WO2016164089A2 - Tgf-beta superfamily type i and type ii receptor heteromultimers and uses thereof - Google Patents

Tgf-beta superfamily type i and type ii receptor heteromultimers and uses thereof Download PDF

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WO2016164089A2
WO2016164089A2 PCT/US2016/000033 US2016000033W WO2016164089A2 WO 2016164089 A2 WO2016164089 A2 WO 2016164089A2 US 2016000033 W US2016000033 W US 2016000033W WO 2016164089 A2 WO2016164089 A2 WO 2016164089A2
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polypeptide
seq
amino acid
heteromultimer
acid sequence
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WO2016164089A3 (en
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Ravindra Kumar
Asya Grinberg
Dianne S. Sako
Robert Scott Pearsall
Roselyne CASTONGUAY
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Acceleron Pharma Inc
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Acceleron Pharma Inc
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Priority to CA2981737A priority Critical patent/CA2981737A1/en
Priority to MX2017012846A priority patent/MX391964B/es
Priority to KR1020177031989A priority patent/KR20180002659A/ko
Priority to AU2016244750A priority patent/AU2016244750B2/en
Priority to HK18108636.3A priority patent/HK1248733B/en
Priority to EP16777003.1A priority patent/EP3280435B1/en
Priority to JP2017552491A priority patent/JP7037363B2/ja
Priority to BR112017021510A priority patent/BR112017021510A2/pt
Priority to CN201680032890.1A priority patent/CN107847561B/zh
Application filed by Acceleron Pharma Inc filed Critical Acceleron Pharma Inc
Priority to EP21161146.2A priority patent/EP3889171B1/en
Priority to EP25162196.7A priority patent/EP4599888A3/en
Priority to CN202210222650.5A priority patent/CN114736307A/zh
Priority to EA201792222A priority patent/EA037293B1/ru
Publication of WO2016164089A2 publication Critical patent/WO2016164089A2/en
Publication of WO2016164089A3 publication Critical patent/WO2016164089A3/en
Anticipated expiration legal-status Critical
Priority to AU2021200492A priority patent/AU2021200492A1/en
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Definitions

  • the Piedmontese and Belgian Blue cattle breeds carry a loss-of-function mutation in the GDF8 (also called myostatin) gene that causes a marked increase in muscle mass. Grobet el al. ( 1997) Nat Genet., 17( l ):71 -4. Furthermore, in humans, inactive alleles of GDF8 are associated with increased muscle mass and, reportedly, exceptional strength. Schuelke et al. (2004) N Engl J Med, 350:2682-8.
  • heteromultimeric complexes disclosed herein e.g., an ActRIIB:ALK4 heterodimer
  • have different ligand binding specificities/profiles compared to their corresponding homomultimer complexes e.g., an ActRIIB homodimer and ALK4 homodimer.
  • Novel properties, including novel ligand binding attributes, are exhibited by heteromultimeric polypeptide complexes comprising type I and type II receptor polypeptides of the TGF-beta superfamily, as shown by Examples herein.
  • heteromultimers described herein comprise a first polypeptide covalently or non-covalently associated with a second polypeptide wherein the first polypeptide comprises the amino acid sequence of a TGF-beta superfamily type I receptor polypeptide and the amino acid sequence of a first member of an interaction pair and the second polypeptide comprises the amino acid sequence of a different TGF-beta superfamily type I receptor polypeptide and the amino acid sequence of a second member of the interaction pair.
  • interaction pairs described herein are designed to promote dimerization or form higher order multimers.
  • the interaction pair may be any two polypeptide sequences that interact to form a complex, particularly a heterodimeric complex although operative embodiments may also employ an interaction pair that forms a
  • a first member of an interaction pair may comprise an amino acid sequence that is derived from an Fc domain of an IgG (IgG 1 , IgG2, IgG3, or IgG4), IgA (IgAl or IgA2), IgE, or IgM immunoglobulin.
  • the first member of an interaction pair may comprise, consist essentially of, or consist of an amino acid sequence that is at least 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any one of SEQ ID NOs: 200-214.
  • ALK6 polypeptides may comprise, consist essentially of, or consist of an amino acid sequence that is at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to a polypeptide that a) begins at any one of amino acids of 26-62 (e.g., amino acid residues 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 52, 53, 54, 55, 56, 57, 58 ,59, 60, 61, and 62) SEQ ID NO: 91, and b) ends at any one of amino acids 132-156 (e.g., amino acid residues 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152,
  • amino acids of 26-62
  • TGFBRII polypeptides may comprise, consist essentially of, or consist of an amino acid sequence that is at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or 1 00% identical to an TGFBRII sequence disclosed herein (e.g., SEQ ID NOs: 42, 43, 67, 68, 127, 129, 130, 132, 157, 158, 1 59, 160, 415, 416, 417, 418, 459, 460, 461 , and 462).
  • a TGFBRIl heteromeric complex may further comprise an AL 7 polypeptide as described herein, including, for example, a polypeptide comprising, consisting essentially of, or consisting of an amino acid sequence that is at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to a sequence selected from SEQ ID NOs: 38, 39, 301 , 302, 305, 306, 309, 310, 313, 112, 114, 183, 184, 405, 406, 475, and 476.
  • a BMPRI I heteromeric complex may further comprise an ActRIIB polypeptide as described herein, including, for example, a polypeptide comprising, consisting essentially of, or consisting of an amino acid sequence that is at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to a sequence selected from SEQ ID NOs: 1 , 2, 3, 4, 5, 6, 100, 102, 153, 154, 401 , 402, 453, and 454.
  • a BMPRII heteromeric complex may further comprise an ActRIIB polypeptide as described herein, including, for example, a polypeptide comprising, consisting essentially of, or consisting of an amino acid sequence that is at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to a sequence selected from SEQ ID NOs: 1 , 2, 3, 4, 5, 6, 100, 102, 153, 154, 401 , 402, 453, and 454.
  • heteromeric complexes that comprise an AL 3 polypeptide further comprise at least one different type I TGF-beta superfamily polypeptide.
  • an AL 3 heteromeric complex may further comprise an ALK2 polypeptide as described herein, including, e.g. , a polypeptide comprising, consisting essentially of, or consisting of an amino acid sequence that is at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to a sequence selected from SEQ ID NOs: 1 8, 19, 1 36, 138, 173, 174, 421 , 422, 465, and 466.
  • an ALK3 heteromeric complex may further comprise an AL 1 polypeptide as described herein, including, e.g.
  • an AL 3 heteromeric complex may further comprise an AL 6 polypeptide as described herein, including, e.g. , a polypeptide comprising, consisting essentially of, or consisting of an amino acid sequence that is at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100%.
  • AL 4 polypeptides may comprise, consist essentially of, or consist of an amino acid sequence that is at least 70%, 80%, 85%, 90%, 95%, 97%, 98%), 99% or 100%) identical to a polypeptide that a) begins at any one of amino acids of 23-34 (e.g., amino acid residues 23, 24, 25, 26, 27, 28, 29, 30, 3 1 , 32, 33, 34) SEQ ID NO: 26 or 83, and b) ends at any one of amino acids 101 - 126 (e.g., amino acid residues 1 01 , 102, 1 03, 104, 105, 106, 1 07, 108, 1 09, 1 1 0, 1 1 1 1 , 1 12, 1 1 3, 1 14, 1 1 5, 1 1 6, 1 1 7, 1 1 8, 1 9, 120, 121 , 122, 123, 124, 125, and 126) of SEQ ID NO: 26 or 83.
  • 23-34 e.g., amino acid residues 23, 24, 25, 26, 27, 28, 29, 30, 3 1 , 32
  • a polypeptide comprising, consisting essentially of, or consisting of an amino acid sequence that is at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to a sequence selected from SEQ ID NOs: 14, 15, 124, 126, 171 , 172, 413, 414, 463, and 464.
  • heteromeric complexes that comprise an ALK7 polypeptide further comprise at least one different type I TGF-beta superfamily polypeptide.
  • an AL 7 heteromeric complex may further comprise an ALK2 polypeptide as described herein, including, e.g., a polypeptide comprising, consisting essentially of, or consisting of an amino acid sequence that is at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to a sequence selected from SEQ ID NOs: 1 8, 19, 136, 138, 173, 174, 421 , 422, 465, and 466.
  • Such a method may include expressing any of the nucleic acids disclosed herein in a suitable cell (e.g., CHO cell or a COS cell). Such a method may comprise: a) obtaining a cell that comprises a nucleic acid comprising the coding sequence for a TGF-beta superfamily type I receptor polypeptide disclosed herein and a nucleic acid comprising the coding sequence for a TGF-beta superfamily type II receptor polypeptide disclosed herein; (b) culturing such cell under conditions suitable for expression of the TGF-beta superfamily type I and type 11 polypeptides described herein; and c) recovering the heteromeric complex comprising such type I and type II polypeptides so expressed.
  • Heteromuitimeric complexes disclosed herein as crude, partially purified, or highly purified fractions using any of the well-known techniques for obtaining protein from cell cultures.
  • a polypeptide that is at least 80%, 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to an extracellular domain of an ActRIIA, ActRIIB, MISRII, B PRII, or TGFBRII protein from humans or other species such as those described herein, e.g., 9, 10, 11, 118, 120, 151, 152,409,410, 451,452, 1,2,3,4, 5,6, 100, 102, 153, 154, 401,402, 453,454, 46,47,71,72, 121, 123, 155, 156,411,412,455,456, 50,51,75,76, 79, 80, 133, 135, 161, 162, 419, 420, 457, 458, 42, 43, 67, 68, 127, 129, 130, 132, 157, 158, 159, 160, 415, 416, 417, 418, 459, 460, 461 , and 462).
  • the first and second members of the interaction pair may be unguided, meaning that the members of the pair may associate with each other or self-associate without substantial preference, and they may have the same or different amino acid sequences. See Figure 15A.
  • the interaction pair may be a guided (asymmetric) pair, meaning that the members of the pair associate preferentially with each other rather than self-associate. See Figure 15B. Complexes of higher order can be envisioned. See Figure 15C and 15D.
  • a linker may be positioned between the type I receptor or type II receptor polypeptide and the corresponding member of the interaction pair, between interaction pairs, and between the VH and VL polypeptides and a member of the interaction pair.
  • and A 2 may be the same or different; B
  • and B 2 may be the same or different, and Ci and C 2 may be the same or different.
  • Suitable interaction pairs included, for example, constant heavy chain and/or light chain immunoglobulin interaction pairs, truncations, and variants thereof as described herein [e.g., Spiess et al (2015) Molecular Immunology 67(2A): 95-106].
  • Figure 17A is an example of an association of guided
  • the signal peptide is indicated by a single underline and the extracellular domain is indicated in bold font.
  • heteromultimer complexes of the disclosure consist or consist essentially of at least one TGFBRI I polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NOs: 42, 43, 67, or 68, with or without insertion of SEQ ID NO: 95.
  • a nucleic acid sequence encoding an extracellular BMPRII polypeptide (isoform 2) is as follows:
  • MISRII polypeptide includes polypeptides comprising any naturally occurring polypeptide of an MISRII family member as well as any variants thereof (including mutants, fragments, fusions, and peptidomimetic forms) that retain a useful activity.
  • the processed extracellular MISRII polypeptide sequence (isoform 3) is as follows:
  • ALK l polypeptide includes polypeptides comprising any naturally occurring polypeptide of an ALK l family member as well as any variants thereof (including mutants, fragments, fusions, and peptidomimetic forms) that retain a useful activity.
  • a nucleic acid sequence encoding processed extracelluar AL 1 polypeptide is as follows: GACCCTGTGAAGCCGTCTCGGGGCCCGCTGGTGACCTGCACGTGTGAGAGCCCACATTGCAA GGGGCCTACCTGCCGGGGGGCCTGGTGCACAGTAGTGCTGGTGCGGGAGGAGGGGAGGCACC CCCAGGAACATCGGGGCTGCGGGAACTTGCACAGGGAGCTCTGCAGGGGGCGCCCCACCGAG TTCGTCAACCACTACTGCTGCGACAGCCACCTCTGCAACCACAACGTGTCCCTGGTGCTGGA GGCCACCCAACCTCCTTCGGAGCAGCCGGGAACAGATGGCCAG (SEQ ID NO: 17)
  • the disclosure relates to heteromultimer complexes that comprise at least one ALK2 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • ALK2 polypeptides for use in accordance with inventions of the disclosure e.g. , heteromultimer complexes comprising an AL 2 polypeptide and uses thereof
  • AL 2 polypeptides for use in accordance with the inventions of the disclosure bind to and/or inhibit (antagonize) activity (e.g., induction of Smad 2/3 and/or
  • the processed extracellular ALK3 polypeptide sequence is as follows:
  • nucleic acid sequence encoding the AL 4 precursor protein (isoform C) is shown below (SEQ ID NO: 85), corresponding to nucleotides 78- 171 5 of Genbank Reference Sequence NM_020328.3. The signal sequence is underlined and the extracellular domain is indicated in bold font. ATGGCGGAGTCGGCCGGAGCCTCCTCCTTCTTCCCCCTTGTTGTCCTCCTGCTCGCCGGCAG
  • Numbering of amino acids for all AL 6-related polypeptides described herein is based on the numbering of the human ALK6 precursor protein sequence below (SEQ ID NO: 34), unless specifically designated otherwise.
  • a nucleic acid sequence encoding the processed ALK.7 polypeptide is as follows (SEQ ID NO: 308):

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CN201680032890.1A CN107847561B (zh) 2015-04-06 2016-04-06 TGF-β超家族I型和II型受体异多聚体及其用途
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MX2017012846A (es) 2018-11-09
CN107847561B (zh) 2022-03-29
EA202190016A1 (ru) 2021-08-31
MX391964B (es) 2025-03-21
CN114736307A (zh) 2022-07-12
MA53400A (fr) 2021-08-04
BR112017021510A2 (pt) 2018-07-03
US20190225669A1 (en) 2019-07-25
US20240158468A1 (en) 2024-05-16
HK1248733A1 (zh) 2018-10-19
EA037293B1 (ru) 2021-03-05
JP2018513147A (ja) 2018-05-24
AU2016246708B2 (en) 2020-12-24
EP3889171A1 (en) 2021-10-06
EP3280435A4 (en) 2018-12-19
JP2021104057A (ja) 2021-07-26
WO2016164089A3 (en) 2016-12-08
DK3280728T3 (da) 2021-03-01
EP3828199A1 (en) 2021-06-02
US20220119491A1 (en) 2022-04-21
EP3280435A2 (en) 2018-02-14
JP2018517399A (ja) 2018-07-05
US10227393B2 (en) 2019-03-12
US20160297867A1 (en) 2016-10-13
AU2016244750B2 (en) 2021-02-18
KR20180002659A (ko) 2018-01-08
JP7037363B2 (ja) 2022-03-16
US20190375820A1 (en) 2019-12-12
EP3280728A4 (en) 2018-09-12
EA201792222A1 (ru) 2018-04-30
US20160298093A1 (en) 2016-10-13
US10227392B2 (en) 2019-03-12
KR20180002661A (ko) 2018-01-08
JP7055636B2 (ja) 2022-04-18
HK1250373A1 (zh) 2018-12-14
US20220396607A1 (en) 2022-12-15
CN107709358A (zh) 2018-02-16
MA41920B1 (fr) 2021-05-31
EP3889171B1 (en) 2025-03-12
EP4599888A3 (en) 2025-10-29
EP3280728B1 (en) 2020-12-16
EP4599888A2 (en) 2025-08-13
MA54328A (fr) 2021-10-06
AU2016244750A1 (en) 2017-10-26
CA2981833A1 (en) 2016-10-13
WO2016164503A1 (en) 2016-10-13
CA2981737A1 (en) 2016-10-13
CN107847561A (zh) 2018-03-27
EP3280728A1 (en) 2018-02-14
US10906958B2 (en) 2021-02-02
US11827689B2 (en) 2023-11-28
HK1252957A1 (zh) 2019-06-06

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