IL325291A - Anti-trailr2 antigen-binding proteins and uses thereof - Google Patents

Anti-trailr2 antigen-binding proteins and uses thereof

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Publication number
IL325291A
IL325291A IL325291A IL32529125A IL325291A IL 325291 A IL325291 A IL 325291A IL 325291 A IL325291 A IL 325291A IL 32529125 A IL32529125 A IL 32529125A IL 325291 A IL325291 A IL 325291A
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seq
amino acid
acid sequence
cdr3
cdr1
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IL325291A
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Odyssey Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/22—Immunoglobulins specific features characterized by taxonomic origin from camelids, e.g. camel, llama or dromedary
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
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    • C07—ORGANIC CHEMISTRY
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/75—Agonist effect on antigen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

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  • Organic Chemistry (AREA)
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  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • General Chemical & Material Sciences (AREA)
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Claims (62)

Claims
1. PCT / US2024 / 035969 An antigen - binding protein that specifically binds TNF - related apoptosis - inducing ligand receptor 2 ( TRAILR2 ) , comprising a complementarity determining region 3 ( CDR3 ) comprising an amino acid sequence selected from a ) . ( A / V ) ASRL ( P / V ) FNSRSA ( I / V ) YTDRIYDS ( SEQ ID NO : 100 ) ; b ) . AVRRSAWY ( S / T ) DSIYTVSQYDY ( SEQ ID NO : 101 ) ; c ) . NAARSYSR ( D / G / N ) { G / Y ) ( E / R ) PL ( E / K ) P ( A / D ) Y ( SEQ ID NO : 102 ) ; d ) . AAASSWSRGG / A / G / I / V ) PYGMDY ( SEQ ID NO : 103 ) ; e ) . AADS ( H / R ) FRR ( P / Y ) ( A / T / V ) PG ( I / Q ) QYEY ( SEQ ID NO : 104 ) ; f ) . NAA ( K / R ) SYHRDY ( K / S ) PL ( K / S ) ( G / P ) DY ( SEQ ID NO : 105 ) ; g ) . AAAPSFGM ( M / R / T ) ( I / N ) PESYVHS ( SEQ ID NO : 106 ) ; h ) . AANRGIMSMRLSRYDD ( SEQ ID NO : 49 ) ; 1 ) . T ( A / V ) GP ( A / T ) MSYSRGGEF ( SEQ ID NO : 107 ) ; j ) . ( A / V ) ADRGAISRSGAGM ( D / N ) Y ( SEQ ID NO : 108 ) ; k ) . TAGP ( A / S ) IS ( L / Y ) SRGGEY ( SEQ ID NO : 109 ) ; I ) . A ( A / T ) NGWGLDP ( S / T ) TYH ( Y / D ) ( SEQ ID NO : 110 ) ; m ) . SAGWTRRIFQY ( SEQ ID NO : 88 ) ; n ) . TAGQSISLSQGGE ( H / Y ) ( SEQ ID NO : 111 ) ; o ) . KAGIRGE ( T / V ) Y ( SEQ ID NO : 112 ) ; p ) . RAYNDGGEY ( SEQ ID NO : 2191 ) ; q ) . HS ( N / R ) WYNL ( SEQ ID NO : 2208 ) ; and r ) . ( F / M / N ) T ( A / S ) DY , wherein one or more non - alanine residues in the CDR3 sequence is optionally replaced with an alanine , and / or one or more alanine residues in the CDR3 sequence is optionally replaced with a glycine .
2. The antigen - binding protein of claim 1 , wherein the CDR3 comprises an amino acid sequence selected from s } . { A / G ) ( A / G ) ( A / G ) ( A / S ) ( A / S ) ( A / W ) ( A / S ) ( A / R ) ( A / G ) ( A / G ) ( A / G / I / V ) ( A / P ) ( A / Y ) ( A / G ) ( A / M ) ( A / D ) ( A / Y ) ; t ) . ( A / T ) ( A / G / V ) ( A / G ) ( A / P ) ( A / T ) ( A / M ) ( A / S ) { A / Y } { A / S ) ( A / R ) ( A / G ) ( A / G } { A / E ) ( A / F ) ; u ) . ( A / R ) ( A / G ) ( A / Y ) ( A / N ) ( A / D ) ( A / G ) ( A / G } { ( A / E ) ( A / Y ) ; v ) . ( A / H ) ( A / S ) ( A / N / R ] ) ( A / W } { A / Y ) ( A / N ) ( A / L ) ; and 218 WO 2025/006846 w ) . ( A / F / M / N ) ( A / T ) ( A / G / S ) ( A / DIY .
3. PCT / US2024 / 035969 The antigen - binding protein of claim 1 , wherein the CDR3 comprises an amino acid sequence selected from VASRLPFNSRSAIYTDRIYDS ( SEQ ID NO : 3 ) ; AVRRSAWYSDSIYTVSQYDY ( SEQ ID NO : 8 ) ; NAARSYSRDYEPLKPDY ( SEQ ID NO : 13 ) ; NAARSYSRNYEPLKPDY ( SEQ ID NO : 16 ) ; NAARSYSRGGEPLKPDY ( SEQ ID NO : 20 ) ; NAARSYSRGGRPLEPAY ( SEQ ID NO : 25 ) ; AAASSWSRGGVPYGMDY ( SEQ ID NO : 30 ) ; AADSHFRRYTPGQQYEY ( SEQ ID NO : 35 ) ; NAAKSYHRDYSPLSPDY ( SEQ ID NO : 40 ) ; AAAPSFGMRNPESYVHS ( SEQ ID NO : 44 } ; AANRGIMSMRLSRYDD ( SEQ ID NO : 49 ) ; TAGPTMSYSRGGEF ( SEQ ID NO : 54 ) ; VADRGAISRSGAGMDY ( SEQ ID NO : 64 ) ; AADRGAISRSGAGMDY ( SEQ ID NO : 69 ) ; TAGPAISLSRGGEY ( SEQ ID NO : 74 ) ; TAGPSISYSRGGEY ( SEQ ID NO : 78 ) ; AANGWGLDPTTYHY ( SEQ ID NO : 83 ) ; SAGWTRRIFQY ( SEQ ID NO : 88 ) ; TAGQSISLSQGGEY ( SEQ ID NO : 92 ) ; KAGIRGEVY ( SEQ ID NO : 97 ) ; RAYNDGGEY ( SEQ ID NO : 2191 ) ; HSRWYNL ( SEQ ID NO : 2197 ) ; FTADY ( SEQ ID NO : 2203 ) ; GAASSWSRGGVPYGMDY ( SEQ ID NO : 2298 ) ; AGASSWSRGGVPYGMDY ( SEQ ID NO : 2299 ) ; AAGSSWSRGGVPYGMDY ( SEQ ID NO : 2300 ) ; AAAASWSRGGVPYGMDY ( SEQ ID NO : 2301 ) ; AAASAWSRGGVPYGMDY ( SEQ ID NO : 2302 ) ; AAASSASRGGVPYGMDY ( SEQ ID NO : 2303 ) ; AAASSWARGGVPYGMDY ( SEQ ID NO : 2304 ) ; AAASSWSAGGVPYGMDY ( SEQ ID NO : 2305 ) ; AAASSWSRAGVPYGMDY ( SEQ ID NO : 2306 ) ; AAASSWSRGAVPYGMDY ( SEQ ID NO : 2307 ) ; AAASSWSRGGAPYGMDY ( SEQ ID NO : 2308 ) ; AAASSWSRGGVAYGMDY ( SEQ ID NO : 2309 ) ; AAASSWSRGGVPAGMDY ( SEQ ID NO : 2310 ) ; AAASSWSRGGVPYAMDY ( SEQ ID NO : 2311 ) ; AAASSWSRGGVPYGADY ( SEQ ID NO : 2312 ) ; AAASSWSRGGVPYGMAY ( SEQ ID NO : 2313 ) ; AAASSWSRGGVPYGMDA ( SEQ ID NO : 2314 ) ; AAGPTMSYSRGGEF ( SEQ ID NO : 2315 ) ; TGGPTMSYSRGGEF ( SEQ ID NO : 2316 ) ; TAAPTMSYSRGGEF ( SEQ ID NO : 2317 ) ; TAGATMSYSRGGEF ( SEQ ID NO : 2318 ) ; TAGPAMSYSRGGEF ( SEQ ID NO : 2319 ) ; TAGPTASYSRGGEF ( SEQ ID NO : 2320 ) ; TAGPTMAYSRGGEF ( SEQ ID NO : 2321 ) ; TAGPTMSASRGGEF ( SEQ ID NO : 2322 ) ; TAGPTMSYARGGEF ( SEQ ID NO : 2323 ) ; TAGPTMSYSAGGEF ( SEQ ID NO : 2324 } ; TAGPTMSYSRAGEF ( SEQ ID NO : 2325 ) ; TAGPTMSYSRGAEF ( SEQ ID NO : 2326 ) ; TAGPTMSYSRGGAF ( SEQ ID NO : 2327 ) ; TAGPTMSYSRGGEA ( SEQ ID NO : 2328 ) ; AAYNDGGEY ( SEQ ID NO : 2329 ) ; RGYNDGGEY ( SEQ ID NO : 2330 ) ; RAANDGGEY ( SEQ ID NO : 2331 ) ; RAYADGGEY ( SEQ ID NO : 2332 ) ; RAYNAGGEY ( SEQ ID NO : 2333 ) ; RAYNDAGEY ( SEQ ID NO : 2334 ) ; RAYNDGAEY ( SEQ ID NO : 2335 ) ; RAYNDGGAY ( SEQ ID NO : 2336 ) ; RAYNDGGEA ( SEQ ID NO : 2337 ) ; ASRWYNL ( SEQ ID NO : 2338 ) ; HARWYNL ( SEQ ID NO : 2339 ) ; HSAWYNL ( SEQ ID NO : 2340 ) ; HSRAYNL ( SEQ ID NO : 2341 ) ; HSRWANL 219 WO 2025/006846 PCT / US2024 / 035969 ( SEQ ID NO : 2342 ) ; HSRWYAL ( SEQ ID NO : 2343 ) ; HSRWYNA ( SEQ ID NO : 2344 ) ; ATADY ( SEQ ID NO : 2345 ) ; FAADY ( SEQ ID NO : 2346 ) ; FTGDY ( SEQ ID NO : 2347 ) ; and FTAAY ( SEQ ID NO : 2348 ) .
4.
5. The antigen - binding protein of any one of claims 1-3 , further comprising a CDR1 comprising an amino acid sequence selected from a ) . GRTFSSNL ( SEQ ID NO : 1 ) ; b ) . GGT ( F / L ) ( A / S ) N ( D / N ) G ( SEQ ID NO : 113 ) ; c ) . GRTL ( D / N / S ) ( A / D / E ) Y ( A / G ) ( SEQ ID NO : 114 ) ; d ) . GRTFS ( N / S ) YA ( SEQ ID NO : 115 ) ; e ) . GRDFSNYV ( SEQ ID NO : 33 ) ; f ) . G ( L / R ) ( I / S ) FS ( D / S ) YA ( SEQ ID NO : 116 ) ; g ) . GR ( A / T ) FSTLA ( SEQ ID NO : 117 ) ; h ) . GRTFSSDI ( SEQ ID NO : 47 ) ; j ) . GRSFGD ( D / F / Y ) A ( SEQ ID NO : 118 ) ; j ) . G ( G / R ) TLSNYA ( SEQ ID NO : 119 ) ; k ) . GRSFGAQGMEG ( SEQ ID NO : 72 } ; 1 ) . GFTLDLGAYA ( SEQ ID NO : 81 ) ; m ) . GFTFGALA ( SEQ ID NO : 86 ) ; n ) . GFTLS ( G / S ) YA ( SEQ ID NO : 120 ) ; o ) . GSIFGGYN ( SEQ ID NO : 2189 ) ; p ) . G ( G / S ) NFRILS ( SEQ ID NO : 2209 ) ; and q ) . G ( F / L ) ( A / T ) F ( R / S ) ( R / S ) YA ( SEQ ID NO : 2212 ) . The antigen - binding protein of claim 4 , wherein the CDR1 comprises an amino acid sequence selected from GRTFSSNL ( SEQ ID NO : 1 ) ; GGTLANNG ( SEQ ID NO : 6 ) ; GRTLDAYG ( SEQ ID NO : 11 ) ; GRTLSDYA ( SEQ ID NO : 23 ) ; GRTFSSYA ( SEQ ID NO : 28 ) ; GRDFSNYV ( SEQ ID NO : 33 ) ; GRSFSSYA ( SEQ ID NO : 38 ) ; GRTFSTLA ( SEQ ID NO : 43 ) ; GRTFSSDI ( SEQ ID NO : 47 ) ; GRSFGDFA ( SEQ ID NO : 52 ) ; GGTLSNYA ( SEQ ID NO : 62 ) ; GRTLSNYA ( SEQ ID NO : 67 ) ; GRSFGAQGMEG ( SEQ ID NO : 72 } ; GFTLDLGAYA ( SEQ ID NO : 81 ) ; GFTFGALA ( SEQ ID NO : 86 ) ; GFTLSGYA ( SEQ ID NO : 95 ) ; GSIFGGYN ( SEQ ID NO : 2189 ) ; GSNFRILS ( SEQ ID NO : 2195 ) ; and GFTFSRYA ( SEQ ID NO : 2201 } . 220 WO 2025/006846
6. PCT / US2024 / 035969 The antigen - binding protein of any one of claims 1-5 , further comprising a CDR2 comprising an amino acid sequence selected from a ) . VSWNGAST ( SEQ ID NO : 2 ) ; b ) . DHR ( S / T ) GT ( SEQ ID NO : 121 ) ; c ) . I ( N / S ) W ( N / S / T ) G ( T / V ) ( D / G ) T ( SEQ ID NO : 122 } ; d ) . LNW ( N / S ) G ( D / E ) ST ( SEQ ID NO : 123 ) ; e ) . INWAD ( E / T ) T ( SEQ ID NO : 124 ) ; f ) . INWSGG ( S / T ) T ( SEQ ID NO : 125 ) ; g ) . ISWSDMSA ( SEQ ID NO : 48 ) ; h ) . I ( N / R ) W ( A / D / T ) G ( D / N ) T ( SEQ ID NO : 126 ) ; i ) . ISQ ( S / T ) S ( D / S ) T ( SEQ ID NO : 127 } ; j ) . ( I / M ) KWTGNT ( SEQ ID NO : 128 ) ; k ) . ISN ( S / T ) GTTT ( SEQ ID NO : 129 ) ; 1 ) . ISNDGEHI ( SEQ ID NO : 87 ) ; m ) . ISWNGDIT ( SEQ ID NO : 91 } ; n ) . IT ( G / S } { A / S ) G ( G / S ) ( N / S ) T ( SEQ ID NO : 130 ) ; o ) . IFISGN ( D / N ) ( SEQ ID NO : 2207 ) ; p ) . ( I / L ) T ( K / M / S ) D ( D / G ) TT ( SEQ ID NO : 2210 ) ; and q ) . ISS ( A / G / S ) ( G / S ) G ( I / Y ) ( I / T / V ) ( SEQ ID NO : 2213 ) .
7.
8. The antigen - binding protein of claim 6 , wherein the CDR2 comprises an amino acid sequence selected from VSWNGAST ( SEQ ID NO : 2 ) ; DHRSGT ( SEQ ID NO : 7 ) ; ISWTGVDT ( SEQ ID NO : 12 ) ; ISWTGTDT ( SEQ ID NO : 19 ) ; ISWSGVDT ( SEQ ID NO : 24 ) ; LNWSGEST ( SEQ ID NO : 29 ) ; INWADET ( SEQ ID NO : 34 ) ; INWSGGST ( SEQ ID NO : 39 ) ; ISWSDMSA ( SEQ ID NO : 48 ) ; IRWTGDT ( SEQ ID NO : 53 ) ; ISQTSST ( SEQ ID NO : 63 ) ; ISQSSDT ( SEQ ID NO : 68 ) ; MKWTGNT ( SEQ ID NO : 73 ) ; IKWTGNT ( SEQ ID NO : 77 ) ; ISNTGTTT ( SEQ ID NO : 82 ) ; ISNDGEHI ( SEQ ID NO : 87 ) ; ISWNGDIT ( SEQ ID NO : 91 } ; ITSAGGST ( SEQ ID NO : 96 ) ; IFISGNN ( SEQ ID NO : 2190 ) ; ITSDDTT ( SEQ ID NO : 2196 ) ; and ISSAGGYI ( SEQ ID NO : 2202 ) . An antigen - binding protein that specifically binds TNF - related apoptosis - inducing ligand receptor 2 ( TRAILR2 ) , comprising a CDR1 comprising an amino acid sequence selected from SEQ ID Nos : 1 , 6 , 11 , 23 , 28 , 33 , 38 , 43 , 47 , 52 , 62 , 67 , 72 , 81 , 86 , 95 , 762-1084 , 2189 , 2195 , 2201 , and 2252-2261 ; a 221 WO 2025/006846 PCT / US2024 / 035969 CDR2 comprising an amino acid sequence selected from SEQ ID NOs : 2 , 7 , 12 , 19 , 24 , 29 , 34 , 39 , 48 , 53 , 63 , 68 , 73 , 77 , 82 , 87 , 91 , 96 , 1085-1407 , 2190 , 2196 , 2202 , and 2262-2271 ; and / or a CDR3 comprising an amino acid sequence selected from SEQ ID NOs : 3 , 8 , 13 , 16 , 20 , 25 , 30 , 35 , 40 , 44 , 49 , 54 , 64 , 69 , 74 , 78 , 83 , 88 , 92 , 97 , 1408-1730 , 2191 , 2197 , 2203 , 2272-2277 , and 2298-2348 .
9. The antigen - binding protein of any one of claims 1 , 3-8 , wherein the antigen - binding protein comprises i ) . a CDR1 comprising an amino acid sequence of GRTFSSNL ( SEQ ID NO : 1 ) , a CDR2 comprising an amino acid sequence of VSWNGAST ( SEQ ID NO : 2 ) , and a CDR3 comprising an amino acid sequence of VASRLPFNSRSAIYTDRIYDS ( SEQ ID NO : 3 ) ; ii ) . a CDR1 comprising an amino acid sequence of GGTLANNG ( SEQ ID NO : 6 ) , a CDR2 comprising an amino acid sequence of DHRSGT ( SEQ ID NO : 7 ) , and a CDR3 comprising an amino acid sequence of AVRRSAWYSDSIYTVSQYDY ( SEQ ID NO : 8 ) ; III ) . a CDR1 comprising an amino acid sequence of GRTLDAYG ( SEQ ID NO : 11 ) , a CDR2 comprising an amino acid sequence of ISWTGVDT ( SEQ ID NO : 12 ) , and a CDR3 comprising an amino acid sequence of NAARSYSRDYEPLKPDY ( SEQ ID NO : 13 ) ; iv ) . a CDR1 comprising an amino acid sequence of GRTLDAYG ( SEQ ID NO : 11 ) , a CDR2 comprising an amino acid sequence of ISWTGVDT ( SEQ ID NO : 12 ) , and a CDR3 comprising an amino acid sequence of NAARSYSRNYEPLKPDY ( SEQ ID NO : 16 ) ; v ) . a CDR1 comprising an amino acid sequence of GRTLDAYG ( SEQ ID NO : 11 ) , a CDR2 comprising an amino acid sequence of ISWTGTDT ( SEQ ID NO : 19 ) , and a CDR3 comprising an amino acid sequence of NAARSYSRGGEPLKPDY ( SEQ ID NO : 20 ) ; vi ) . a CDR1 comprising an amino acid sequence of GRTLSDYA ( SEQ ID NO : 23 ) , a CDR2 comprising an amino acid sequence of ISWSGVDT ( SEQ ID NO : 24 ) , and a CDR3 comprising an amino acid sequence of NAARSYSRGGRPLEPAY ( SEQ ID NO : 25 ) ; vii ) . a CDR1 comprising an amino acid sequence of GRTFSSYA ( SEQ ID NO : 28 ) , a CDR2 comprising an amino acid sequence of LNWSGEST ( SEQ ID NO : 29 ) , and a CDR3 comprising an amino acid sequence of AAASSWSRGGVPYGMDY ( SEQ ID NO : 30 ) ; viii ) . a CDR1 comprising an amino acid sequence of GRDFSNYV ( SEQ ID NO : 33 ) , a CDR2 comprising an amino acid sequence of INWADET ( SEQ ID NO : 34 ) , and a CDR3 comprising an amino acid sequence of AADSHFRRYTPGQQYEY ( SEQ ID NO : 35 ) ; 222 WO 2025/006846 PCT / US2024 / 035969 ix ) . a CDR1 comprising an amino acid sequence of GRSFSSYA ( SEQ ID NO : 38 ) , a CDR2 comprising an amino acid sequence of INWSGGST ( SEQ ID NO : 39 ) , and a CDR3 comprising an amino acid sequence of NAAKSYHRDYSPLSPDY ( SEQ ID NO : 40 ) ; x ) . a CDR1 comprising an amino acid sequence of GRTFSTLA ( SEQ ID NO : 43 ) , a CDR2 comprising an amino acid sequence of INWSGGST ( SEQ ID NO : 39 ) , and a CDR3 comprising an amino acid sequence of AAAPSFGMRNPESYVHS ( SEQ ID NO : 44 ) ; xi ) . a CDR1 comprising an amino acid sequence of GRTFSSDI ( SEQ ID NO : 47 ) , a CDR2 comprising an amino acid sequence of ISWSDMSA ( SEQ ID NO : 48 ) , and a CDR3 comprising an amino acid sequence of AANRGIMSMRLSRYDD ( SEQ ID NO : 49 ) ; xii ) . a CDR1 comprising an amino acid sequence of GRSFGDFA ( SEQ ID NO : 52 ) , a CDR2 comprising an amino acid sequence of IRWTGDT ( SEQ ID NO : 53 ) , and a CDR3 comprising an amino acid sequence of TAGPTMSYSRGGEF ( SEQ ID NO : 54 ) ; xiii ) . a CDR1 comprising an amino acid sequence of GGTLSNYA ( SEQ ID NO : 62 ) , a CDR2 comprising an amino acid sequence of ISQTSST ( SEQ ID NO : 63 ) , and a CDR3 comprising an amino acid sequence of VADRGAISRSGAGMDY ( SEQ ID NO : 64 ) ; xiv ) . a CDR1 comprising an amino acid sequence of GRTLSNYA ( SEQ ID NO : 67 ) , a CDR2 comprising an amino acid sequence of ISQSSDT ( SEQ ID NO : 68 ) , and a CDR3 comprising an amino acid sequence of AADRGAISRSGAGMDY ( SEQ ID NO : 69 ) ; xv ) . a CDR1 comprising an amino acid sequence of GRSFGAQGMEG ( SEQ ID NO : 72 ) , a CDR2 comprising an amino acid sequence of MKWTGNT ( SEQ ID NO : 73 ) , and a CDR3 comprising an amino acid sequence of TAGPAISLSRGGEY ( SEQ ID NO : 74 ) ; xvi ) . a CDR1 comprising an amino acid sequence of GRSFGAQGMEG ( SEQ ID NO : 72 ) , a CDR2 comprising an amino acid sequence of IKWTGNT ( SEQ ID NO : 77 ) , and a CDR3 comprising an amino acid sequence of TAGPSISYSRGGEY ( SEQ ID NO : 78 ) ; xvii ) . a CDR1 comprising an amino acid sequence of GFTLDLGAYA ( SEQ ID NO : 81 ) , a CDR2 comprising an amino acid sequence of ISNTGTTT ( SEQ ID NO : 82 ) , and a CDR3 comprising an amino acid sequence of AANGWGLDPTTYHY ( SEQ ID NO : 83 ) ; xviii ) . a CDR1 comprising an amino acid sequence of GFTFGALA ( SEQ ID NO : 86 ) , a CDR2 comprising an amino acid sequence of ISNDGEHI ( SEQ ID NO : 87 ) , and a CDR3 comprising an amino acid sequence of SAGWTRRIFQY ( SEQ ID NO : 88 ) ; 223 WO 2025/006846 PCT / US2024 / 035969 xix ) . a CDR1 comprising an amino acid sequence of GRTFSSYA ( SEQ ID NO : 28 ) , a CDR2 comprising an amino acid sequence of ISWNGDIT ( SEQ ID NO : 91 ) , and a CDR3 comprising an amino acid sequence of TAGQSISLSQGGEY ( SEQ ID NO : 92 ) ; xx ) . a CDR1 comprising an amino acid sequence of GFTLSGYA ( SEQ ID NO : 95 ) , a CDR2 comprising an amino acid sequence of ITSAGGST ( SEQ ID NO : 96 ) , and a CDR3 comprising an amino acid sequence of KAGIRGEVY ( SEQ ID NO : 97 ) ; xxi ) . a CDR1 comprising an amino acid sequence of GSIFGGYN ( SEQ ID NO : 2189 ) , a CDR2 comprising an amino acid sequence of IFISGNN ( SEQ ID NO : 2190 ) , and a CDR3 comprising an amino acid sequence of RAYNDGGEY ( SEQ ID NO : 2191 ) ; xxii ) . a CDR1 comprising an amino acid sequence of GSNFRILS ( SEQ ID NO : 2195 ) , a CDR2 comprising an amino acid sequence of ITSDDTT ( SEQ ID NO : 2196 ) , and a CDR3 comprising an amino acid sequence of HSRWYNL ( SEQ ID NO : 2197 ) ; xxiii ) . a CDR1 comprising an amino acid sequence of GFTFSRYA ( SEQ ID NO : 2201 ) , a CDR2 comprising an amino acid sequence of ISSAGGYI ( SEQ ID NO : 2202 ) , and a CDR3 comprising an amino acid sequence of FTADY ( SEQ ID NO : 2203 ) ; xxiv ) . a CDR1 comprising an amino acid sequence of GRTFSSYA ( SEQ ID NO : 28 ) , a CDR2 comprising an amino acid sequence of LNWSGEST ( SEQ ID NO : 29 ) , and a CDR3 comprising an amino acid sequence of GAASSWSRGGVPYGMDY ( SEQ ID NO : 2298 ) ; xxv ) . a CDR1 comprising an amino acid sequence of GRTFSSYA ( SEQ ID NO : 28 ) , a CDR2 comprising an amino acid sequence of LNWSGEST ( SEQ ID NO : 29 ) , and a CDR3 comprising an amino acid sequence of AGASSWSRGGVPYGMDY ( SEQ ID NO : 2299 ) ; xxvi ) . a CDR1 comprising an amino acid sequence of GRTFSSYA ( SEQ ID NO : 28 ) , a CDR2 comprising an amino acid sequence of LNWSGEST ( SEQ ID NO : 29 ) , and a CDR3 comprising an amino acid sequence of AAGSSWSRGGVPYGMDY ( SEQ ID NO : 2300 ) ; xxvii ) , a CDR1 comprising an amino acid sequence of GRTFSSYA ( SEQ ID NO : 28 ) , a CDR2 comprising an amino acid sequence of LNWSGEST ( SEQ ID NO : 29 ) , and a CDR3 comprising an amino acid sequence of AAAASWSRGGVPYGMDY ( SEQ ID NO : 2301 ) ; xxviii ) . a CDR1 comprising an amino acid sequence of GRTFSSYA ( SEQ ID NO : 28 ) , a CDR2 comprising an amino acid sequence of LNWSGEST ( SEQ ID NO : 29 ) , and a CDR3 comprising an amino acid sequence of AAASAWSRGGVPYGMDY ( SEQ ID NO : 2302 ) ; 224 WO 2025/006846 PCT / US2024 / 035969 xxix ) . a CDR1 comprising an amino acid sequence of GRTFSSYA ( SEQ ID NO : 28 ) , a CDR2 comprising an amino acid sequence of LNWSGEST ( SEQ ID NO : 29 ) , and a CDR3 comprising an amino acid sequence of AAASSASRGGVPYGMDY ( SEQ ID NO : 2303 ) ; xxx ) . a CDR1 comprising an amino acid sequence of GRTFSSYA ( SEQ ID NO : 28 ) , a CDR2 comprising an amino acid sequence of LNWSGEST ( SEQ ID NO : 29 ) , and a CDR3 comprising an amino acid sequence of AAASSWARGGVPYGMDY ( SEQ ID NO : 2304 ) ; xxxi ) . a CDR1 comprising an amino acid sequence of GRTFSSYA ( SEQ ID NO : 28 ) , a CDR2 comprising an amino acid sequence of LNWSGEST ( SEQ ID NO : 29 ) , and a CDR3 comprising an amino acid sequence of AAASSWSAGGVPYGMDY ( SEQ ID NO : 2305 ) ; xxxii ) . a CDR1 comprising an amino acid sequence of GRTFSSYA ( SEQ ID NO : 28 ) , a CDR2 comprising an amino acid sequence of LNWSGEST ( SEQ ID NO : 29 ) , and a CDR3 comprising an amino acid sequence of AAASSWSRAGVPYGMDY ( SEQ ID NO : 2306 ) ; xxxiii ) , a CDR1 comprising an amino acid sequence of GRTFSSYA ( SEQ ID NO : 28 ) , a CDR2 comprising an amino acid sequence of LNWSGEST ( SEQ ID NO : 29 ) , and a CDR3 comprising an amino acid sequence of AAASSWSRGAVPYGMDY ( SEQ ID NO : 2307 ) ; xxxiv ) . a CDR1 comprising an amino acid sequence of GRTFSSYA ( SEQ ID NO : 28 ) , a CDR2 comprising an amino acid sequence of LNWSGEST ( SEQ ID NO : 29 ) , and a CDR3 comprising an amino acid sequence of AAASSWSRGGAPYGMDY ( SEQ ID NO : 2308 ) ; xxxv ) . a CDR1 comprising an amino acid sequence of GRTFSSYA ( SEQ ID NO : 28 ) , a CDR2 comprising an amino acid sequence of LNWSGEST ( SEQ ID NO : 29 ) , and a CDR3 comprising an amino acid sequence of AAASSWSRGGVAYGMDY ( SEQ ID NO : 2309 ) ; xxxvi ) . a CDR1 comprising an amino acid sequence of GRTFSSYA ( SEQ ID NO : 28 ) , a CDR2 comprising an amino acid sequence of LNWSGEST ( SEQ ID NO : 29 ) , and a CDR3 comprising an amino acid sequence of AAASSWSRGGVPAGMDY ( SEQ ID NO : 2310 ) ; xxxvii ) . a CDR1 comprising an amino acid sequence of GRTFSSYA ( SEQ ID NO : 28 ) , a CDR2 comprising an amino acid sequence of LNWSGEST ( SEQ ID NO : 29 ) , and a CDR3 comprising an amino acid sequence of AAASSWSRGGVPYAMDY ( SEQ ID NO : 2311 ) ; xxxviii ) . a CDR1 comprising an amino acid sequence of GRTFSSYA ( SEQ ID NO : 28 ) , a CDR2 comprising an amino acid sequence of LNWSGEST ( SEQ ID NO : 29 ) , and a CDR3 comprising an amino acid sequence of AAASSWSRGGVPYGADY ( SEQ ID NO : 2312 ) ; 225 WO 2025/006846 PCT / US2024 / 035969 xxxix ) . a CDR1 comprising an amino acid sequence of GRTFSSYA ( SEQ ID NO : 28 ) , a CDR2 comprising an amino acid sequence of LNWSGEST ( SEQ ID NO : 29 ) , and a CDR3 comprising an amino acid sequence of AAASSWSRGGVPYGMAY ( SEQ ID NO : 2313 ) ; xl ) . a CDR1 comprising an amino acid sequence of GRTFSSYA ( SEQ ID NO : 28 ) , a CDR2 comprising an amino acid sequence of LNWSGEST ( SEQ ID NO : 29 ) , and a CDR3 comprising an amino acid sequence of AAASSWSRGGVPYGMDA ( SEQ ID NO : 2314 ) ; xli ) . a CDR1 comprising an amino acid sequence of GRSFGDFA ( SEQ ID NO : 52 ) , a CDR2 comprising an amino acid sequence of IRWTGDT ( SEQ ID NO : 53 ) , and a CDR3 comprising an amino acid sequence of AAGPTMSYSRGGEF ( SEQ ID NO : 2315 ) ; xlii ) . a CDR1 comprising an amino acid sequence of GRSFGDFA ( SEQ ID NO : 52 ) , a CDR2 comprising an amino acid sequence of IRWTGDT ( SEQ ID NO : 53 ) , and a CDR3 comprising an amino acid sequence of TGGPTMSYSRGGEF ( SEQ ID NO : 2316 ) ; xliii ) . a CDR1 comprising an amino acid sequence of GRSFGDFA ( SEQ ID NO : 52 ) , a CDR2 comprising an amino acid sequence of IRWTGDT ( SEQ ID NO : 53 ) , and a CDR3 comprising an amino acid sequence of TAAPTMSYSRGGEF ( SEQ ID NO : 2317 ) ; xliv ) . a CDR1 comprising an amino acid sequence of GRSFGDFA ( SEQ ID NO : 52 ) , a CDR2 comprising an amino acid sequence of IRWTGDT ( SEQ ID NO : 53 ) , and a CDR3 comprising an amino acid sequence of TAGATMSYSRGGEF ( SEQ ID NO : 2318 } ; xlv ) . a CDR1 comprising an amino acid sequence of GRSFGDFA ( SEQ ID NO : 52 ) , a CDR2 comprising an amino acid sequence of IRWTGDT ( SEQ ID NO : 53 ) , and a CDR3 comprising an amino acid sequence of TAGPAMSYSRGGEF ( SEQ ID NO : 2319 ) ; xlvi ) . a CDR1 comprising an amino acid sequence of GRSFGDFA ( SEQ ID NO : 52 ) , a CDR2 comprising an amino acid sequence of IRWTGDT ( SEQ ID NO : 53 ) , and a CDR3 comprising an amino acid sequence of TAGPTASYSRGGEF ( SEQ ID NO : 2320 ) ; xlvii ) . a CDR1 comprising an amino acid sequence of GRSFGDFA ( SEQ ID NO : 52 ) , a CDR2 comprising an amino acid sequence of IRWTGDT ( SEQ ID NO : 53 ) , and a CDR3 comprising an amino acid sequence of TAGPTMAYSRGGEF ( SEQ ID NO : 2321 ) ; xlviii ) . a CDR1 comprising an amino acid sequence of GRSFGDFA ( SEQ ID NO : 52 ) , a CDR2 comprising an amino acid sequence of IRWTGDT ( SEQ ID NO : 53 ) , and a CDR3 comprising an amino acid sequence of TAGPTMSASRGGEF ( SEQ ID NO : 2322 ) ; 226 WO 2025/006846 PCT / US2024 / 035969 xlix ) , a CDR1 comprising an amino acid sequence of GRSFGDFA ( SEQ ID NO : 52 ) , a CDR2 comprising an amino acid sequence of IRWTGDT ( SEQ ID NO : 53 ) , and a CDR3 comprising an amino acid sequence of TAGPTMSYARGGEF ( SEQ ID NO : 2323 ) ; I ) , a CDR1 comprising an amino acid sequence of GRSFGDFA ( SEQ ID NO : 52 ) , a CDR2 comprising an amino acid sequence of IRWTGDT ( SEQ ID NO : 53 ) , and a CDR3 comprising an amino acid sequence of TAGPTMSYSAGGEF ( SEQ ID NO : 2324 ) ; li ) . a CDR1 comprising an amino acid sequence of GRSFGDFA ( SEQ ID NO : 52 ) , a CDR2 comprising an amino acid sequence of IRWTGDT ( SEQ ID NO : 53 ) , and a CDR3 comprising an amino acid sequence of TAGPTMSYSRAGEF ( SEQ ID NO : 2325 ) ; lii ) . a CDR1 comprising an amino acid sequence of GRSFGDFA ( SEQ ID NO : 52 ) , a CDR2 comprising an amino acid sequence of IRWTGDT ( SEQ ID NO : 53 ) , and a CDR3 comprising an amino acid sequence of TAGPTMSYSRGAEF ( SEQ ID NO : 2326 ) ; liii ) , a CDR1 comprising an amino acid sequence of GRSFGDFA ( SEQ ID NO : 52 ) , a CDR2 comprising an amino acid sequence of IRWTGDT ( SEQ ID NO : 53 ) , and a CDR3 comprising an amino acid sequence of TAGPTMSYSRGGAF ( SEQ ID NO : 2327 ) ; liv ) . a CDR1 comprising an amino acid sequence of GRSFGDFA ( SEQ ID NO : 52 ) , a CDR2 comprising an amino acid sequence of IRWTGDT ( SEQ ID NO : 53 ) , and a CDR3 comprising an amino acid sequence of TAGPTMSYSRGGEA ( SEQ ID NO : 2328 ) ; lv ) . a CDR1 comprising an amino acid sequence of GSIFGGYN ( SEQ ID NO : 2189 ) , a CDR2 comprising an amino acid sequence of IFISGNN ( SEQ ID NO : 2190 ) , and a CDR3 comprising an amino acid sequence of AAYNDGGEY ( SEQ ID NO : 2329 ) ; Ivi ) . a CDR1 comprising an amino acid sequence of GSIFGGYN ( SEQ ID NO : 2189 ) , a CDR2 comprising an amino acid sequence of IFISGNN ( SEQ ID NO : 2190 ) , and a CDR3 comprising an amino acid sequence of RGYNDGGEY ( SEQ ID NO : 2330 ) ; \ vii ) . a CDR1 comprising an amino acid sequence of GSIFGGYN ( SEQ ID NO : 2189 ) , a CDR2 comprising an amino acid sequence of IFISGNN ( SEQ ID NO : 2190 ) , and a CDR3 comprising an amino acid sequence of RAANDGGEY ( SEQ ID NO : 2331 ) ; ( viii ) . a CDR1 comprising an amino acid sequence of GSIFGGYN ( SEQ ID NO : 2189 ) , a CDR2 comprising an amino acid sequence of IFISGNN ( SEQ ID NO : 2190 ) , and a CDR3 comprising an amino acid sequence of RAYADGGEY ( SEQ ID NO : 2332 ) ; 227 WO 2025/006846 PCT / US2024 / 035969 lix ) . a CDR1 comprising an amino acid sequence of GSIFGGYN ( SEQ ID NO : 2189 ) , a CDR2 comprising an amino acid sequence of IFISGNN ( SEQ ID NO : 2190 ) , and a CDR3 comprising an amino acid sequence of RAYNAGGEY ( SEQ ID NO : 2333 ) ; lx ) . a CDR1 comprising an amino acid sequence of GSIFGGYN ( SEQ ID NO : 2189 ) , a CDR2 comprising an amino acid sequence of IFISGNN ( SEQ ID NO : 2190 ) , and a CDR3 comprising an amino acid sequence of RAYNDAGEY ( SEQ ID NO : 2334 } ; Ixi ) . a CDR1 comprising an amino acid sequence of GSIFGGYN ( SEQ ID NO : 2189 ) , a CDR2 comprising an amino acid sequence of IFISGNN ( SEQ ID NO : 2190 ) , and a CDR3 comprising an amino acid sequence of RAYNDGAEY ( SEQ ID NO : 2335 ) ; ( xii ) . a CDR1 comprising an amino acid sequence of GSIFGGYN ( SEQ ID NO : 2189 ) , a CDR2 comprising an amino acid sequence of IFISGNN ( SEQ ID NO : 2190 ) , and a CDR3 comprising an amino acid sequence of RAYNDGGAY ( SEQ ID NO : 2336 ) ; Ixiii ) , a CDR1 comprising an amino acid sequence of GSIFGGYN ( SEQ ID NO : 2189 ) , a CDR2 comprising an amino acid sequence of IFISGNN ( SEQ ID NO : 2190 ) , and a CDR3 comprising an amino acid sequence of RAYNDGGEA ( SEQ ID NO : 2337 ) ; ( xiv ) . a CDR1 comprising an amino acid sequence of GSNFRILS ( SEQ ID NO : 2195 ) , a CDR2 comprising an amino acid sequence of ITSDDTT ( SEQ ID NO : 2196 ) , and a CDR3 comprising an amino acid sequence of ASRWYNL ( SEQ ID NO : 2338 ) ; lxv ) . a CDR1 comprising an amino acid sequence of GSNFRILS ( SEQ ID NO : 2195 ) , a CDR2 comprising an amino acid sequence of ITSDDTT ( SEQ ID NO : 2196 ) , and a CDR3 comprising an amino acid sequence of HARWYNL ( SEQ ID NO : 2339 ) ; lxvi ) . a CDR1 comprising an amino acid sequence of GSNFRILS ( SEQ ID NO : 2195 ) , a CDR2 comprising an amino acid sequence of ITSDDTT ( SEQ ID NO : 2196 ) , and a CDR3 comprising an amino acid sequence of HSAWYNL ( SEQ ID NO : 2340 ) ; lxvii ) . a CDR1 comprising an amino acid sequence of GSNFRILS ( SEQ ID NO : 2195 ) , a CDR2 comprising an amino acid sequence of ITSDDTT ( SEQ ID NO : 2196 ) , and a CDR3 comprising an amino acid sequence of HSRAYNL ( SEQ ID NO : 2341 ) ; Ixviii ) . a CDR1 comprising an amino acid sequence of GSNFRILS ( SEQ ID NO : 2195 ) , a CDR2 comprising an amino acid sequence of ITSDDTT ( SEQ ID NO : 2196 ) , and a CDR3 comprising an amino acid sequence of HSRWANL ( SEQ ID NO : 2342 ) ; 228 WO 2025/006846 PCT / US2024 / 035969 Ixix ) , a CDR1 comprising an amino acid sequence of GSNFRILS ( SEQ ID NO : 2195 ) , a CDR2 comprising an amino acid sequence of ITSDDTT ( SEQ ID NO : 2196 ) , and a CDR3 comprising an amino acid sequence of HSRWYAL ( SEQ ID NO : 2343 ) ; ( xx ) , a CDR1 comprising an amino acid sequence of GSNFRILS ( SEQ ID NO : 2195 ) , a CDR2 comprising an amino acid sequence of ITSDDTT ( SEQ ID NO : 2196 ) , and a CDR3 comprising an amino acid sequence of HSRWYNA ( SEQ ID NO : 2344 ) ; lxxi ) . a CDR1 comprising an amino acid sequence of GFTFSRYA ( SEQ ID NO : 2201 ) , a CDR2 comprising an amino acid sequence of ISSAGGYI ( SEQ ID NO : 2202 ) , and a CDR3 comprising an amino acid sequence of ATADY ( SEQ ID NO : 2345 ) ; lxxii ) . a CDR1 comprising an amino acid sequence of GFTFSRYA ( SEQ ID NO : 2201 ) , a CDR2 comprising an amino acid sequence of ISSAGGYI ( SEQ ID NO : 2202 ) , and a CDR3 comprising an amino acid sequence of FAADY ( SEQ ID NO : 2346 ) ; lxxiii ) , a CDR1 comprising an amino acid sequence of GFTFSRYA ( SEQ ID NO : 2201 ) , a CDR2 comprising an amino acid sequence of ISSAGGYI ( SEQ ID NO : 2202 ) , and a CDR3 comprising an amino acid sequence of FTGDY ( SEQ ID NO : 2347 ) ; or ( xxiv ) , a CDR1 comprising an amino acid sequence of GFTFSRYA ( SEQ ID NO : 2201 ) , a CDR2 comprising an amino acid sequence of ISSAGGYI ( SEQ ID NO : 2202 ) , and a CDR3 comprising an amino acid sequence of FTAAY ( SEQ ID NO : 2348 ) .
10. The antigen - binding protein of any one of claims 1-9 , wherein the antigen - binding protein comprises i ) , a CDR1 comprising an amino acid sequence of GRTFSSYA ( SEQ ID NO : 28 ) , a CDR2 comprising an amino acid sequence of LNWSGEST ( SEQ ID NO : 29 ) , and a CDR3 comprising an amino acid sequence of AAASSWSRGGVPYGMDY ( SEQ ID NO : 30 ) ; ii ) , a CDR1 comprising an amino acid sequence of GRSFGDFA ( SEQ ID NO : 52 ) , a CDR2 comprising an amino acid sequence of IRWTGDT ( SEQ ID NO : 53 ) , and a CDR3 comprising an amino acid sequence of TAGPTMSYSRGGEF ( SEQ ID NO : 54 ) ; iii ) . a CDR1 comprising an amino acid sequence of GSIFGGYN ( SEQ ID NO : 2189 ) , a CDR2 comprising an amino acid sequence of IFISGNN ( SEQ ID NO : 2190 ) , and a CDR3 comprising an amino acid sequence of RAYNDGGEY ( SEQ ID NO : 2191 } ; iv ) . a CDR1 comprising an amino acid sequence of GSNFRILS ( SEQ ID NO : 2195 ) , a CDR2 comprising an amino acid sequence of ITSDDTT ( SEQ ID NO : 2196 ) , and a CDR3 comprising an amino acid sequence of HSRWYNL ( SEQ ID NO : 2197 ) ; or 229 WO 2025/006846 PCT / US2024 / 035969 v ) , a CDR1 comprising an amino acid sequence of GFTFSRYA ( SEQ ID NO : 2201 ) , a CDR2 comprising an amino acid sequence of ISSAGGYI ( SEQ ID NO : 2202 ) , and a CDR3 comprising an amino acid sequence of FTADY ( SEQ ID NO : 2203 ) .
11. The antigen - binding protein of any one of claims 1-10 , wherein the antigen - binding protein is a single - domain antibody .
12. The antigen - binding protein of claim 11 , wherein the single - domain antibody is a VHH , a VNAR , or a VH domain .
13. The antigen - binding protein of claim 12 , wherein the VHH is a camelid VHH .
14. The antigen - binding protein of claim 13 , wherein the VHH comprises an amino acid sequence selected from any one of SEQ ID NOS : 4 , 9 , 14 , 17 , 21 , 26 , 31 , 36 , 41 , 45 , 50 , 55 , 65 , 70 , 75 , 79 , 84 , 89 , 93 , 98 , 146-468 , 2192 , 2198 , 2204 , and 2214-2233 , or an amino acid sequence having at least 75 % identity thereto .
15. The antigen - binding protein of claim 13 or 14 , wherein the VHH comprises an amino acid sequence selected from any one of SEQ ID NOs : 4 , 9 , 14 , 17 , 21 , 26 , 31 , 36 , 41 , 45 , 50 , 55 , 65 , 70 , 75 , 79 , 84 , 89 , 93 , 98 , 2192 , 2198 , and 2204 , or an amino acid sequence having at least 75 % identity thereto .
16. The antigen - binding protein of any one of claims 13-15 , wherein the VHH comprises an amino acid sequence selected from any one of SEQ ID NOS : 31 , 55 , 2192 , 2198 , and 2204 , or an amino acid sequence having at least 75 % identity thereto .
17. The antigen - binding protein of claim 12 , wherein the VHH is a humanized VHH .
18. The antigen - binding protein of claim 17 , wherein the humanized VHH comprises an amino acid sequence selected from any one of SEQ ID NOs : 5 , 10 , 15 , 18 , 22 , 27 , 32 , 37 , 42 , 46 , 51 , 56 , 66 , 71 , 76 , 80 , 85 , 90 , 94 , 99 , 469-761 , 2194 , 2200 , 2206 , 2234-2251 , and 2354-2404 , or an amino acid sequence having at least 75 % identity thereto . 230 WO 2025/006846 PCT / US2024 / 035969
19. The antigen - binding protein of claim 17 or 18 , wherein the humanized VHH comprises an amino acid sequence selected from any one of SEQ ID NOS : 5 , 10 , 15 , 18 , 22 , 27 , 32 , 37 , 42 , 46 , 51 , 56 , 61 , 66 , 71 , 76 , 80 , 85 , 90 , 94 , 99 , 2194 , 2200 , 2206 , and 2354-2404 , or an amino acid sequence having at least 75 % identity thereto .
20. The antigen - binding protein of any one of claims 17-19 , wherein the humanized VHH comprises an amino acid sequence selected from any one of SEQ ID NOs : 32 , 56 , 2200 , 2206 , 2194 , and 2354- 2404 , or an amino acid sequence having at least 75 % identity thereto .
21. The antigen - binding protein of any one of claims 1-20 , wherein the antigen - binding protein binds to human TRAILR2 .
22. The antigen - binding protein of claim 21 , wherein the antigen - binding protein binds to human TRAILR2 with a Ko of less than about 3 × 107 M.
23. The antigen - binding protein of claim 22 , wherein the antigen - binding protein binds to human TRAILR2 with a Ko of about 1 × 10-10 to 5 × 10-8 M.
24. The antigen - binding protein of any one of claims 1-23 , wherein the antigen - binding protein binds to Cyno TRAILR2 .
25. The antigen - binding protein of claim 24 , wherein the antigen - binding protein binds to cyno TRAILR2 with a Ko of less than about 3 × 107 M.
26. The antigen - binding protein of claim 25 , wherein the antigen - binding protein binds to cyno TRAILR2 with a Ko of about 1 × 10- to 1 × 10-7 M.
27. The antigen - binding protein of any one of claims 1-26 , wherein the antigen - binding protein does not block binding of TNF - related apoptosis - inducing ligand ( TRAIL ) to TRAILR2 .
28. The antigen - binding protein of any one of claims 1-26 , wherein the antigen - binding protein blocks binding of TRAIL to TRAILR2 . 231 WO 2025/006846 PCT / US2024 / 035969
29. The antigen - binding protein of any one of claims 1-28 , wherein the antigen - binding protein does not bind specifically to TRAILR1 , TRAILR3 and / or TRAILR4 .
30. The antigen - binding protein of any one of claims 1-28 , wherein the antigen - binding protein binds cysteine - rich domain ( CRD ) domain 1 ( CRD1 ) and / or CRD2 of TRAILR2 .
31. The antigen - binding protein of claim 30 , wherein the antigen - binding protein binds CRD1 of TRAILR2 .
32. The antigen - binding protein of claim 30 , wherein the antigen - binding protein binds CRD2 of TRAILR2 .
33. The antigen - binding protein of claim 30 , wherein the antigen - binding protein binds CRD1 and CRD2 of TRAILR2 .
34. The antigen - binding protein of any one of claims 1-28 , wherein the antigen - binding protein binds CRD2 and CRD3 of TRAILR2 .
35. The antigen - binding protein of any one of claims 1-34 , wherein the antigen - binding protein comprises one or more modifications that reduce binding of said antigen - binding protein by pre- existing antibodies found in human blood or serum .
36. A fusion protein that specifically binds TNF - related apoptosis - inducing ligand receptor 2 ( TRAILR2 ) , comprising one or more of said antigen - binding proteins of any one of claims 1-35 .
37. The fusion protein of claim 36 , which comprises three or more said antigen - binding proteins .
38. The fusion protein of claim 37 , which comprises four said antigen - binding proteins .
39. The fusion protein of any one of claims 36-38 , wherein the one or more antigen - binding proteins bind to the same epitope on TRAILR2 . 232 WO 2025/006846 PCT / US2024 / 035969
40. The fusion protein of any one of claims 36-38 , wherein the one or more antigen - binding proteins bind to different epitopes on TRAILR2 .
41. The fusion protein of any one of claims 36-40 , wherein the one or more antigen - binding proteins are one or more single - domain antibodies .
42. The fusion protein of claim 41 , wherein one or more single - domain antibodies are one or more VHHS .
43. The fusion protein of any one of claims 36-42 , which further comprises an immunoglobulin Fc region .
44. The fusion protein of claim 43 , wherein the immunoglobulin Fc region is an Fc region of a human immunoglobulin .
45. The fusion protein of claim 44 , wherein the immunoglobulin Fc region is an Fc region of human IgG1 , IgG2 , IgG3 or IgG4 , or a variant thereof .
46. The fusion protein of claim 45 , wherein the immunoglobulin Fc region is an Fc region of human IgG1 , or a variant thereof .
47. The fusion protein of claim 46 , wherein the Fc region of human IgG1 comprises one or more mutations selected from Leu234Ala ( L234A ) , Leu234Gly ( L234G ) , Leu2345er ( L234S ) , Leu234Thr ( L234T ) , Leu234Ala ( L234A ) , Leu235Ala ( L235A ) , Leu235Glu ( L235E ) , Leu235Ser ( L235S ) , Leu235Thr ( L235T ) , Leu235Val ( L235V ) , Leu235Gin ( L235Q ) , Gly236Arg ( G236R ) , Met252Tyr ( M252Y ) , Ser254Thr ( 5254T ) , Thr256Glu ( T256E ) , Asp265Asn ( D265N ) , Asp265Ala ( D265A ) , Asp270Asn ( D270N ) , Ser298Asn ( S298N ) , Asn297Ala ( N297A ) , Pro329Ala ( P329A ) , Pro239Gly ( P329G ) , Asn325Glu ( N325E ) and / or Ala327Ser ( A327S ) according to EU numbering .
48. The fusion protein of claim 47 , wherein the Fc region of human IgG1 comprises a set of mutations selected from 1 ) . L234A and L235A ; 233 WO 2025/006846 2 ) . 3 ) . 4 ) . 5 ) . 6 ) . 7 ) . 8 ) . 9 ) . 10 ) . 11 ) . L234A , L235A , and P329A ; D265A , N297A and P329A ; L234A , L235A , and G237A ; L234G , L235S , and G236R ; L234S , L235T , and G236R ; L2345 , L235V , and G236R ; L234T , L235Q , and G236R ; L234T , L235T , and G236R ; L234A , L235A , and P329G ; and M252Y , S254T , and T256E . PCT / US2024 / 035969
49. The fusion protein of claim 45 , wherein the immunoglobulin Fc region is an Fc region of human IgG4 , or a variant thereof .
50. The fusion protein of claim 49 , wherein the Fc region of human IgG4 comprises one or more mutations selected from Ser228Pro ( S228P ) , Leu235Glu ( L235E ) , Leu235Ala ( L235A ) , Phe234Ala ( F234A ) , and / or Pro329Gly ( P329G ) according to EU numbering .
51. The fusion protein of claim 50 , wherein the Fc region of human IgG4 comprises a set of mutations selected from 1 ) . 2 ) . 3 ) . 4 ) . 5 ) . S228P and L235E ; S228P and L235A ; S228P , F234A , and L235E ; S228P , F234A , and L235A ; and P329G , S228P , and L235E .
52. The fusion protein of any one of claims 36-51 , which further comprises a moiety that binds to serum albumin .
53. The fusion protein of claim 36 , which comprises the amino acid sequence of any one of SEQ ID Nos : 2054-2070 , or a sequence having at least 75 % identity thereto . 234 WO 2025/006846 PCT / US2024 / 035969
54. The fusion protein of any one of claims 36-53 , wherein the fusion protein has an agonist effect upon binding to TRAILR2 .
55. A conjugate comprising the antigen - binding protein of any one of claims 1-35 or the fusion protein of any one of claims 36-54 , wherein the antigen - binding protein or fusion protein is conjugated to a second molety .
56. The conjugate of claim 55 , wherein the second moiety is selected from a detectable label , a drug , a toxin , a radionuclide , an enzyme , an immunomodulatory agent , a cytokine , a cytotoxic agent , a chemotherapeutic agent , a diagnostic agent , or a combination thereof .
57. A polynucleotide molecule encoding the antigen - binding protein of any one of claims 1-35 or the fusion protein of any one of claims 36-54 .
58. The polynucleotide molecule of claim 57 , which comprises the nucleotide sequence of any one of SEQ ID NOS : 57-61 , 131-145 , 1731-2053 , 2071-2087 , 2193 , 2199 , 2205 , and 2278-2297 , or a nucleotide sequence having at least 70 % identity thereto .
59. The polynucleotide molecule of claim 57 or 58 , which comprises the nucleotide sequence of any one of SEQ ID NOs : 57-61 , 131-145 , 2071-2087 , 2193 , 2199 , and 2205 , or a nucleotide sequence having at least 70 % identity thereto .
60. The polynucleotide molecule of any one of claims 57-59 , which comprises the nucleotide sequence of any one of SEQ ID NOs : 132 , 137 , 2193 , 2199 , and 2205 , or a nucleotide sequence having at least 70 % identity thereto .
61. A recombinant vector comprising the polynucleotide molecule of any one of claims 57-60 .
62. A host cell comprising polynucleotide molecule of any one of claims 57-60 , or the recombinant vector of claim 61 .
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