US2023227552A1PendingUtilityA1
Anti-tcr antibody molecules and uses thereof

Assignee: MARENGO THERAPEUTICS INCPriority: Jan 3, 2020Filed: Jun 30, 2022Published: Jul 20, 2023
Est. expiryJan 3, 2040(~13.5 yrs left)· nominal 20-yr term from priority
Inventors:Seng-Lai Tan Brian Edward Vash Jonathan Hsu Dilini Charmain Gunasekera Sangeetha Sagar Palakurthi Andreas Loew Madan Katragadda Peter Marek Gurkan Guntas
C07K 16/2809A61P 37/04A61P 35/00C07K 2317/565C07K 2317/52C07K 16/2803C07K 2317/622C07K 2317/24C07K 2317/33C07K 2317/31C07K 2317/75C07K 2317/90C07K 2317/92C07K 2317/94C07K 2317/70C07K 2317/73A61K 2039/545A61K 2039/505C07K 16/2878
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References
Claims
Abstract

The disclosure provides antibody molecules that bind to TCR VP regions and multispecific molecules comprising said antibody molecules. Additionally, disclosed are nucleic acids encoding the same, methods of producing the aforesaid molecules, pharmaceutical compositions comprising aforesaid molecules, and methods of treating a cancer using the aforesaid molecules.
Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 .- 183 . (canceled) 
     
     
         184 . A method of treating cancer in a human subject in need thereof comprising administering to the human subject a therapeutically effective amount of a molecule comprising an antigen binding domain that binds to a T cell receptor beta variable (TCRβV) region, wherein the antigen binding domain comprises:
 a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 3 (HC CDR3) comprising the sequence SYYSYDVLDY (SEQ ID NO: 47) or the sequence SLNWDYGLDY (SEQ ID NO: 1104); 
 thereby treating the cancer in the human subject. 
 
     
     
         185 . The method of  claim 184 , wherein the VH comprises:
 (i) the HC CDR3 comprising the sequence SYYSYDVLDY (SEQ ID NO: 47);   (ii) a HC CDR1 comprising:
 the sequence TYYIH (SEQ ID NO: 45), 
 the sequence GHDFRLTYIH (amino acids 26-35 of SEQ ID NO: 1346), or 
 the sequence GHDFKLTYIH (amino acids 26-35 of SEQ ID NO: 1370); and 
   (iii) a HC CDR2 comprising:
 the sequence WFFPGSGNIKYNEKFKG (SEQ ID NO: 46), 
 the sequence RVSAGSGNVKYNEKFKG (amino acids 50-66 of SEQ ID NO: 1346), 
 the sequence RVYAGSGNTKYNEKFKG (amino acids 50-66 of SEQ ID NO: 1356), or 
 the sequence RVSAGSGNVNYAQKFQG (amino acids 50-66 of SEQ ID NO: 1370). 
   
     
     
         186 . The method of  claim 185 , wherein the VH comprises:
 (i) the HC CDR3 comprising the sequence SYYSYDVLDY (SEQ ID NO: 47);   (ii) the HC CDR1 comprising the sequence TYYIH (SEQ ID NO: 45); and   (iii) the HC CDR2 comprising the sequence WFFPGSGNIKYNEKFKG (SEQ ID NO: 46).   
     
     
         187 . The method of  claim 185 , wherein the VH comprises:
 (i) the HC CDR3 comprising the sequence SYYSYDVLDY (SEQ ID NO: 47);   (ii) the HC CDR1 comprising the sequence GHDFRLTYIH (amino acids 26-35 of SEQ ID NO: 1346); and   (iii) the HC CDR2 comprising the sequence RVSAGSGNVKYNEKFKG (amino acids 50-66 of SEQ ID NO: 1346).   
     
     
         188 . The method of  claim 185 , wherein the VH comprises:
 (i) the HC CDR3 comprising the sequence SYYSYDVLDY (SEQ ID NO: 47);   (ii) the HC CDR1 comprising the sequence GHDFRLTYIH (amino acids 26-35 of SEQ ID NO: 1356); and   (iii) the HC CDR2 comprising the sequence RVYAGSGNTKYNEKFKG (amino acids 50-66 of SEQ ID NO: 1356).   
     
     
         189 . The method of  claim 185 , wherein the VH comprises:
 (i) the HC CDR3 comprising the sequence SYYSYDVLDY (SEQ ID NO: 47);   (ii) the HC CDR1 comprising the sequence GHDFKLTYIH (amino acids 26-35 of SEQ ID NO: 1370); and   (iii) the HC CDR2 comprising the sequence RVSAGSGNVNYAQKFQG (amino acids 50-66 of SEQ ID NO: 1370).   
     
     
         190 . The method of  claim 184 , wherein the VH comprises:
 (i) the HC CDR3 comprising the sequence SLNWDYGLDY (SEQ ID NO: 1104);   (ii) a HC CDR1 comprising:
 the sequence SAYMH (SEQ ID NO: 1102), or 
 the sequence DTYMY (SEQ ID NO: 1120); and 
   (iii) a HC CDR2 comprising:
 the sequence RIDPATGKTKYAPKFQA (SEQ ID NO: 1103), or 
 the sequence RIDPANGNTKYDPKFQD (SEQ ID NO: 1121). 
   
     
     
         191 . The method of  claim 190 , wherein the VH comprises:
 (i) the HC CDR3 comprising the sequence SLNWDYGLDY (SEQ ID NO: 1104);   (ii) the HC CDR1 comprising the sequence SAYMH (SEQ ID NO: 1102); and   (iii) the HC CDR2 comprising the sequence RIDPATGKTKYAPKFQA (SEQ ID NO: 1103).   
     
     
         192 . The method of  claim 190 , wherein the VH comprises:
 (i) the HC CDR3 comprising the sequence SLNWDYGLDY (SEQ ID NO: 1104);   (ii) the HC CDR1 comprising the sequence DTYMY (SEQ ID NO: 1120); and   (iii) the HC CDR2 comprising the sequence RIDPANGNTKYDPKFQD (SEQ ID NO: 1121).   
     
     
         193 . The method of  claim 190 , wherein the antigen binding domain comprises a light chain variable region (VL) comprising:
 (i) a light chain complementarity determining region 3 (LC CDR3) comprising the sequence QQSIEDPWT (SEQ ID NO:1109) or the sequence QQSNEDPYT (SEQ ID NO:1128);   (ii) a light chain complementarity determining region 1 (LC CDR1) comprising the sequence RASKSVSILGTHLIH (SEQ ID NO:1107) or the sequence RASESVDSYGNSFMH (SEQ ID NO:1126); and   (iii) a light chain complementarity determining region 2 (LC CDR2) comprising the sequence AASNLES (SEQ ID NO: 1108) or the sequence RASNLES (SEQ ID NO:1127).   
     
     
         194 . The method of  claim 193 , wherein the VL comprises:
 (i) the LC CDR3 comprising the sequence QQSIEDPWT (SEQ ID NO:1109);   (ii) a LC CDR1 comprising the sequence RASKSVSILGTHLIH (SEQ ID NO:1107); and   (iii) a LC CDR2 comprising the sequence AASNLES (SEQ ID NO: 1108).   
     
     
         195 . The method of  claim 193 , wherein the VL comprises:
 (i) the LC CDR3 comprising the sequence QQSNEDPYT (SEQ ID NO:1128);   (ii) a LC CDR1 comprising the sequence RASESVDSYGNSFMH (SEQ ID NO:1126); and   (iii) a LC CDR2 comprising the sequence RASNLES (SEQ ID NO:1127).   
     
     
         196 . The method of  claim 185 , wherein the antigen binding domain comprises a VL comprising:
 (i) a LC CDR3 comprising:
 the sequence QQFKSYPLT (SEQ ID NO: 53), 
 the sequence QQFTSSPFT (SEQ ID NO: 65), 
 the sequence QQSIEDPWT (SEQ ID NO: 1109), or 
 the sequence QQSNEDPYT (SEQ ID NO:1128); 
   (ii) a LC CDR1 comprising:
 the sequence KASQNVGINVV (SEQ ID NO: 51), 
 the sequence RASSSVNYIY (SEQ ID NO: 63), 
 the sequence RASKSVSILGTHLIH (SEQ ID NO: 1107), 
 the sequence RASESVDSYGNSFMH (SEQ ID NO: 1126), 
 the sequence KASQNVADRVV (amino acids 24-34 of SEQ ID NO: 1349), 
 the sequence KASQNVEDRVV (amino acids 24-34 of SEQ ID NO: 1357), or 
 the sequence RASQNVDNRLG (amino acids 24-34 of SEQ ID NO: 1365); and 
   (iii) a LC CDR2 comprising:
 the sequence SSSHRYS (SEQ ID NO: 52), 
 the sequence YTSNLAP (SEQ ID NO: 64), 
 the sequence AASNLES (SEQ ID NO: 1108), 
 the sequence RASNLES (SEQ ID NO:1127), or 
 the sequence SSSHRYK (amino acids 50-56 of SEQ ID NO: 1349). 
   
     
     
         197 . The method of  claim 196 , wherein the VL comprises:
 (i) the LC CDR3 comprising the sequence QQFKSYPLT (SEQ ID NO: 53);   (ii) the LC CDR1 comprising the sequence KASQNVGINVV (SEQ ID NO: 51); and   (iii) the LC CDR2 comprising the sequence SSSHRYS (SEQ ID NO: 52).   
     
     
         198 . The method of  claim 186 , wherein the VL comprises:
 (i) the LC CDR3 comprising the sequence QQFKSYPLT (SEQ ID NO: 53);   (ii) the LC CDR1 comprising the sequence KASQNVGINVV (SEQ ID NO: 51); and   (iii) the LC CDR2 comprising the sequence SSSHRYS (SEQ ID NO: 52).   
     
     
         199 . The method of  claim 196 , wherein the VL comprises:
 (i) the LC CDR3 comprising the sequence QQFTSSPFT (SEQ ID NO: 65);   (ii) the LC CDR1 comprising the sequence RASSSVNYIY (SEQ ID NO: 63); and   (iii) the LC CDR2 comprising the sequence YTSNLAP (SEQ ID NO: 64).   
     
     
         200 . The method of  claim 196 , wherein the VL comprises:
 (i) the LC CDR3 comprising the sequence QQSIEDPWT (SEQ ID NO: 1109);   (ii) the LC CDR1 comprising the sequence RASKSVSILGTHLIH (SEQ ID NO: 1107); and   (iii) the LC CDR2 comprising the sequence AASNLES (SEQ ID NO: 1108).   
     
     
         201 . The method of  claim 196 , wherein the VL comprises:
 (i) the LC CDR3 comprising the sequence QQSNEDPYT (SEQ ID NO:1128);   (ii) the LC CDR1 comprising the sequence RASESVDSYGNSFMH (SEQ ID NO: 1126); and   (iii) the LC CDR2 comprising the sequence RASNLES (SEQ ID NO:1127).   
     
     
         202 . The method of  claim 196 , wherein the VL comprises:
 (i) the LC CDR3 comprising the sequence QQFKSYPLT (SEQ ID NO: 53);   (ii) the LC CDR1 comprising the sequence KASQNVADRVV (amino acids 24-34 of SEQ ID NO: 1349); and   (iii) the LC CDR2 comprising the sequence SSSHRYK (amino acids 50-56 of SEQ ID NO: 1349).   
     
     
         203 . The method of  claim 187 , wherein VL comprises:
 (i) the LC CDR3 comprising the sequence QQFKSYPLT (SEQ ID NO: 53);   (ii) the LC CDR1 comprising the sequence KASQNVADRVV (amino acids 24-34 of SEQ ID NO: 1349); and   (iii) the LC CDR2 comprising the sequence SSSHRYK (amino acids 50-56 of SEQ ID NO:   1349).   
     
     
         204 . The method of  claim 196 , wherein the VL comprises:
 (i) the LC CDR3 comprising the sequence QQFKSYPLT (SEQ ID NO: 53);   (ii) the LC CDR1 comprising the sequence KASQNVEDRVV (amino acids 24-34 of SEQ ID NO: 1357); and   (iii) the LC CDR2 comprising the sequence SSSHRYK (amino acids 50-56 of SEQ ID NO:   1349).   
     
     
         205 . The method of  claim 188 , wherein VL comprises:
 (i) the LC CDR3 comprising the sequence QQFKSYPLT (SEQ ID NO: 53);   (ii) the LC CDR1 comprising the sequence KASQNVEDRVV (amino acids 24-34 of SEQ ID NO: 1357); and   (iii) the LC CDR2 comprising the sequence SSSHRYK (amino acids 50-56 of SEQ ID NO: 1349).   
     
     
         206 . The method of  claim 196 , wherein the VL comprises:
 (i) the LC CDR3 comprising the sequence QQFKSYPLT (SEQ ID NO: 53);   (ii) the LC CDR1 comprising the sequence RASQNVDNRLG (amino acids 24-34 of SEQ ID NO: 1365); and   (iii) the LC CDR2 comprising the sequence SSSHRYK (amino acids 50-56 of SEQ ID NO: 1349).   
     
     
         207 . The method of  claim 189 , wherein VL comprises:
 (i) the LC CDR3 comprising the sequence QQFKSYPLT (SEQ ID NO: 53);   (ii) the LC CDR1 comprising the sequence RASQNVDNRLG (amino acids 24-34 of SEQ ID NO: 1365); and   (iii) the LC CDR2 comprising the sequence SSSHRYK (amino acids 50-56 of SEQ ID NO: 1349).   
     
     
         208 . The method of  claim 191 , wherein the VL comprises:
 (i) the LC CDR3 comprising the sequence QQSIEDPWT (SEQ ID NO:1109);   (ii) a LC CDR1 comprising the sequence RASKSVSILGTHLIH (SEQ ID NO:1107); and   (iii) a LC CDR2 comprising the sequence AASNLES (SEQ ID NO: 1108).   
     
     
         209 . The method of  claim 203 , wherein
 the VH comprises a sequence having at least 80% sequence identity to SEQ ID NO: 1346, and the VL comprises a sequence having at least 80% sequence identity to SEQ ID NO: 1349.   
     
     
         210 . The method of  claim 208 , wherein
 the VH comprises a sequence having at least 80% sequence identity to SEQ ID NO: 1113, and the VL comprises a sequence having at least 80% sequence identity to SEQ ID NO: 1111.   
     
     
         211 . The method of  claim 198 , wherein
 the VH comprises a sequence having at least 80% sequence identity to SEQ ID NO: 1100, and the VL comprises a sequence having at least 80% sequence identity to SEQ ID NO: 1101.   
     
     
         212 . The method of  claim 205 , wherein
 the VH comprises a sequence having at least 80% sequence identity to SEQ ID NO: 1356, and the VL comprises a sequence having at least 80% sequence identity to SEQ ID NO: 1357.   
     
     
         213 . The method of  claim 207 , wherein
 the VH comprises a sequence having at least 80% sequence identity to SEQ ID NO: 1370, and the VL comprises a sequence having at least 80% sequence identity to SEQ ID NO: 1365.   
     
     
         214 . The method of  claim 184 , wherein the antigen binding domain comprises:
 (i) a VH comprising a sequence having at least 80% sequence identity to the sequence of SEQ ID NO: 1100, and a VL comprising a sequence having at least 80% sequence identity to the sequence of SEQ ID NO: 1101;   (ii) a VH comprising a sequence having at least 80% sequence identity to the sequence of SEQ ID NO: 1346, and a VL comprising a sequence having at least 80% sequence identity to the sequence of SEQ ID NO: 1349;   (iii) a VH comprising a sequence having at least 80% sequence identity to the sequence of SEQ ID NO: 1356, and a VL comprising a sequence having at least 80% sequence identity to the sequence of SEQ ID NO: 1357;   (iv) a VH comprising a sequence having at least 80% sequence identity to the sequence of SEQ ID NO: 1370, and a VL comprising a sequence having at least 80% sequence identity to the sequence of SEQ ID NO: 1365; or   (v) a VH comprising a sequence having at least 80% sequence identity to the sequence of SEQ ID NO: 1112, SEQ ID NO: 1113, SEQ ID NO: 1114, SEQ ID NO: 1115, or SEQ ID NO: 1116, and a VL comprising a sequence having at least 80% sequence identity to the sequence of SEQ ID NO: 1111, SEQ ID NO: 1117, SEQ ID NO: 1118, or SEQ ID NO: 1119.   
     
     
         215 . The method of  claim 214 , wherein the antigen binding domain comprises:
 (i) a VH comprising the sequence of SEQ ID NO: 1100, and a VL comprising the sequence of SEQ ID NO: 1101;   (ii) a VH comprising the sequence of SEQ ID NO: 1346, and a VL comprising the sequence of SEQ ID NO: 1349;   (iii) a VH comprising the sequence of SEQ ID NO: 1356, and a VL comprising the sequence of SEQ ID NO: 1357;   (iv) a VH comprising the sequence of SEQ ID NO: 1370, and a VL comprising the sequence of SEQ ID NO: 1365; or   (v) a VH comprising the sequence of SEQ ID NO: 1112, SEQ ID NO: 1113, SEQ ID NO: 1114, SEQ ID NO: 1115, or SEQ ID NO: 1116, and a VL comprising a sequence having at least 80% sequence identity to the sequence of SEQ ID NO: 1111, SEQ ID NO: 1117, SEQ ID NO: 1118, or SEQ ID NO: 1119.   
     
     
         216 . The method of  claim 214 , wherein the antigen binding domain is a Fab or a single chain Fv (scFv). 
     
     
         217 . The method of  claim 214 , wherein the molecule comprises at least two non-contiguous polypeptide chains; wherein a first polypeptide chain of the at least two non-contiguous polypeptide chains comprises a first Fc region, and a second polypeptide chain of the at least two non-contiguous polypeptide chains comprises a second Fc region; and wherein the first Fc region and the second Fc region comprise an Fc interface with a knob-in-a hole. 
     
     
         218 . The method of  claim 217 , wherein the molecule comprises the first polypeptide chain, the second polypeptide chain, and a third polypeptide chain, wherein the first polypeptide chain, the second polypeptide chain, and the third polypeptide chain are non-contiguous, and wherein:
 (i) the first polypeptide chain comprises a VH comprising the sequence of SEQ ID NO: 1346, wherein the VH is linked to the first Fc region,   (ii) the second polypeptide chain comprises a cytokine molecule, wherein the cytokine molecule is linked to the second Fc region, wherein the cytokine molecule comprises:
 (a) IL-2 or functional variant thereof comprising the sequence of SEQ ID NO: 2270, or 
 (b) IL-15 or functional variant thereof comprising the sequence of SEQ ID NO: 2170, wherein the IL-15 or functional variant thereof is covalently linked to an IL15Ralpha dimerizing domain, and 
   (iii) the third polypeptide chain comprises a VL comprising the sequence of SEQ ID NO: 1349, wherein the VL is linked to a light chain constant region comprising the sequence of SEQ ID NO: 39.   
     
     
         219 . The method of  claim 217 , wherein the molecule comprises the first polypeptide chain, the second polypeptide chain, and a third polypeptide chain, wherein the first polypeptide chain, the second polypeptide chain, and the third polypeptide chain are non-contiguous, and wherein:
 (i) the first polypeptide chain comprises a VH comprising the sequence of SEQ ID NO: 1113, wherein the VH is linked to the first Fc region,   (ii) the second polypeptide chain comprises a cytokine molecule, wherein the cytokine molecule is linked to the second Fc region, and   (iii) the third polypeptide chain comprises a VL comprising a sequence having at least 80% sequence identity to SEQ ID NO: 1111, wherein the VL is linked to a light chain constant region comprising the sequence of SEQ ID NO: 39.   
     
     
         220 . The method of  claim 217 , wherein the molecule comprises the first polypeptide chain, the second polypeptide chain, and a third polypeptide chain, wherein the first polypeptide chain, the second polypeptide chain, and the third polypeptide chain are non-contiguous, and wherein:
 (i) the first polypeptide chain comprises a VH comprising the sequence of SEQ ID NO: 1100, wherein the VH is linked to the first Fc region,   (ii) the second polypeptide chain comprises a cytokine molecule, wherein the cytokine molecule is linked to the second Fc region, wherein the cytokine molecule comprises:
 (a) IL-2 or functional variant thereof comprising the sequence of SEQ ID NO: 2270, or 
 (b) IL-15 or functional variant thereof comprising the sequence of SEQ ID NO: 2170, wherein the IL-15 or functional variant thereof is covalently linked to an IL15Ralpha dimerizing domain, and 
   (iii) the third polypeptide chain comprises a VL comprising a sequence having at least 80% sequence identity to SEQ ID NO: 1101, wherein the VL is linked to a light chain constant region comprising the sequence of SEQ ID NO: 39.   
     
     
         221 . The method of  claim 217 , wherein the molecule comprises the first polypeptide chain, the second polypeptide chain, and a third polypeptide chain, wherein the first polypeptide chain, the second polypeptide chain, and the third polypeptide chain are non-contiguous, and wherein:
 (i) the first polypeptide chain comprises a VH comprising the sequence of SEQ ID NO: 1356, wherein the VH is linked to the first Fc region,   (ii) the second polypeptide chain comprises a cytokine molecule, wherein the cytokine molecule is linked to the second Fc region, and   (iii) the third polypeptide chain comprises a VL comprising a sequence having at least 80% sequence identity to SEQ ID NO: 1357, wherein the VL is linked to a light chain constant region comprising the sequence of SEQ ID NO: 39.   
     
     
         222 . The method of  claim 217 , wherein the molecule comprises the first polypeptide chain, the second polypeptide chain, and a third polypeptide chain, wherein the first polypeptide chain, the second polypeptide chain, and the third polypeptide chain are non-contiguous, and wherein:
 (i) the first polypeptide chain comprises a VH comprising the sequence of SEQ ID NO: 1370, wherein the VH is linked to the first Fc region,   (ii) the second polypeptide chain comprises a cytokine molecule, wherein the cytokine molecule is linked to the second Fc region, wherein the cytokine molecule comprises:
 (a) IL-2 or functional variant thereof comprising the sequence of SEQ ID NO: 2270, or 
 (b) IL-15 or functional variant thereof comprising the sequence of SEQ ID NO: 2170, wherein the IL-15 or functional variant thereof is covalently linked to an IL15Ralpha dimerizing domain, and 
   (iii) the third polypeptide chain comprises a VL comprising a sequence having at least 80% sequence identity to SEQ ID NO: 1365, wherein the VL is linked to a light chain constant region comprising the sequence of SEQ ID NO: 39.   
     
     
         223 . The method of  claim 218 , wherein:
 (1) the first Fc region and the second Fc region each comprises an Asn297Ala mutation   (2) the first Fc region and the second Fc region each comprises a sequence having at least 98% sequence identity to the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and   (3) the first Fc region comprises T366S, L368A, and Y407V substitutions, and the second Fc region comprises T366W substitution; or the first Fc region comprises T366W substitution, and the second Fc region comprises T366S, L368A, and Y407V substitutions.   
     
     
         224 . The method of  claim 219 , wherein:
 (1) the first Fc region and the second Fc region each comprises an Asn297Ala mutation   (2) the first Fc region and the second Fc region each comprises a sequence having at least 98% sequence identity to the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and   (3) the first Fc region comprises T366S, L368A, and Y407V substitutions, and the second Fc region comprises T366W substitution; or the first Fc region comprises T366W substitution, and the second Fc region comprises T366S, L368A, and Y407V substitutions.   
     
     
         225 . The method of  claim 220 , wherein:
 (1) the first Fc region and the second Fc region each comprises an Asn297Ala mutation   (2) the first Fc region and the second Fc region each comprises a sequence having at least 98% sequence identity to the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and   (3) the first Fc region comprises T366S, L368A, and Y407V substitutions, and the second Fc region comprises T366W substitution; or the first Fc region comprises T366W substitution, and the second Fc region comprises T366S, L368A, and Y407V substitutions.   
     
     
         226 . The method of  claim 221 , wherein:
 (1) the first Fc region and the second Fc region each comprises an Asn297Ala mutation   (2) the first Fc region and the second Fc region each comprises a sequence having at least 98% sequence identity to the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and   (3) the first Fc region comprises T366S, L368A, and Y407V substitutions, and the second Fc region comprises T366W substitution; or the first Fc region comprises T366W substitution, and the second Fc region comprises T366S, L368A, and Y407V substitutions.   
     
     
         227 . The method of  claim 222 , wherein:
 (1) the first Fc region and the second Fc region each comprises an Asn297Ala mutation   (2) the first Fc region and the second Fc region each comprises a sequence having at least 98% sequence identity to the sequence of SEQ ID NO: 41 or SEQ ID NO: 42, and   (3) the first Fc region comprises T366S, L368A, and Y407V substitutions, and the second Fc region comprises T366W substitution; or the first Fc region comprises T366W substitution, and the second Fc region comprises T366S, L368A, and Y407V substitutions.   
     
     
         228 . The method of  claim 218 , wherein:
 (i) the first Fc region comprising the sequence of amino acids 1-328 of SEQ ID NO: 42, with the proviso that Tyr at the position 349, Thr at the position 366, Leu at the position 368, and Tyr at the position 407 according to EU Numbering are replaced with Cys, Ser, Ala, and Val, respectively; and   (ii) the second polypeptide chain comprises the cytokine molecule linked to the second Fc region via the sequence of SEQ ID NO: 3308, wherein the second Fc region comprises the sequence of amino acids 104-328 of SEQ ID NO: 42, with the proviso that Ser at the position 354 and Thr at the position 366 according to EU Numbering are replaced with Cys and Trp, respectively.   
     
     
         229 . The method of  claim 219 , wherein:
 (i) the first Fc region comprising the sequence of amino acids 1-328 of SEQ ID NO: 42, with the proviso that Tyr at the position 349, Thr at the position 366, Leu at the position 368, and Tyr at the position 407 according to EU Numbering are replaced with Cys, Ser, Ala, and Val, respectively; and   (ii) the second polypeptide chain comprises the cytokine molecule linked to the second Fc region via the sequence of SEQ ID NO: 3308, wherein the second Fc region comprises the sequence of amino acids 104-328 of SEQ ID NO: 42, with the proviso that Ser at the position 354 and Thr at the position 366 according to EU Numbering are replaced with Cys and Trp, respectively.   
     
     
         230 . The method of  claim 220 , wherein:
 (i) the first Fc region comprising the sequence of amino acids 1-328 of SEQ ID NO: 42, with the proviso that Tyr at the position 349, Thr at the position 366, Leu at the position 368, and Tyr at the position 407 according to EU Numbering are replaced with Cys, Ser, Ala, and Val, respectively; and   (ii) the second polypeptide chain comprises the cytokine molecule linked to the second Fc region via the sequence of SEQ ID NO: 3308, wherein the second Fc region comprises the sequence of amino acids 104-328 of SEQ ID NO: 42, with the proviso that Ser at the position 354 and Thr at the position 366 according to EU Numbering are replaced with Cys and Trp, respectively.   
     
     
         231 . The method of  claim 221 , wherein:
 (i) the first Fc region comprising the sequence of amino acids 1-328 of SEQ ID NO: 42, with the proviso that Tyr at the position 349, Thr at the position 366, Leu at the position 368, and Tyr at the position 407 according to EU Numbering are replaced with Cys, Ser, Ala, and Val, respectively; and   (ii) the second polypeptide chain comprises the cytokine molecule linked to the second Fc region via the sequence of SEQ ID NO: 3308, wherein the second Fc region comprises the sequence of amino acids 104-328 of SEQ ID NO: 42, with the proviso that Ser at the position 354 and Thr at the position 366 according to EU Numbering are replaced with Cys and Trp, respectively.   
     
     
         232 . The method of  claim 222 , wherein:
 (i) the first Fc region comprising the sequence of amino acids 1-328 of SEQ ID NO: 42, with the proviso that Tyr at the position 349, Thr at the position 366, Leu at the position 368, and Tyr at the position 407 according to EU Numbering are replaced with Cys, Ser, Ala, and Val, respectively; and   (ii) the second polypeptide chain comprises the cytokine molecule linked to the second Fc region via the sequence of SEQ ID NO: 3308, wherein the second Fc region comprises the sequence of amino acids 104-328 of SEQ ID NO: 42, with the proviso that Ser at the position 354 and Thr at the position 366 according to EU Numbering are replaced with Cys and Trp, respectively.   
     
     
         233 . The method of  claim 217 , wherein the second polypeptide chain comprises the antigen binding domain comprising the sequence of SEQ ID NO: 1331, and a cytokine molecule, wherein the cytokine molecule comprises IL-2 or functional variant thereof comprising the sequence of SEQ ID NO: 2270, and
 wherein the antigen binding domain, the cytokine molecule, and the second Fc region are linked.   
     
     
         234 . A method of expanding an immune cell population comprising contacting the immune cell population with a composition a molecule comprising an antigen binding domain that binds to a T cell receptor beta variable (TCRβV) region, wherein the antigen binding domain comprises:
 (i) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 3 (HC CDR3) comprising the sequence SYYSYDVLDY (SEQ ID NO: 47) or the sequence SLNWDYGLDY (SEQ ID NO: 1104), 
 thereby expanding the immune cell population, and 
 wherein the expansion occurs in vivo or ex vivo.
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