US2023073034A1PendingUtilityA1
Multispecific antibodies, compositions comprising the same, and vectors and uses thereof
Est. expiryJan 24, 2040(~13.5 yrs left)· nominal 20-yr term from priority
Inventors:Sang Hoon Cha
C07K 16/18C07K 16/241C07K 2317/31C07K 16/244C07K 2317/94C07K 16/249C07K 2317/92C07K 2317/56C07K 2317/55C07K 2317/76C07K 2317/622C07K 2317/62C07K 16/2875C07K 16/2866A61K 2039/505
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Claims
Abstract
The present disclosure provides multispecific antibodies having increased in vivo sustainability, the multispecific antibodies comprising one or more bioactive effector moieties linked to either or both of an N-terminal and a C-terminal of an antigen binding fragment Fab that binds to human serum albumin.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A multispecific antibody comprising a structural formula of:
wherein the antigen binding fragment (Fab) is a serum albumin Fab;
wherein R 1 and R 2 are bioactive effector moieties linked to an N-terminus of the Fab, each linked to a heavy chain variable domain or a light chain variable domain of the Fab;
wherein R 3 and R 4 are bioactive effector moieties linked to a C-terminus of the Fab, each linked to a heavy chain variable domain or a light chain variable domain of the Fab;
wherein m is 0 or an integer of 1 or greater; and
wherein n is 0 or an integer of 1 or greater.
2 . The antibody of claim 1 , wherein R 1 and R 2 are same or different single-chain variable fragments (scFv).
3 . The antibody of claim 1 or 2 , wherein R 3 and R 4 are same or different Fv fragments or disulfide-stabilized Fv (dsFv) fragments.
4 . The antibody of any of claims 1 - 3 , wherein each of R 1 , R 2 , R 3 , and R 4 is linked to the Fab by one or more linkers.
5 . The antibody of any of claims 1 - 4 , wherein the Fab comprises a heavy chain variable domain comprising
(a) a heavy chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of SYGIS (SEQ ID NO:61),
a heavy chain CDR2 comprising the amino acid sequence of WINTYSGGTKYAQKFQG (SEQ ID NO:62), and
a heavy chain CDR3 comprising the amino acid sequence of
(SEQ ID NO: 63)
LGHCQRGICSDALDT
(b) a heavy chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of SYGIS (SEQ ID NO:61),
a heavy chain CDR2 comprising the amino acid sequence of RINTYNGNTGYAQRLQG (SEQ ID NO:64), and
a heavy chain CDR3 comprising the amino acid sequence of
(SEQ ID NO: 63)
LGHCQRGICSDALDT
(c) a heavy chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of NYGIH (SEQ ID NO:65),
a heavy chain CDR2 comprising the amino acid sequence of SISYDGSNKYYADSVKG (SEQ ID NO:66), and
a heavy chain CDR3 comprising the amino acid sequence of DVHYYGSGSYYNAFDI (SEQ ID NO:67;
(SEQ ID NO: 67)
DVHYYGSGSYYNAFDI
(d) a heavy chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of SYAMS (SEQ ID NO:68),
a heavy chain CDR2 comprising the amino acid sequence of VISHDGGFQYYADSVKG (SEQ ID NO:69), and
a heavy chain CDR3 comprising the amino acid sequence of
(SEQ ID NO: 70)
AGWLRQYGMDV
(e) a heavy chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of AYWIA (SEQ ID NO:71),
a heavy chain CDR2 comprising the amino acid sequence of MIWPPDADARYSPSFQG (SEQ ID NO:72), and
a heavy chain CDR3 comprising the amino acid sequence of LYSGSYSP (SEQ ID NO:73); or
(f) a heavy chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of AYSMN (SEQ ID NO:74),
a heavy chain CDR2 comprising the amino acid sequence of SISSSGRYIHYADSVKG (SEQ ID NO:75), and
a heavy chain CDR3 comprising the amino acid sequence of ETVMAGKALDY (SEQ ID NO:76).
6 . The antibody of any of claims 1 - 5 , wherein the Fab comprises a light chain variable domain comprising
(g) a light chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of RASQSISRYLN (SEQ ID NO:77),
a light chain CDR2 comprising the amino acid sequence of GASRLES (SEQ ID NO:78), and
a light chain CDR3 comprising the amino acid sequence of QQSDSVPVT (SEQ ID NO:79);
(h) a light chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of RASQSISSYLN (SEQ ID NO:80),
a light chain CDR2 comprising the amino acid sequence of AASSLQS (SEQ ID NO:81), and
a light chain CDR3 comprising the amino acid sequence of QQSYSTPPYT (SEQ ID NO:82);
(i) a light chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of RASQSIFNYVA (SEQ ID NO:83),
a light chain CDR2 comprising the amino acid sequence of DASNRAT (SEQ ID NO:84), and
a light chain CDR3 comprising the amino acid sequence of QQRSKWPPTWT (SEQ ID NO:85);
(j) a light chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of RASETVSSRQLA (SEQ ID NO:86),
a light chain CDR2 comprising the amino acid sequence of GASSRAT (SEQ ID NO:87), and
a light chain CDR3 comprising the amino acid sequence of QQYGSSPRT (SEQ ID NO:88);
(k) a light chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of RASQSVSSSSLA (SEQ ID NO:89),
a light chain CDR2 comprising the amino acid sequence of GASSRAT (SEQ ID NO:87), and
a light chain CDR3 comprising the amino acid sequence of QKYSSYPLT (SEQ ID NO:90); or
(l) a light chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of RASQSVGSNLA (SEQ ID NO:91),
a light chain CDR2 comprising the amino acid sequence of GASTGAT (SEQ ID NO:92), and
a light chain CDR3 comprising the amino acid sequence of QQYYSFLAKT (SEQ ID NO:93).
7 . The antibody of any of claims 1 - 6 , wherein the Fab comprises
a heavy chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of AYSMN (SEQ ID NO:74), a heavy chain CDR2 comprising the amino acid sequence of SISSSGRYIHYADSVKG (SEQ ID NO:75), and a heavy chain CDR3 comprising the amino acid sequence of ETVMAGKALDY (SEQ ID NO:76), and a light chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of RASQSVGSNLA (SEQ ID NO:91), a light chain CDR2 comprising the amino acid sequence of GASTGAT (SEQ ID NO:92), and a light chain CDR3 comprising the amino acid sequence of QQYYSFLAKT (SEQ ID NO:93).
8 . The antibody of any of claims 1 - 7 , wherein the Fab comprises a heavy chain variable domain comprising an amino acid sequence having at least 80% identity to SEQ ID NO:94, 95, 96, 97, 98, or 99.
9 . The antibody of any of claims 1 - 8 , wherein the Fab comprises a light chain variable domain comprising an amino acid sequence having at least 80% identity to SEQ ID NO:100, 101, 102, 103, 104, or 105.
10 . The antibody of any of claims 1 - 9 , wherein the Fab comprises a heavy chain variable domain comprising an amino acid sequence having at least 80% identity to SEQ ID NO:94, 95, 96, 97, 98, or 99, and a light chain variable domain comprising an amino acid sequence having at least 80% identity to SEQ ID NO:100, 101, 102, 103, 104, or 105, respectively.
11 . The antibody of any of claims 1 - 10 , wherein the Fab comprises a heavy chain domain comprising an amino acid sequence of SEQ ID NO:45 (V H −CH1 domain) and a light chain domain comprising an amino acid sequence of SEQ ID NO:46 (V L −C L domain).
12 . The antibody of any of claims 1 - 11 , wherein each linker comprises 1 to 20 amino acids.
13 . The antibody of any of claims 1 - 12 , wherein each linker comprises an amino acid sequence having at least 90% identity to SEQ ID NO:3 or SEQ ID NO:4.
14 . The antibody of any of claims 1 - 13 , wherein each linker comprises an amino acid sequence of SEQ ID NO:3 or SEQ ID NO:4.
15 . The antibody of any of claims 1 - 14 , wherein each of the R 1 and R 2 is an anti-CD40L hu5c8 scFv.
16 . The antibody of any of claims 1 - 15 , wherein each of the R 1 and R 2 is an anti-CD40L hu5c8 scFv comprising an amino acid sequence having at least 80% identity to SEQ ID NO:47 or SEQ ID NO:48.
17 . The antibody of any of claims 1 - 16 , wherein each of the R 1 and R 2 is an anti-CD40L hu5c8 scFv comprising an amino acid sequence of SEQ ID NO:47 or SEQ ID NO:48.
18 . The antibody of any of claims 1 - 17 , wherein each of R 3 and R 4 is one or more bioactive effector moieties selected from the group consisting of anti-TNF-α Fv, anti-TNF-α disulfide-stabilized Fv (dsFv), anti-TL-23 Fv, anti-TL-23 dsFv, anti-IFNAR1, and anti-IFNAR1 dsFv.
19 . The antibody of any of claims 1 - 18 , wherein each of R 3 and R 4 is one or more bioactive effector moieties comprising an anti-TNF-α Fv comprising a heavy chain amino acid sequence having 80% identity to SEQ ID NO:49 and a light chain amino acid sequence having 80% identity to SEQ ID NO:50, anti-TNF-α disulfide-stabilized Fv (dsFv) comprising a heavy chain amino acid sequence having 80% identity to SEQ ID NO:51 and a light chain amino acid sequence having 80% identity to SEQ ID NO:52, anti-TL-23 Fv comprising a heavy chain amino acid sequence having 80% identity to SEQ ID NO:53 and a light chain amino acid sequence having 80% identity to SEQ ID NO:54, anti-TL-23 dsFv comprising a heavy chain amino acid sequence having 80% identity to SEQ ID NO:55 and a light chain amino acid sequence having 80% identity to SEQ ID NO:56, anti-IFNAR1 comprising a heavy chain amino acid sequence having 80% identity to SEQ ID NO:57 and a light chain amino acid sequence having 80% identity to SEQ ID NO:58, and/or anti-IFNAR1 dsFv comprising a heavy chain amino acid sequence having 80% identity to SEQ ID NO:59 and a light chain amino acid sequence having 80% identity to SEQ ID NO:60.
20 . The antibody of any of claims 1 - 19 , wherein each of R 3 and R 4 is one or more bioactive effector moieties comprising an anti-TNF-α Fv comprising a heavy chain of SEQ ID NO:49 and a light chain of SEQ ID NO:50, anti-TNF-α disulfide-stabilized Fv (dsFv) comprising a heavy chain of SEQ ID NO:51 and a light chain of SEQ ID NO:52, anti-IL-23 Fv comprising a heavy chain of SEQ ID NO:53 and a light chain of SEQ ID NO:54, anti-IL-23 dsFv comprising a heavy chain of SEQ ID NO:55 and a light chain of SEQ ID NO:56, anti-IFNAR1 comprising a heavy chain of SEQ ID NO:57 and a light chain of SEQ ID NO:58, and/or anti-IFNAR1 dsFv comprising a heavy chain of SEQ ID NO:59 and a light chain of SEQ ID NO:60.
21 . A composition comprising the multispecific antibody of any of claims 1 - 20 and an excipient.
22 . A pharmaceutical composition comprising the multispecific antibody of any of claims 1 - 20 and a pharmaceutically accepted excipient.
23 . A method of treating an autoimmune disease in a subject in need thereof, the method comprising administering the pharmaceutical composition of claim 22 to the subject.
24 . An expression vector comprising:
(a) a promoter, (b) a first nucleic acid molecule encoding an antigen binding fragment (Fab) that binds to serum albumin, and (c) a second nucleic acid molecule encoding a bioactive effector moiety and a linker, wherein the promoter, the first nucleic acid sequence, and the second nucleic acid molecules are operably linked.
25 . The vector of claim 24 , wherein the second nucleic acid molecule encodes 2 or more bioactive effector moieties and linkers.
26 . The vector of claim 24 or 25 , wherein the first nucleic acid molecule comprises a nucleic acid sequence encoding a Fab comprising a heavy chain variable domain comprising
(a) a heavy chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of SYGIS (SEQ ID NO:61),
a heavy chain CDR2 comprising the amino acid sequence of WINTYSGGTKYAQKFQG (SEQ ID NO:62), and
a heavy chain CDR3 comprising the amino acid sequence of LGHCQRGICSDALDT (SEQ ID NO:63;
(SEQ ID NO: 63)
LGHCQRGICSDALDT
(b) a heavy chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of SYGIS (SEQ ID NO:61),
a heavy chain CDR2 comprising the amino acid sequence of RINTYNGNTGYAQRLQG (SEQ ID NO:64), and
a heavy chain CDR3 comprising the amino acid sequence of LGHCQRGICSDALDT (SEQ ID NO:63;
(SEQ ID NO: 63)
LGHCQRGICSDALDT
(c) a heavy chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of NYGIH (SEQ ID NO:65),
a heavy chain CDR2 comprising the amino acid sequence of SISYDGSNKYYADSVKG (SEQ ID NO:66), and
a heavy chain CDR3 comprising the amino acid sequence of DVHYYGSGSYYNAFDI (SEQ ID NO:67;
(SEQ ID NO: 67)
DVHYYGSGSYYNAFDI
(d) a heavy chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of SYAMS (SEQ ID NO:68),
a heavy chain CDR2 comprising the amino acid sequence of VISHDGGFQYYADSVKG (SEQ ID NO:69), and
a heavy chain CDR3 comprising the amino acid sequence of
(SEQ ID NO: 70)
AGWLRQYGMDV
(e) a heavy chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of AYWIA (SEQ ID NO:71),
a heavy chain CDR2 comprising the amino acid sequence of MIWPPDADARYSPSFQG (SEQ ID NO:72), and
a heavy chain CDR3 comprising the amino acid sequence of LYSGSYSP (SEQ ID NO:73); or
(f) a heavy chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of AYSMN (SEQ ID NO:74),
a heavy chain CDR2 comprising the amino acid sequence of SISSSGRYIHYADSVKG (SEQ ID NO:75), and
a heavy chain CDR3 comprising the amino acid sequence of ETVMAGKALDY (SEQ ID NO:76).
27 . The vector of any of claims 24 - 26 , wherein the first nucleic acid molecule comprises a nucleic acid sequence encoding a Fab comprising a light chain variable domain comprising
(g) a light chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of RASQSISRYLN (SEQ ID NO:77),
a light chain CDR2 comprising the amino acid sequence of GASRLES (SEQ ID NO:78), and
a light chain CDR3 comprising the amino acid sequence of QQSDSVPVT (SEQ ID NO:79);
(h) a light chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of RASQSISSYLN (SEQ ID NO:80),
a light chain CDR2 comprising the amino acid sequence of AASSLQS (SEQ ID NO:81), and
a light chain CDR3 comprising the amino acid sequence of QQSYSTPPYT (SEQ ID NO:82);
(i) a light chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of RASQSIFNYVA (SEQ ID NO:83),
a light chain CDR2 comprising the amino acid sequence of DASNRAT (SEQ ID NO:84), and
a light chain CDR3 comprising the amino acid sequence of QQRSKWPPTWT (SEQ ID NO:85);
(j) a light chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of RASETVSSRQLA (SEQ ID NO:86),
a light chain CDR2 comprising the amino acid sequence of GASSRAT (SEQ ID NO:87), and
a light chain CDR3 comprising the amino acid sequence of QQYGSSPRT (SEQ ID NO:88);
(k) a light chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of RASQSVSSSSLA (SEQ ID NO:89),
a light chain CDR2 comprising the amino acid sequence of GASSRAT (SEQ ID NO:87), and
a light chain CDR3 comprising the amino acid sequence of QKYSSYPLT (SEQ ID NO:90); or
(l) a light chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of RASQSVGSNLA (SEQ ID NO:91),
a light chain CDR2 comprising the amino acid sequence of GASTGAT (SEQ ID NO:92), and
a light chain CDR3 comprising the amino acid sequence of QQYYSFLAKT (SEQ ID NO:93).
28 . The vector of any of claims 24 - 27 , wherein the first nucleic acid molecule comprises a nucleic acid sequence encoding a Fab comprising
a heavy chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of AYSMN (SEQ ID NO:74), a heavy chain CDR2 comprising the amino acid sequence of SISSSGRYIHYADSVKG (SEQ ID NO:75), and a heavy chain CDR3 comprising the amino acid sequence of ETVMAGKALDY (SEQ ID NO:76), and a light chain complementarity determining domain 1 (CDR1) comprising the amino acid sequence of RASQSVGSNLA (SEQ ID NO:91), a light chain CDR2 comprising the amino acid sequence of GASTGAT (SEQ ID NO:92), and a light chain CDR3 comprising the amino acid sequence of QQYYSFLAKT (SEQ ID NO:93).
29 . The vector of any of claims 24 - 28 , wherein the first nucleic acid molecule comprises a nucleic acid sequence encoding a Fab comprising a heavy chain variable domain comprising an amino acid sequence having at least 80% identity to SEQ ID NO:94, 95, 96, 97, 98, or 99.
30 . The vector of any of claims 24 - 29 , wherein the first nucleic acid molecule comprises a nucleic acid sequence encoding a Fab comprising a light chain variable domain comprising an amino acid sequence having at least 80% identity to SEQ ID NO:100, 101, 102, 103, 104, or 105.
31 . The vector of any of claims 24 - 30 , wherein the first nucleic acid molecule comprises a nucleic acid sequence encoding a Fab comprising a heavy chain variable domain comprising an amino acid sequence having at least 80% identity to SEQ ID NO:94, 95, 96, 97, 98, or 99, and a light chain variable domain comprising an amino acid sequence having at least 80% identity to SEQ ID NO:100, 101, 102, 103, 104, or 105, respectively.
32 . The vector of any of claims 24 - 31 , wherein the first nucleic acid molecule comprises a nucleic acid sequence encoding a Fab comprising a heavy chain domain comprising an amino acid sequence of SEQ ID NO:45 (V H −C H1 domain) and a light chain domain comprising an amino acid sequence of SEQ ID NO:46 (V L −C L domain).
33 . The vector of any of claims 24 - 32 , wherein the bioactive effector moieties are anti-TNF-α Fv, anti-TNF-α dsFv, anti-IL-23 Fv, anti-IL-23 dsFv, anti-IFNAR1 Fv, and/or anti-IFNAR1 dsFv.
34 . The vector of any of claims 23 - 33 , wherein the second nucleic acid molecule comprises a nucleotide sequence encoding the amino acid sequence of one or more of SEQ ID NOs: 49-60.Cited by (0)
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