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EP-4735116-A2 - ANTI-TRAILR2 ANTIGEN-BINDING PROTEINS AND USES THEREOF

EP4735116A2EP 4735116 A2EP4735116 A2EP 4735116A2EP-4735116-A2

Abstract

The present application provides antigen-binding proteins (e.g., antibodies such as single-domain antibodies) that specifically bind TNF-related apoptosis-inducing ligand receptor 2 (TRA5LR2). The application also provides fusion proteins and conjugates comprising the antigen-binding proteins, polynucleotides and recombinant vectors encoding the antigen-binding proteins, as well as host cellsand methods for preparing the antigen-binding proteins. The application further providespharmaceutical compositions comprising the antigen-binding proteins and methods for treating a disease or disorder using the antigen-binding proteins.

Inventors

  • FRANCHI, LUIGI
  • OPIPARI, ANTHONY, W.
  • PINHEIRO, Elaine, Maria
  • ABRAHAM, Robert, Thomas
  • PREISS, Laura
  • HUBER, FERDINAND
  • KÖNIG, Paul-Albert
  • DAKE, Tamara

Assignees

  • ODYSSEY THERAPEUTICS, INC.

Dates

Publication Date
20260506
Application Date
20240628

Claims (1)

  1. Attorney Docket No: 260525.000049 Claims 1. An antigen-binding protein that specificaly 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); i). 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); l). 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 optionaly replaced with an alanine, and/or one or more alanine residues in the CDR3 sequence is optionaly 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 Attorney Docket No: 260525.000049 w). (A/F/M/N)(A/T)(A/G/S)(A/D)Y. 3. 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 Attorney Docket No: 260525.000049 (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. 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); i). GRSFGD(D/F/Y)A (SEQ ID NO: 118); j). G(G/R)TLSNYA (SEQ ID NO: 119); k). GRSFGAQGMEG (SEQ ID NO: 72); l). 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). 5. 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). Attorney Docket No: 260525.000049 6. 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); l). 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. 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). 8. An antigen-binding protein that specificaly 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 Attorney Docket No: 260525.000049 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); i). 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); ii). 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); vi). 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); vii). 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); Attorney Docket No: 260525.000049 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); xi). 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); xii). 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); xvi). 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); xvii). 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); Attorney Docket No: 260525.000049 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); xxi). 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); xxii). 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); 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 AAAASWSRGGVPYGMDY (SEQ ID NO: 2301); 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 AAASAWSRGGVPYGMDY (SEQ ID NO: 2302); Attorney Docket No: 260525.000049 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); 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 AAASSWSRAGVPYGMDY (SEQ ID NO: 2306); 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 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); 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 AAASSWSRGGVPYAMDY (SEQ ID NO: 2311); 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 AAASSWSRGGVPYGADY (SEQ ID NO: 2312); Attorney Docket No: 260525.000049 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); 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 TGGPTMSYSRGGEF (SEQ ID NO: 2316); 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 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); 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 TAGPTMAYSRGGEF (SEQ ID NO: 2321); 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 TAGPTMSASRGGEF (SEQ ID NO: 2322); Attorney Docket No: 260525.000049 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); l). 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); 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 TAGPTMSYSRGAEF (SEQ ID NO: 2326); 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 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); lvi). 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); lvi). 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); lvii). 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); Attorney Docket No: 260525.000049 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); lxi). 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); lxi). 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); lxii). 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); lxiv). 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); 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 HSRAYNL (SEQ ID NO: 2341); 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 HSRWANL (SEQ ID NO: 2342); Attorney Docket No: 260525.000049 lxix). 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); lxx). 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); 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 FAADY (SEQ ID NO: 2346); 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 FTGDY (SEQ ID NO: 2347); or lxxiv). 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); 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 TAGPTMSYSRGGEF (SEQ ID NO: 54); ii). 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 Attorney Docket No: 260525.000049 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. Attorney Docket No: 260525.000049 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 K of less than about 3× −7 D 10 M. 23. The antigen-binding protein of claim 22, wherein the antigen-binding protein binds to human TRAILR2 with a K of about −10 −8 D 1×10 to 5×10 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 K −7 D of less than about 3×10 M. 26. The antigen-binding protein of claim 25, wherein the antigen-binding protein binds to cyno TRAILR2 with a K of about 1×10−9 t −7 D o 1×10 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. Attorney Docket No: 260525.000049 29. The antigen-binding protein of any one of claims 1-28, wherein the antigen-binding protein does not bind specificaly 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 specificaly 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. Attorney Docket No: 260525.000049 40. The fusion protein of any one of claims 36-38, wherein the one or more antigen-binding proteins bind to diferent 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), Leu234Ser (L234S), Leu234Thr (L234T), Leu234Ala (L234A), Leu235Ala (L235A), Leu235Glu (L235E), Leu235Ser (L235S), Leu235Thr (L235T), Leu235Val (L235V), Leu235Gln (L235Q), Gly236Arg (G236R), Met252Tyr (M252Y), Ser254Thr (S254T), 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; Attorney Docket No: 260525.000049 2). L234A, L235A, and P329A; 3). D265A, N297A and P329A; 4). L234A, L235A, and G237A; 5). L234G, L235S, and G236R; 6). L234S, L235T, and G236R; 7). L234S, L235V, and G236R; 8). L234T, L235Q, and G236R; 9). L234T, L235T, and G236R; 10). L234A, L235A, and P329G; and 11). M252Y, S254T, and T256E. 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). S228P and L235E; 2). S228P and L235A; 3). S228P, F234A, and L235E; 4). S228P, F234A, and L235A; and 5). 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. Attorney Docket No: 260525.000049 54. The fusion protein of any one of claims 36-53, wherein the fusion protein has an agonist efect 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 moiety. 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 cel comprising polynucleotide molecule of any one of claims 57-60, or the recombinant vector of claim 61. Attorney Docket No: 260525.000049 63. A kit comprising the antigen-binding protein of any one of claims 1-35, the fusion protein of any one of claims 36-54, or the conjugate of any one of claims 55 -56, the polynucleotide molecule of any one of claims 57-60, or the recombinant vector of claim 61, and optionaly, instructions and/or packaging for the same. 64. A pharmaceutical composition comprising the antigen-binding protein of any one of claims 1-35, the fusion protein of any one of claims 36-54, or the conjugate of any one of claims 55-56, the polynucleotide molecule of any one of claims 57-60, or the recombinant vector of claim 61, and a pharmaceuticaly acceptable carrier and/or excipient. 65. A method for preparing an antigen-binding protein or a fusion protein that specificaly binds TNF- related apoptosis-inducing ligand receptor 2 (TRAILR2), comprising the steps of: (a) culturing the host cel of claim 62 in a culture medium under conditions suitable for expression of the antigen-binding protein or fusion protein, and (b) isolating the antigen-binding protein or fusion protein from the host cel and/or culture medium. 66. A method for inducing cel death in a cel expressing TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2) comprising contacting the cel with the antigen-binding protein of claim 1-35, the fusion protein of any one of claims 36-54, or the conjugate of any one of claims 55 -56. 67. The method of claim 66, wherein said contacting occurs in vitro. 68. The method of claim 66, wherein said contacting occurs in vivo. 69. The method of claim 68, wherein the method further comprises administering the antigen-binding protein, the fusion protein, or the conjugate into a subject in need thereof. 70. The method of any one of claims 66-69, wherein the cel expressing TRAILR2 is a cel of a cancer. 71. The method of claim 70, wherein the cancer is a solid tumor. Attorney Docket No: 260525.000049 72. The method of claim 70, wherein the cancer is selected from adenoid cystic carcinoma, adrenal gland tumor, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxia-telangiectasia, Beckwith-Wiedemann syndrome, bile duct cancer (cholangiocarcinoma), Birt-Hogg-Dubé syndrome, bladder cancer, bone cancer (sarcoma of bone), brain stem glioma, brain tumor, breast cancer, inflammatory breast cancer, metastatic breast cancer, male breast cancer, Carney complex, central nervous system tumors (brain and spinal cord), cervical cancer, childhood cancer, colorectal cancer, Cowden syndrome, craniopharyngioma, desmoid tumor, desmoplastic infantile ganglioglioma, childhood tumor, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial pancreatic cancer, galbladder cancer, gastrointestinal stromal tumor (GIST), germ cel tumor, gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary difuse gastric cancer, hereditary leiomyomatosis and renal cel cancer, hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditary papilary renal carcinoma, HIV/AIDS-related cancer, juvenile polyposis syndrome, kidney cancer, lacrimal gland tumor, laryngeal and hypopharyngeal cancer, Li-Fraumeni syndrome, liver cancer, lung cancer, non-smal cel lung cancer, smal cel lung cancer, lynch syndrome, mastocytosis, meduloblastoma, melanoma, meningioma, mesothelioma, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2, multiple myeloma, MUTYH (or MYH)-associated polyposis, myelodysplastic syndromes (MDS), nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumor of the gastrointestinal tract, neuroendocrine tumor of the lung, neuroendocrine tumor of the pancreas, neuroendocrine tumors, neurofibromatosis type 1, neurofibromatosis type 2, nevoid basal cel carcinoma syndrome, oral and oropharyngeal cancer, osteosarcoma, ovarian, falopian tube, and peritoneal cancer, pancreatic cancer, parathyroid cancer, penile cancer, Peutz-Jeghers syndrome, pheochromocytoma and paraganglioma, pituitary gland tumor, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Kaposi sarcoma, soft tissue sarcomas, skin cancer (non-melanoma), smal bowel cancer, stomach cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis complex, uterine cancer, vaginal cancer, Von Hippel-Lindau syndrome, vulvar cancer, Werner syndrome, Wilms tumor, or xeroderma pigmentosum. 73. The method of claim 70, wherein the cancer is gastrointestinal cancer, breast cancer, or lung cancer. Attorney Docket No: 260525.000049 74. The method of claim 73, wherein the gastrointestinal cancer is colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, or cholangiocarcinoma cancer. 75. The method of any one of claims 66-74, wherein the method further comprises contacting the cel with one or more additional therapeutic agents. 76. A method of treating or preventing a cancer in a subject in need thereof, said method comprising administering to the subject the antigen-binding protein of claim 1-35, the fusion protein of any one of claims 36-54, or the conjugate of any one of claims 55 -56. 77. The method of claim 76, wherein the cancer is a solid tumor. 78. The method of claim 76, wherein the cancer is selected from adenoid cystic carcinoma, adrenal gland tumor, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxia-telangiectasia, Beckwith-Wiedemann syndrome, bile duct cancer (cholangiocarcinoma), Birt-Hogg-Dubé syndrome, bladder cancer, bone cancer (sarcoma of bone), brain stem glioma, brain tumor, breast cancer, inflammatory breast cancer, metastatic breast cancer, male breast cancer, Carney complex, central nervous system tumors (brain and spinal cord), cervical cancer, childhood cancer, colorectal cancer, Cowden syndrome, craniopharyngioma, desmoid tumor, desmoplastic infantile ganglioglioma, childhood tumor, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial pancreatic cancer, galbladder cancer, gastrointestinal stromal tumor (GIST), germ cel tumor, gestational trophoblastic disease, head and neck cancer, hereditary breast and ovarian cancer, hereditary difuse gastric cancer, hereditary leiomyomatosis and renal cel cancer, hereditary mixed polyposis syndrome, hereditary pancreatitis, hereditary papilary renal carcinoma, HIV/AIDS-related cancer, juvenile polyposis syndrome, kidney cancer, lacrimal gland tumor, laryngeal and hypopharyngeal cancer, Li-Fraumeni syndrome, liver cancer, lung cancer, non-smal cel lung cancer, smal cel lung cancer, lynch syndrome, mastocytosis, meduloblastoma, melanoma, meningioma, mesothelioma, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2, multiple myeloma, MUTYH (or MYH)-associated polyposis, myelodysplastic syndromes (MDS), nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumor of the gastrointestinal tract, neuroendocrine tumor of the lung, neuroendocrine tumor of the pancreas, Attorney Docket No: 260525.000049 neuroendocrine tumors, neurofibromatosis type 1, neurofibromatosis type 2, nevoid basal cel carcinoma syndrome, oral and oropharyngeal cancer, osteosarcoma, ovarian, falopian tube, and peritoneal cancer, pancreatic cancer, parathyroid cancer, penile cancer, Peutz-Jeghers syndrome, pheochromocytoma and paraganglioma, pituitary gland tumor, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Kaposi sarcoma, soft tissue sarcomas, skin cancer (non-melanoma), smal bowel cancer, stomach cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis complex, uterine cancer, vaginal cancer, Von Hippel-Lindau syndrome, vulvar cancer, Werner syndrome, Wilms tumor, or xeroderma pigmentosum. 79. The method of claim 76, wherein the cancer is gastrointestinal cancer, breast cancer, or lung cancer. 80. The method of claim 79, wherein the gastrointestinal cancer is colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, or cholangiocarcinoma cancer. 81. The method of any one of claims 76-80, wherein the method further comprises administering one or more additional therapeutic agents. 82. The method of claim 75 or 81, wherein the one or more additional therapeutic agents are selected from a chemotherapeutic agent, a vascular endothelial growth factor (VEGF) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, or an apoptosis-inducing agent, an immunotherapeutic agent, or a combination thereof. 83. The method of claim 82, wherein the chemotherapeutic agent is selected from bleomycin, carboplatin, chlorambucil, cisplatin, colchicine, cyclophosphamide, daunorubicin, doxorubicin or liposomal doxorubicin, mitomycin C, actinomycin, diethylstilbestrol, etoposide, 5-fluorouracil, floxuridine, melphalan, methotrexate, mitomycin, 6-mercaptopurine, teniposide, 6-thioguanine, vincristine and vinblastine, leflunomide, tamoxifen, interferon α-2b, glutamic acid, plicamycin, mercaptopurine, 6-thioguanine, carmustine, BCNU, limousine, CCNU, cytosine arabinose, estramustine, hydroxyurea, procarbazine, busulfan, medroxyprogesterone, estramustine phosphate sodium, ethenyl estradiol, estradiol, megestrol acetate, methyltestosterone, diethylstilbestrol diphosphate, chlorotrianisene, testolactone, melphalan, chlorambucil, mechlorethamine, thiourea, Attorney Docket No: 260525.000049 bethamethasone sodium phosphate, dicarbazine, asparagine, mitotane, vincristine sulfate, vinblastine sulfate, FOLFOX (folinic acid, 5-fluorouracil and oxaliplatin) or FOLFIRI (folinic acid, 5- fluorouracil, and irinotecan), and a combination thereof. 84. The method of claim 82, wherein the VEGF inhibitor is bevacizumab, ramucirumab, regorafenib, ziv- aflibercept. 85. The method of claim 82, wherein the EGFR inhibitor is selected from cetuximab and/or panitumumab. 86. The method of claim 82, wherein the apoptosis-inducing agent is selected from a B-cel lymphoma 2 (BCL2) inhibitor, a BCL-extra large (BCL-XL) inhibitor, or an inhibitor of apoptosis proteins (IAP) inhibitor, or a combination thereof. 87. The method of claim 82, wherein the immunotherapeutic agent is an anti-CTLA4 agent, anti-PD1 agent, anti-PD-L1 agent, anti-LAG3 agent, and anti-TIM3 agent. 88. The method of any one of claims 69-87, wherein the subject is a mammal. 89. The method of claim 88, wherein the mammal is human.

Description

Attorney Docket No: 260525.000049 ANTI-TRAILR2 ANTIGEN-BINDING PROTEINS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No.63/524,095, filed June 29, 2023, the disclosure of which is herein incorporated by reference in its entirety. SEQUENCE LISTING [0002] The instant application contains a Sequence Listing which has been submited electronicaly in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on June 12, 2024, is named 260525_000049_SL.xml and is 2,376,169 bytes in size. FIELD OF THE INVENTION [0003] The present application relates to antigen-binding proteins (e.g., antibodies such as single- domain antibodies) that specificaly bind TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2), methods for their preparation, and uses thereof. BACKGROUND OF THE INVENTION [0004] Apoptosis controls celular homeostasis of normal tissue compartments and is tightly regulated on multiple levels. Cancer cels often evade apoptotic cel death through downregulation of pro- apoptotic proteins and/or overexpression of anti-apoptotic proteins which leads to intrinsic resistance to anticancer therapies. Apoptosis can be induced with TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2, also known as death receptor 5 or DR5) agonists or recombinant TNF-related apoptosis- inducing ligand (TRAIL). High TRAILR2 expression is observed across multiple indications. Preclinical data have consistently demonstrated efective activation of the apoptotic pathway in vitro and significant anti-tumor eficacy by TRAILR2 agonists in vivo using xenograft models. However, IgG based TRAILR2 agonists disappointed in the clinic with very limited response rate and this poor translation of preclinical to clinical performance was hypothesized to be due to suboptimal clustering of the receptor agonists and subsequent weak activation of the apoptotic pathway. Accordingly, there is a need in the art to develop therapeutic molecules that can efectively mimic TRAIL-induced activation, e.g., through TRAILR2 multimerization for potent apoptotic signaling downstream. Attorney Docket No: 260525.000049 SUMMARY OF THE INVENTION [0005] As mentioned in the background section above, there is an unmet need in the art to develop therapeutic molecules designed for optimal multimerization of TRAILR2 and subsequent induction of potent apoptotic signaling. This application provides compositions and methods to address this and other related needs. [0006] In one aspect, provided herein is an antigen-binding protein that specificaly 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); i). 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); l). 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 optionaly replaced with an alanine, and/or one or more alanine residues in the CDR3 sequence is optionaly replaced with a glycine. [0007] In some embodiments, 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) (SEQ ID NO: 2350); 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 w). (A/F/M/N)(A/T)(A/G/S)(A/D)Y. [0008] In some embodiments, 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 Attorney Docket No: 260525.000049 ID NO: 88); TAGQSISLSQGGEY (SEQ ID NO: 92); KAGIRGEVY