In some embodiments, the present application provides a method of using the Fc fusion molecule described herein for the treatment of a disorder or disease in a patient requiring treatment for the disorder or disease. In some embodiments, a method of treating a patient requiring treatment with the Fc fusion molecule described herein is described herein, said method comprising the step of administering to the patient a therapeutically effective amount of the Fc fusion molecule described herein or a pharmaceutical composition comprising the Fc fusion molecule. In some embodiments, the present application provides a method of treating a disorder or disease associated with elevated levels of IgG in a subject by administering the Fc fusion molecule described herein.

[0321] In some embodiments, a method for treating pathology related to IgG activity is described herein, and the method comprises the step of administering a therapeutically effective amount of the Fc fusion molecule described herein or a pharmaceutical composition comprising the Fc fusion molecule to a patient who requires treatment for pathology related to IgG activity.

[0322] In some embodiments, a method for treating a pathology associated with elevated FcRn levels in a patient requiring treatment for the pathology associated with elevated FcRn levels is described herein, said method comprising the step of administering to the patient a therapeutically effective amount of the Fc fusion molecule described herein or a pharmaceutical composition comprising the Fc fusion molecule.

[0323] In some embodiments, a method for treating or preventing an antibody-related disorder or disease in a patient requiring treatment or prevention of the antibody-related disorder or disease (e.g., an autoimmune disease or a disorder related to unwanted side effects of a therapeutic antibody) is described herein, said method comprising the step of administering to the patient a therapeutically effective amount of the Fc fusion molecule disclosed herein or the pharmaceutical composition disclosed herein. In some embodiments, the inflammatory disorder or disease is an autoimmune disease. In some embodiments, the inflammatory disorder or disease is myasthenia gravis (gMG). In some embodiments, the inflammatory disorder or disease is immune thrombocytopenia (ITP).

[0324] In some embodiments, a method for treating a pathology associated with elevated levels of IgG in a patient requiring treatment for a pathology associated with elevated levels of IgG is described herein, said method comprising the step of administering to the patient a therapeutically effective amount of the Fc fusion molecule disclosed herein or the pharmaceutical composition disclosed herein.

[0325] In some embodiments, a method for reducing the biological activity of IgG in a patient requiring a reduction in the biological activity of IgG is described herein, and said method comprises the step of administering to the patient a therapeutically effective amount of the Fc fusion molecule disclosed herein or the pharmaceutical composition disclosed herein.

[0326] In some embodiments, a method for treating or preventing an autoimmune disease is described herein. In some embodiments, the autoimmune disease is caused by an autoreactive antibody.

[0327] In some embodiments, the disease or disorder is generalized myasthenia gravis (gMG), chronic inflammatory demyelinating polyneuropathy, myositis, autoimmune encephalitis, myelin oligodendrocyte glycoprotein antibody disorder (MOG antibody disorder), membranous nephropathy, lupus nephritis, thyroid eye disease, warm autoimmune hemolytic anemia, fetal and neonatal hemolytic disease, idiopathic thrombocytopenic purpura, primary Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, bullous pemphigus, pemphigus foliaceus, pemphigus vulgaris, or cutaneous lupus erythematosus.

[0328] In some embodiments, the disease or disorder is an autoimmune disease.

[0329] In some embodiments, autoimmune diseases include allogeneic islet transplant rejection, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, Alzheimer's disease, anti-neutrophil cytoplasmic autoantibody (ANCA), adrenal autoimmune disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune myocarditis, autoimmune neutropenia, autoimmune oophoritis and orchitis, autoimmune thrombocytopenia, autoimmune urticaria, Behcet's disease, bullous pemphigus, cardiomyopathy, Castleman syndrome, intra-abdominal spruce dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), Churg-Strauss syndrome, cicatricial pemphigus, CREST syndrome, cold agglutinin disease, Crohn's disease, dermatomyositis, dilated cardiomyopathy, discoid lupus, acquired Epidermolysis, Essential mixed cryoglobulinemia, Factor VIII deficiency, Fibromyalgia-fibromyositis, Glomerulonephritis, Graves' disease, Guillain-Barré syndrome, Goodpasture syndrome, Graft-versus-host disease (GVHD), Hashimoto's thyroiditis, Hemophilia A, Idiopathic inflammatory myopathy, Idiopathic membranous neuropathy, Idiopathic pulmonary fibrosis, Idiopathic thrombocytopenic purpura (ITP), IgA neuropathy, IgM polyneuropathy, Immune-mediated thrombocytopenia, Juvenile arthritis, Kawasaki disease, Lichen planus, Lichen sclerosus, Lupus erythematosus, Meniere's disease, Mixed connective tissue disease, Mucomembranous pemphigus, Multiple sclerosis, Type 1 diabetes mellitus, Polymotor neuropathy (MMN), Myasthenia gravis, Tumor-associated bullous pemphigus, Pregnancy pemphigus, Pemphigus vulgaris, Pemphigus foliaceus, pernicious anemia, polyarteritis nodosum, polychondritis, polydysplasia syndrome, polymyalgia rheumaticis, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, recurrent polychondritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, organ transplant rejection, spasticity syndrome, systemic lupus erythematosus, Takayasu's arteritis, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS),It is selected from the group consisting of temporal arteritis / giant cell arteritis, thrombotic thrombocytopenic purpura, ulcerative colitis, uveitis, herpes-like dermatitis, vasculitis, anti-neutrophil cytoplasmic antibody-associated vasculitis, vitiligo, and Wegner granulomatosis.

[0330] In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 50% within 7 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 50% within 5 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 50% within 3 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 50% within 2 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 50% within 1 day of the first administration.

[0331] In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 75% within 7 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 75% within 6 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 75% within 5 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 75% within 4 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 75% within 3 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 75% within 2 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 75% within 1 day of the first administration.

[0332] In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 80% within 7 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 80% within 6 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 80% within 5 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 80% within 4 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 80% within 3 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 80% within 2 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 80% within 1 day of the first administration.

[0333] In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 90% within 7 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 90% within 6 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 90% within 5 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 90% within 4 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 90% within 3 days of the first administration. In some embodiments, administration of the Fc fusion molecule reduces the IgG level by at least 90% within 2 days of the first administration.

[0334] In some embodiments, administration of the Fc fusion molecule reduces IgG levels by at least 90% within 1 day of the first administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 60%, less than 50%, less than 40%, less than 30%, or less than 25% over at least 5, 7, 10, 15, or 20 days after administration.

[0335] In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 60% for at least 5 days after administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 60% for at least 7 days after administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 60% for at least 10 days after administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 60% for at least 15 days after administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 60% for at least 20 days after administration.

[0336] In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 50% for at least 5 days after administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 50% for at least 7 days after administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 50% for at least 10 days after administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 50% for at least 15 days after administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 50% for at least 20 days after administration.

[0337] In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 40% for at least 5 days after administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 40% for at least 7 days after administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 40% for at least 10 days after administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 40% for at least 15 days after administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 40% for at least 20 days after administration.

[0338] In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 30% for at least 5 days after administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 30% for at least 7 days after administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 30% for at least 10 days after administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 30% for at least 15 days after administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 30% for at least 20 days after administration.

[0339] In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 25% for at least 5 days after administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 25% for at least 7 days after administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 25% for at least 10 days after administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 25% for at least 15 days after administration. In some embodiments, administration of the Fc fusion molecule reduces IgG levels to less than 25% for at least 20 days after administration.

[0340] In some embodiments, IgG levels are reduced compared to baseline. In some embodiments, baseline is the IgG level in the patient before administration. In some embodiments, baseline is the IgG level in a comparable patient without administration of the Fc fusion molecule described herein.

[0341] Manufacturing method

[0342] The Fc fusion molecule described above can be produced using recombinant DNA technology well known to those skilled in the art. For example, one or more isolated polynucleotides encoding the Fc fusion molecule are ligated to another suitable nucleotide sequence, for example, including an invariant region coding sequence and an expression control sequence, to form a conventional gene expression construct encoding the desired Fc fusion molecule ( in other words It is possible to produce expression vectors. The production of defined gene constructs is within the ordinary technical scope of the art.

[0343] The nucleic acid encoding the desired Fc fusion molecule can be incorporated (ligated) into an expression vector and introduced into a host cell via conventional transfection or transformation techniques. An exemplary host cell is E. coliCells, Chinese hamster ovary (CHO) cells, human embryonic kidney 293 (HEK 293) cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells ( for example These are myeloma cells that do not otherwise produce Hep G2), and IgG proteins. Transformed host cells can be grown under conditions that allow the host cells to express a gene encoding an Fc fusion molecule.

[0344] Specific expression and purification conditions will vary depending on the expression system used. For example, a gene E. coli In cases where it is expressed in, this is a suitable bacterial promoter, for example The engineered gene is first cloned into an expression vector by positioning it downstream from the Trp or Tac and prokaryotic signal sequences. The expressed protein can be secreted. The expressed protein can be accumulated within a refractory body or inclusion body, which can be harvested after the cell is destroyed by French pressing or sonication. Subsequently, the refractory body is solubilized, and the protein can be refolded / folded or cleaved by methods known in the art.

[0345] The manipulated gene in the eukaryotic host cell, for example When expressed in CHO cells, it is first inserted into an expression vector containing a suitable eukaryotic promoter, a secretion signal, a poly A sequence, and a stop codon. Optionally, the vector or gene construct may contain enhancers and introns. In some embodiments, the expression vector contains a sequence encoding all or part of an invariant region that allows all or part of the heavy chain or light chain to be optionally expressed. The gene construct may be introduced into a eukaryotic host cell using conventional techniques.

[0346] In some embodiments, an N-terminal signal sequence is included in the protein composition. Exemplary N-terminal signal sequences include signal sequences from interleukin-2, CD-5, IgG kappa light chain, trypsinogen, serum albumin, and prolactin.

[0347] After transfection, a single clone can be isolated for cell bank production using methods known in the art, such as limited dilution, ELISA, FACS, microscopy, or CloneFix. The clone can be cultured under conditions suitable for bioreactor scale-up and maintain the expression of the Fc fusion molecule.

[0348] Fc fusion molecules can be isolated and purified using methods known in the art, including centrifugation, deep filtration, cell lysis, homogenization, freeze-thaw, affinity purification, gel filtration, ion exchange chromatography, hydrophobic interaction exchange chromatography, and mixed-mode chromatography.

[0349] Examples

[0350] The present disclosure, as described generally, will be more easily understood by referring to the following examples, which are included merely for the purpose of illustrating specific aspects and embodiments of the present disclosure and are not intended to limit the present disclosure.

[0351] Example 1: Measurement of binding kinetics of Fc fusion molecules to albumin and huFcRn using surface plasmon resonance

[0352] Binding kinetics rates and affinity constants were determined using a Biacore 8K SPR system equipped with a CM5 sensor chip immobilized with an anti-human Fc specific antibody via amine coupling at 25°C in a running buffer of pH 6.0 or pH 7.4 (10 mM HEPES, 150 mM NaCl, 3 mM EDTA, 0.05% surfactant P20). After a stabilization period in the running buffer, 20 nM of Fc fusion molecules were captured on flow cell 2 (active) for 60 seconds at a flow rate of 30 uL / min. Recombinant in-house human FcRn (huFCRN) protein or human serum albumin (HSA) were prepared at concentrations of 0, 26.25, 52.5, 125, 250, and 500 nM and injected into flow cell 1 (reference) and flow cell 2 (active) for 120 seconds at a flow rate of 30 μL / min. Recombinant Fc molecules were prepared at concentrations of 0, 25, 50, 100, 200, and 400 nM and injected into flow cell 1 (reference) and flow cell 2 (active) for 120 seconds at a flow rate of 30 μL / min. Samples were injected in a multi-cycle manner for newly captured Fc fusion molecules by regenerating the capture surface through the injection of 10 mM glycine pH 1.5 at a flow rate of 30 μL / min for 30 seconds. The data was processed and analyzed using Biacore Insight Evaluation Software Version 2.0.15.12933 (GE Healthcare) as follows. The reaction from flow cell 1 (reference) was subtracted from the reaction from flow cell 2 (active). Then, the reaction from the blank injection of the two buffers was subtracted from the data (2-1) subtracted from the reference to obtain double reference data, which was fitted to a 1:1 coupling model to determine the apparent association (ka) and dissociation rate constant (kd). The ratio of these provided the apparent equilibrium dissociation constant or affinity constant (KD = kd / ka).

[0353] Coupling dynamics is Table 2 and FIGS. 2a to 2d , FIGS. 3a to 3d , FIGS. 4a to 4d , and FIGS. 5a to 5d It appears in.

[0354]

[0355] Example 2: Production of Fc fusion molecules in CHO cells

[0356] The production of Fc fusion molecules in CHO cell cultures was carried out as described in the methods section disclosed herein.

[0357] Culture yield, percentage of monomers determined by analytical size exclusion chromatography (aSEC), and amount of LPS measured in endotoxin units / milligram (EU / mg). Table 3 It appears in.

[0358]

[0359] Example 3: Characteristics of Fc Fusion Molecules

[0360] Fc fusion molecules were evaluated for DNA and insulin responsiveness as well as their self-association tendency (methods provided below). Additionally, the Tm and Tagg of the Fc fusion molecules were determined using differential scanning fluorescence (DSF) and SLS signals at 266 nm as a function of temperature. DSF and SLS were performed as described in the methods section disclosed herein. All corresponding results Table 4 It appears in.

[0361] The DNA and insulin responsiveness of Fc fusion molecules were screened using a polyreactive ELISA assay. For this assay, plates were coated overnight at 4°C with DNA (10 μg / ml) and 5 μg / ml (insulin) in PBS pH 7.5. Wells were washed with water, blocked with 50 μl of polyreactive ELISA buffer (PEB; PBS containing 0.05% Tween-20 and 1 mM EDTA) at room temperature for 1 hour, and washed three times with water. 25 μl of serially diluted Fc fusion molecules were added to the wells in quadruples and incubated at room temperature for 1 hour. Plates were washed three times with water, and 25 μl of 10 ng / ml goat anti-human IgG (Fc-specific) conjugated to Hallsradish peroxidase was added to each well. The plates were incubated at room temperature for 1 hour, washed three times with 80 μl of water, and 25 μl of TMB substrate was added to each well. 25 μl of 0.18 M orthophosphate was added to each well, the reaction was stopped after approximately 7 minutes, and the absorbance was read at 450 nm. The DNA and insulin binding scores were calculated as the ratio of the ELISA signal of 10 μg / ml of Fc fusion molecule to the signal in wells containing buffer instead of the primary antibody.

[0362] Affinity-capture self-interaction nanoparticle spectroscopy (AC-SINS) assay was performed to determine the self-association tendency of Fc fusion molecules. Briefly, 20 nm gold nanoparticles were coated with a mixture of 80% goat anti-human Fc and 20% non-specific goat polyclonal antibody diluted to 0.4 mg / ml, buffered with 20 mM sodium acetate at pH 4.3. After incubation at room temperature for 1 hour, unoccupied sites on the gold nanoparticles were blocked with thiolated polyethylene glycol (2 kD). Subsequently, the coated nanoparticles were concentrated 10-fold using a syringe filter, and 10 μl was added to 100 μl of 0.05 mg / ml mAb in PBS pH 7.2. Coated nanoparticles were incubated with the Fc fusion molecule of interest in a 96-well polypropylene plate for 2 hours, then transferred to a 384-well polystyrene plate and read on a spectrophotometer. Absorbance was read at 450–650 in 2 nm increments. The antibody AC-SINS score was determined by subtracting the smoothed maximum absorbance of the average blank (PBS alone) from the smoothed maximum absorbance of the antibody sample.

[0363] Most Fc fusion molecules exhibited favorable DNA binding, insulin binding, and AC-SINS scores. DSF analysis revealed that Fc fusion molecule 7 had a TM value of nearly 80°C, while most of the remaining samples exhibited TM values ​​ranging from 60 to 76°C. Fc fusion molecule 7 had the highest Tagg value (72.9°C), while other Fc fusion molecules exhibited TM values ​​ranging from 65.3 to 72.2°C.

[0364]

[0365] Example 4: Pharmacokinetics (PK) and Pharmacodynamics (PD) of Fc Fusion Molecules in Mice

[0366] This example describes a pharmacokinetic (PK) / pharmacodynamic (PD) study of an Fc fusion molecule in mice.

[0367] An exemplary workflow is also 6It is shown in, and the summary of the research parameters is Table 5 It is shown in. Briefly, mice were divided into different cohorts. Various fusion molecules were administered intravenously to the mice. An exemplary control Fc fusion molecule (PAL02-173) containing an RSV binding domain instead of the Fc fragment and albumin binding domain was similarly administered intravenously to the mice. The study period spanned 21 days using blood samples taken at 11 time points.

[0368]

[0369] The data FIGS. 7a to 7e As shown in [figure]. The PK / PD profile demonstrated that Fc fusion molecule 6 exhibited superior improved PD effects and prolonged serum exposure compared to Fc fragment 1 (Fig. 7a and 7b Fc fusion molecule 6 also showed a difference compared to Fc fragment 1 and Fc fusion molecule 5 in human IVIG tracer reduction using one-way ANOVA analysis.

[0370] Example 5. Binding kinetics of exemplary Fc fragments to FcRn from different species

[0371] This example demonstrated the binding kinetics of exemplary Fc fragments to FcRn from different species at acidic and physiological pH.

[0372] The binding kinetics of exemplary Fc fragments to FcRn in humans, cynomolgus monkeys, mice, and rats were measured using surface plasmon resonance (SPR). The binding affinity (K D )Is In Table 6 As shown, calculations were performed at both pH 6.0 and pH 7.4.

[0373]

[0374]

[0375] Dynamic values ​​were adjusted from the reference doi.org / 10.1080 / 19420862.2015.1008353

[0376] Example 6. An exemplary Fc fragment blocks IgG binding to human FcRn.

[0377] This example demonstrates the ability of an exemplary Fc fragment to block IgG binding to human FcRn.

[0378] Briefly, the ability of an exemplary Fc fragment to block IgG and a comparative Fc fragment 1—a C-terminal lysine-free e.g.gartigimod that binds to human FcRn—was measured by a competitive binding ELISA assay at pH 6.0. IC 50 The value is calculated for an exemplary Fc fragment, and this Table 7 It appears in.

[0379]

[0380] Example 7. Optimization of Linker Length of Exemplary Fc Fusion Molecule

[0381] In this embodiment, the linker length of an exemplary Fc fusion molecule In a test tube It demonstrates that it can affect the decomposition of FcRn.

[0382] Briefly, seed HEK cells stably expressing FcRn-GFP, and 5% CO Incubated overnight in IgG-depleted medium at 37°C. The following day, cells were treated with the experimental Fc fusion molecule at a final concentration of 100 μM in the presence or absence of human serum albumin (HSA). After treatment, cells were harvested, washed with PBS, fixed, and collected for flow cytometry. Viability and GFP signal were evaluated using a CytoFLEX LX flow cytometer.

[0383] The residual FcRn after treatment with an exemplary Fc fusion molecule is Fig. 8 It appears in, Table 8 It was quantified in [location]. The results show reduced FcRn degradation as linker length increases, regardless of the exemplary albumin binding domain.

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397] Enumerated embodiments

[0398] Example 1. An Fc fusion molecule that binds to a neonatal Fc receptor (FcRn), comprising moving from the N-terminus to the C-terminus or from the C-terminus to the N-terminus:

[0399] a) an Fc fragment comprising a sequence having at least 80% sequence identity with any one of SEQ ID NOs 1 to 9 amino acid sequences;

[0400] b) Linker; and

[0401] c) an albumin or albumin binding domain comprising a sequence having at least 80% sequence identity with any one of the amino acid sequences of SEQ ID NOs 10 to 13.

[0402] Embodiment 2. The Fc fusion molecule of Embodiment 1, wherein the linker comprises a sequence according to any one of SEQ ID NOs 13 to 15.

[0403] Embodiment 3. In any one of Embodiments 1 to 2, the Fc fusion molecule wherein the Fc fragment is derived from an IgG1, IgG2, or IgG4 immunoglobulin domain.

[0404] Example 4. In any one of Examples 1 to 2, the Fc fragment is an Fc fusion molecule derived from the IgG1 immunoglobulin domain.

[0405] Example 5. In any one of Examples 1 to 2, the Fc fragment is an Fc fusion molecule derived from an IgG2 immunoglobulin domain.

[0406] Example 6. In any one of Examples 1 to 2, the Fc fragment is an Fc fusion molecule derived from an IgG4 immunoglobulin domain.

[0407] Example 7. An Fc fusion molecule in any one of Examples 1 to 6, wherein the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 1, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 10.

[0408] Example 8. An Fc fusion molecule in any one of Examples 1 to 6, wherein the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 1, the linker comprises a sequence according to SEQ ID NO. 14, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 10.

[0409] Example 9. An Fc fusion molecule in any one of Examples 1 to 6, wherein the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 1, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11.

[0410] Example 10. An Fc fusion molecule in any one of Examples 1 to 6, wherein the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 1, the linker comprises a sequence according to SEQ ID NO. 15, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11.

[0411] Example 11. An Fc fusion molecule in any one of Examples 1 to 6, wherein the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 4 or SEQ ID NO. 5, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11.

[0412] Example 12. An Fc fusion molecule in any one of Examples 1 to 6, wherein the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 4 or SEQ ID NO. 5, the linker comprises a sequence according to SEQ ID NO. 15, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11.

[0413] Example 13. An Fc fusion molecule in any one of Examples 1 to 6, wherein the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 3, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 10.

[0414] Example 14. An Fc fusion molecule in any one of Examples 1 to 6, wherein the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 3, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 12.

[0415] Example 15. An Fc fusion molecule in any one of Examples 1 to 6, wherein the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 3, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11.

[0416] Example 16. An Fc fusion molecule in any one of Examples 1 to 6, wherein the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 3, the linker comprises a sequence according to SEQ ID NO. 15, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 12.

[0417] Example 17. An Fc fusion molecule in any one of Examples 1 to 6, wherein the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 3, the linker comprises a sequence according to SEQ ID NO. 15, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11.

[0418] Example 18. An Fc fusion molecule in any one of Examples 1 to 6, wherein the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 6 or SEQ ID NO. 7, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 12.

[0419] Example 19. An Fc fusion molecule in any one of Examples 1 to 6, wherein the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 6 or SEQ ID NO. 7, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11.

[0420] Example 20. An Fc fusion molecule in any one of Examples 1 to 6, wherein the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 6 or SEQ ID NO. 7, the linker comprises a sequence according to SEQ ID NO. 15, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 12.

[0421] Example 21. An Fc fusion molecule in any one of Examples 1 to 6, wherein the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 6 or SEQ ID NO. 7, the linker comprises a sequence according to SEQ ID NO. 15, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11.

[0422] Example 22. An Fc fusion molecule in any one of Examples 1 to 6, wherein the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 2, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 10.

[0423] Example 23. An Fc fusion molecule in any one of Examples 1 to 6, wherein the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 8 or SEQ ID NO. 9, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11.

[0424] Example 24. An Fc fusion molecule in any one of Examples 1 to 6, wherein the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 8 or SEQ ID NO. 9, the linker comprises a sequence according to SEQ ID NO. 15, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11.

[0425] Example 25. An Fc fusion molecule in any one of Examples 1 to 6, wherein the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 2, the linker comprises a sequence according to SEQ ID NO. 13, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11.

[0426] Example 26. An Fc fusion molecule in any one of Examples 1 to 6, wherein the Fc fragment comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO. 2, the linker comprises a sequence according to SEQ ID NO. 15, and the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO. 11.

[0427] Example 27. An Fc fusion molecule comprising, in any one of Examples 1 to 26, a second Fc fragment having at least 80% sequence identity with an amino acid sequence of any one of SEQ ID NOs 1 to 9.

[0428] Example 28. An Fc fusion molecule that binds to a newborn Fc receptor (FcRn), comprising a sequence having at least 80% sequence identity with any one of SEQ ID NOs 16 to 55.

[0429] Example 29. In any one of Examples 1 to 28, the Fc fusion molecule is a molecule that binds to FcRn with a KD of about 1 x 10⁻⁸ M or less at pH 6.0 or pH 7.4 as measured by surface plasmon resonance (SPR).

[0430] Example 30. An Fc fusion molecule having a half-life at least twice as long as that of an Fc fusion molecule not comprising albumin or an albumin binding domain, in any one of Examples 1 to 29.

[0431] Example 31. The Fc fusion molecule of Example 30, wherein the albumin or albumin domain comprises a sequence having at least 80% sequence identity with any one of SEQ ID NOs 10 to 12.

[0432] Example 32. A pharmaceutical composition comprising an Fc fusion molecule of any one of Examples 1 to 31 and a pharmaceutically acceptable carrier.

[0433] Embodiment 33. A method for treating a disease or disorder in a patient requiring treatment for the disease or disorder, comprising the step of administering an effective amount of any one of the Fc fusion molecules of Embodiments 1 to 31 or the pharmaceutical composition of Embodiment 32 to the patient.

[0434] Embodiment 34. The method of Embodiment 33, wherein the disease or disorder is an autoimmune disease.

[0435] Embodiment 35. The method according to Embodiment 33 or Embodiment 34, wherein the disease or disorder is generalized myasthenia gravis (gMG), chronic inflammatory demyelinating polyneuropathy, myositis, autoimmune encephalitis, myelin oligodendrocyte glycoprotein antibody disorder (MOG antibody disorder), membranous nephropathy, lupus nephritis, thyroid eye disease, warm autoimmune hemolytic anemia, fetal and neonatal hemolytic disease, idiopathic thrombocytopenic purpura, primary Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, bullous pemphigus, pemphigus foliaceus, pemphigus vulgaris, or cutaneous lupus erythematosus.

[0436] Embodiment 36. The method of Embodiment 33 or Embodiment 34, wherein the method reduces disease severity in a patient, and the disease severity is evaluated by the gMG disease severity result scale.

[0437] Embodiment 37. A method for treating a pathology associated with elevated levels of IgG in a patient requiring treatment for a pathology associated with elevated levels of IgG, comprising the step of administering to the patient a therapeutically effective amount of an isolated Fc fusion molecule of any one of Embodiments 1 to 31 or a pharmaceutical composition of Embodiment 32.

[0438] Embodiment 38. A method for reducing the biological activity of IgG in a patient requiring a reduction in the biological activity of IgG, comprising the step of administering an effective amount of any one of Embodiments 1 to 31 Fc fusion molecule or the pharmaceutical composition of Embodiment 32 to the patient.

[0439] Embodiment 39. The method of Embodiment 38, wherein the disease is an autoimmune disease.

[0440] Embodiment 40. A method for preventing a disorder in a patient requiring prevention of a disorder, comprising the step of administering to the patient a therapeutically effective amount of any one of the Fc fusion molecules of Embodiments 1 to 31 or the pharmaceutical composition of Embodiment 32; wherein the disorder is an unwanted side effect of the therapeutic antibody.

[0441] Equivalents and categories

[0442] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. Furthermore, materials, methods, and examples are merely illustrative and are not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as generally understood by those skilled in the art to which the invention pertains. Methods and materials similar or equivalent to those described herein may be used in the practice or testing of the invention, but suitable methods and materials are described herein.

Claims

Claim 1 An Fc fusion molecule bound to a newborn Fc receptor (FcRn), comprising: a) an Fc fragment comprising amino acid substitutions (i) N434Y and (ii) H433R or H433K compared to the amino acid sequence presented in SEQ ID NO. 56; b) a linker; and c) an albumin or an albumin binding domain. Claim 2 In claim 1, the Fc fragment is an Fc fusion molecule comprising amino acid substitutions N434Y and H433R. Claim 3 In claim 1, the Fc fragment is an Fc fusion molecule comprising amino acid substitutions N434Y and H433K. Claim 4 An Fc fusion molecule bound to a newborn Fc receptor (FcRn), comprising: a) an Fc fragment comprising amino acid substitutions M428L and N434F compared to the amino acid sequence presented in SEQ ID NO. 56, from N-terminus to C-terminus or C-terminus to N-terminus; b) a linker; and c) an albumin or an albumin binding domain. Claim 5 In paragraph 4, the Fc fusion molecule further comprising the amino acid substitution H433K. Claim 6 An Fc fusion molecule bound to a newborn Fc receptor (FcRn), comprising: a) an Fc fragment comprising amino acid substitutions H433R and N434F compared to the amino acid sequence presented in SEQ ID NO. 56, from N-terminus to C-terminus or C-terminus to N-terminus; b) a linker; and c) an albumin or an albumin binding domain. Claim 7 In claim 6, the Fc fusion molecule further comprising the amino acid substitution M428L, wherein the Fc fragment is an Fc fusion molecule. Claim 8 An Fc fusion molecule according to any one of claims 1 to 7, wherein the Fc fragment further comprises amino acid substitutions M252Y, S254T, and T256E. Claim 9 An Fc fusion molecule according to any one of claims 1 to 8, wherein the Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to any one of SEQ ID NOs 1 to 9 or 57 to 67. Claim 10 An Fc fusion molecule according to any one of claims 1 to 9, wherein the Fc fragment comprises an amino acid sequence identical to any one of SEQ ID NOs 1 to 9 or 57 to 67. Claim 11 An Fc fusion molecule comprising albumin, in any one of claims 1 to 10. Claim 12 In claim 11, the albumin is an Fc fusion molecule comprising an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical to SEQ ID NO.

10. Claim 13 In claim 11 or 12, the albumin is an Fc fusion molecule comprising the same amino acid sequence as SEQ ID NO.

10. Claim 14 An Fc fusion molecule comprising an albumin binding domain, in any one of claims 1 to 10. Claim 15 In claim 14, the albumin binding domain comprises an amino acid sequence that is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical to SEQ ID NO. 11 or SEQ ID NO. 12, in an Fc fusion molecule. Claim 16 An Fc fusion molecule according to claim 14 or 15, wherein the albumin binding domain comprises the same amino acid sequence as SEQ ID NO. 11 or SEQ ID NO.

12. Claim 17 In any one of claims 1 to 16, the linker is an Fc fusion molecule comprising glycine and serine. Claim 18 In claim 17, the linker is an Fc fusion molecule comprising one or more repeating units of GGGGS (Sequence No. 13). Claim 19 An Fc fusion molecule according to claim 17 or 18, wherein the linker comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, or at least 8 repeating units of GGGGS (SEQ No. 13). Claim 20 An Fc fusion molecule according to any one of claims 17 to 19, wherein the linker comprises six repeating units of GGGGS (Sequence No. 13). Claim 21 An Fc fusion molecule according to any one of claims 17 to 19, wherein the linker comprises eight repeating units of GGGGS (Sequence No. 13). Claim 22 An Fc fusion molecule according to any one of claims 1 to 20, wherein the linker comprises a sequence according to any one of SEQ ID NOs 13 to 15. Claim 23 In any one of claims 1 to 21, the Fc fusion molecule is derived from an IgG1, IgG2, or IgG4 immunoglobulin domain. Claim 24 In any one of claims 1 to 22, the Fc fragment is an Fc fusion molecule derived from the IgG1 immunoglobulin domain. Claim 25 In any one of claims 1 to 23, the Fc fragment is an Fc fusion molecule derived from an IgG2 immunoglobulin domain. Claim 26 An Fc fusion molecule derived from the Fc fragment IgG4 immunoglobulin domain in any one of claims 1 to 23. Claim 27 An Fc fusion molecule according to any one of claims 1 to 26, wherein a) the Fc fragment comprises a sequence having at least 80% sequence identity with SEQ ID NO. 1, b) the linker comprises the sequence of SEQ ID NO. 13, and c) the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with SEQ ID NO.

10. Claim 28 An Fc fusion molecule according to any one of claims 1 to 26, wherein a) the Fc sequence comprises a sequence having at least 80% sequence identity with SEQ ID NO. 1, b) the linker comprises the sequence of SEQ ID NO. 14, and c) the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with SEQ ID NO.

10. Claim 29 An Fc fusion molecule according to any one of claims 1 to 26, wherein a) the Fc fragment comprises a sequence having at least 80% sequence identity with SEQ ID NO. 1, b) the linker comprises the sequence of SEQ ID NO. 13, and c) the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with SEQ ID NO.

11. Claim 30 An Fc fusion molecule according to any one of claims 1 to 26, wherein a) the Fc fragment comprises a sequence having at least 80% sequence identity with SEQ ID NO. 1, b) the linker comprises the sequence of SEQ ID NO. 15, and c) the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with SEQ ID NO.

11. Claim 31 An Fc fusion molecule according to any one of claims 1 to 26, wherein a) the Fc fragment comprises a sequence having at least 80% sequence identity with SEQ ID NO. 4 or SEQ ID NO. 5, b) the linker comprises the sequence of SEQ ID NO. 13, and c) the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with SEQ ID NO.

11. Claim 32 An Fc fusion molecule according to any one of claims 1 to 26, wherein a) the Fc fragment comprises a sequence having at least 80% sequence identity with SEQ ID NO. 4 or SEQ ID NO. 5, b) the linker comprises the sequence of SEQ ID NO. 15, and c) the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with SEQ ID NO.

11. Claim 33 An Fc fusion molecule according to any one of claims 1 to 26, wherein a) the Fc fragment comprises a sequence having at least 80% sequence identity with SEQ ID NO. 3, b) the linker comprises the sequence of SEQ ID NO. 13, and c) the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with SEQ ID NO.

10. Claim 34 An Fc fusion molecule according to any one of claims 1 to 26, wherein a) the Fc fragment comprises a sequence having at least 80% sequence identity with SEQ ID NO. 3, b) the linker comprises the sequence of SEQ ID NO. 13, and c) the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with SEQ ID NO.

12. Claim 35 An Fc fusion molecule according to any one of claims 1 to 26, wherein a) the Fc fragment comprises a sequence having at least 80% sequence identity with SEQ ID NO. 3, b) the linker comprises the sequence of SEQ ID NO. 13, and c) the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with SEQ ID NO.

11. Claim 36 An Fc fusion molecule according to any one of claims 1 to 26, wherein a) the Fc fragment comprises a sequence having at least 80% sequence identity with SEQ ID NO. 3, b) the linker comprises the sequence of SEQ ID NO. 15, and c) the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with SEQ ID NO.

12. Claim 37 An Fc fusion molecule according to any one of claims 1 to 26, wherein a) the Fc fragment comprises a sequence having at least 80% sequence identity with SEQ ID NO. 3, b) the linker comprises the sequence of SEQ ID NO. 15, and c) the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with SEQ ID NO.

11. Claim 38 An Fc fusion molecule according to any one of claims 1 to 26, wherein a) the Fc fragment comprises a sequence having at least 80% sequence identity with SEQ ID NO. 6 or SEQ ID NO. 7, b) the linker comprises the sequence of SEQ ID NO. 13, and c) the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with SEQ ID NO.

12. Claim 39 An Fc fusion molecule according to any one of claims 1 to 26, wherein a) the Fc fragment comprises a sequence having at least 80% sequence identity with SEQ ID NO. 6 or SEQ ID NO. 7, b) the linker comprises the sequence of SEQ ID NO. 13, and c) the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with SEQ ID NO.

11. Claim 40 An Fc fusion molecule according to any one of claims 1 to 26, wherein a) the Fc fragment comprises a sequence having at least 80% sequence identity with SEQ ID NO. 6 or SEQ ID NO. 7, b) the linker comprises the sequence of SEQ ID NO. 15, and c) the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with SEQ ID NO.

12. Claim 41 An Fc fusion molecule according to any one of claims 1 to 26, wherein a) the Fc fragment comprises a sequence having at least 80% sequence identity with SEQ ID NO. 6 or SEQ ID NO. 7, b) the linker comprises the sequence of SEQ ID NO. 15, and c) the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with SEQ ID NO.

11. Claim 42 An Fc fusion molecule according to any one of claims 1 to 26, wherein a) the Fc fragment comprises a sequence having at least 80% sequence identity with SEQ ID NO. 2, b) the linker comprises the sequence of SEQ ID NO. 13, and c) the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with SEQ ID NO.

10. Claim 43 An Fc fusion molecule according to any one of claims 1 to 26, wherein a) the Fc fragment comprises a sequence having at least 80% sequence identity with SEQ ID NO. 8 or SEQ ID NO. 9, b) the linker comprises the sequence of SEQ ID NO. 13, and c) the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with SEQ ID NO.

11. Claim 44 An Fc fusion molecule according to any one of claims 1 to 26, wherein a) the Fc fragment comprises a sequence having at least 80% sequence identity with SEQ ID NO. 8 or SEQ ID NO. 9, b) the linker comprises the sequence of SEQ ID NO. 15, and c) the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with SEQ ID NO.

11. Claim 45 An Fc fusion molecule according to any one of claims 1 to 26, wherein a) the Fc fragment comprises a sequence having at least 80% sequence identity with SEQ ID NO. 2, b) the linker comprises the sequence of SEQ ID NO. 13, and c) the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with SEQ ID NO.

11. Claim 46 An Fc fusion molecule according to any one of claims 1 to 26, wherein a) the Fc fragment comprises a sequence having at least 80% sequence identity with SEQ ID NO. 2, b) the linker comprises the sequence of SEQ ID NO. 15, and c) the albumin or albumin binding domain comprises a sequence having at least 80% sequence identity with SEQ ID NO.

11. Claim 47 An Fc fusion molecule according to any one of claims 1 to 46, comprising the Fc fragment, the linker, and the albumin or albumin binding domain from the N-terminus to the C-terminus. Claim 48 An Fc fusion molecule according to any one of claims 1 to 46, comprising the Fc fragment, the linker, and the albumin or albumin binding domain from the C-terminus to the N-terminus. Claim 49 An Fc fusion molecule that binds to a newborn Fc receptor (FcRn), comprising a sequence having at least 80%, at least 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity with any one of SEQ ID NOs 16 to 55 or 68 to 73. Claim 50 In claim 42, an Fc fusion molecule comprising a sequence identical to any one of SEQ ID NOs 16 to 55 or 68 to 73. Claim 51 An Fc fusion molecule comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity with SEQ ID NOs 28 to 55 or 68 to 73 in any one of claims 1 to 50. Claim 52 An Fc fusion molecule comprising an amino acid sequence identical to any one of SEQ ID NOs 28 to 55 or 68 to 73, in any one of claims 1 to 51. Claim 53 An Fc fusion molecule comprising a second Fc fragment in any one of claims 1 to 52. Claim 54 In paragraph 53, the Fc fusion molecule wherein the second Fc fragment comprises the same amino acid substitution as the first Fc fragment. Claim 55 In paragraph 54, the first Fc fragment and the second Fc fragment are further modified to promote Fc heteromerization, in a Fc fusion molecule. Claim 56 An Fc fusion molecule according to claim 54 or 55, wherein the first Fc fragment and the second Fc fragment further comprise one or more amino acid substitutions selected from Y349C, S354C, T366S, T366W, T366Y, L368A, Y407T, and Y407V. Claim 57 In any one of claims 54 to 56, a) the first Fc fragment further comprises amino acid substitutions Y349C, T366S, L368A, and Y407V, and the second Fc fragment further comprises amino acid substitutions S354C and T366W; b) the second Fc fragment further comprises amino acid substitutions Y349C, T366S, L368A, and Y407V, and the first Fc fragment further comprises amino acid substitutions S354C and T366W; c) the first Fc fragment further comprises amino acid substitutions T366S, L368A, and Y407V, and the second Fc fragment further comprises amino acid substitution T266W; or d) the second Fc fragment further comprises amino acid substitutions T366S, L368A, and Y407V, and the first Fc fragment further comprises amino acid substitution T266W, Fc fusion molecule. Claim 58 An Fc fusion molecule according to any one of claims 53 to 57, wherein the second Fc fragment comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to any one of SEQ ID NOs 1 to 9 or 57 to 67. Claim 59 An Fc fusion molecule according to any one of claims 53 to 58, wherein the second Fc fragment comprises an amino acid sequence identical to any one of SEQ ID NOs 1 to 9 or 57 to 67. Claim 60 In any one of claims 1 to 59, the Fc fusion molecule is about 1 x 10⁻⁶ at pH 6.0 or pH 7.4 as measured by surface plasmon resonance (SPR). -8 K less than or equal to M D Fc fusion molecule that binds to FcRn. Claim 61 An Fc fusion molecule according to any one of claims 1 to 60, comprising a half-life at least twice as long as that of an Fc fusion molecule not comprising albumin or an albumin binding domain. Claim 62 An Fc fusion molecule that reduces IgG levels to less than 50%, less than 40%, less than 30%, or less than 25% in any one of claims 1 to 61. Claim 63 A pharmaceutical composition comprising an Fc fusion molecule of any one of claims 1 to 62 and a pharmaceutically acceptable carrier. Claim 64 A method for treating a disease or disorder in a patient requiring treatment of the disease or disorder, comprising the step of administering an effective amount of the Fc fusion molecule of any one of claims 1 to 62 or the pharmaceutical composition of claim 63 to the patient. Claim 65 In paragraph 64, the above disease or disorder is an autoimmune disease. Claim 66 In paragraph 64 or 65, the said disease or disorder is generalized myasthenia gravis (gMG), chronic inflammatory demyelinating polyneuropathy, myositis, autoimmune encephalitis, myelin oligodendrocyte glycoprotein antibody disorder (MOG antibody disorder), membranous nephropathy, lupus nephritis, thyroid eye disease, warm autoimmune hemolytic anemia, fetal and neonatal hemolytic disease, idiopathic thrombocytopenic purpura, primary Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, bullous pemphigus, pemphigus foliaceus, pemphigus vulgaris, or cutaneous lupus erythematosus. Claim 67 A method according to any one of claims 64 to 66, wherein the method reduces disease severity in a patient, and disease severity is evaluated by the gMG disease severity result scale. Claim 68 A method for treating a pathology associated with elevated levels of IgG in a patient requiring treatment for a pathology associated with elevated levels of IgG, comprising the step of administering to the patient a therapeutically effective amount of the Fc fusion molecule of any one of claims 1 to 62 or the pharmaceutical composition of claim 63. Claim 69 A method for reducing the biological activity of IgG in a patient requiring a reduction in the biological activity of IgG, comprising the step of administering to the patient a therapeutically effective amount of the Fc fusion molecule of any one of claims 1 to 62 or the pharmaceutical composition of claim 63. Claim 70 A method for reducing IgG levels in a patient requiring a reduction in IgG levels, comprising the step of administering a therapeutically effective amount of the Fc fusion molecule of any one of claims 1 to 62 or the pharmaceutical composition of claim 63 to the patient. Claim 71 A method according to claim 69 or 70, wherein the Fc fusion molecule reduces IgG levels by 50% within 2, 3, 5, or 7 days after administration. Claim 72 A method according to claim 69 or 70, wherein the Fc fusion molecule reduces IgG levels by 75% within 2, 3, 5, or 7 days after administration. Claim 73 A method according to any one of claims 68 to 72, wherein the administration of the Fc fusion molecule reduces IgG levels to less than 50%, less than 40%, less than 30%, or less than 25% for at least 5, 7, 10, 15, or 20 days after administration. Claim 74 A method for preventing a disorder in a patient requiring prevention of a disorder, comprising the step of administering to the patient a therapeutically effective amount of the Fc fusion molecule of any one of claims 1 to 62 or the pharmaceutical composition of claim 63; wherein the disorder is an unwanted side effect of the therapeutic antibody.

Images