CD5-BINDING POLYPEPTIDES, COMPOSITIONS COMPRISING THE SAME, AND METHODS FOR USE THEREOF
As described below, the present disclosure features polypeptides capable of binding a cluster of differentiation 5 (CD5) antigen and polynucleotides encoding said CD5-binding polypeptides, compositions comprising the same, and methods for use thereof. The disclosure also features lipid nanoparticles comprising the CD5-binding polypeptides and methods for use thereof for delivery of a polynucleotide (e.g., a polynucleotide encoding a chimeric antigen receptor) to a T cell in vivo.
1 . A VHH antibody or an antigen binding fragment thereof that specifically binds to a cluster of differentiation 5 (CD5) polypeptide, wherein the VHH antibody comprises three Complementarity Determining Regions (CDRs): CDR1, CDR2 and CDR3, that are structurally positioned between four camelid VHH framework (FR) regions (FR1-FR4) as follows: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4; wherein
a) CDR1 is selected from the group consisting of: NYAAG (SEQ ID NO: 478), SYTMG (SEQ ID NO: 479), TYTMG (SEQ ID NO: 480), SYAMG (SEQ ID NO: 481), TYNMG (SEQ ID NO: 482), AYAMG (SEQ ID NO: 483), SSGMG (SEQ ID NO: 484), VDATT (SEQ ID NO: 485), INVIG (SEQ ID NO: 505), SSFMS (SEQ ID NO: 506), TNVMG (SEQ ID NO: 507), TNNMG (SEQ ID NO: 508), TNNMA (SEQ ID NO: 509), RVAMN (SEQ ID NO: 510), RVGMN (SEQ ID NO: 511), FVGWG (SEQ ID NO: 512), FIGWG (SEQ ID NO: 513), MYSMS (SEQ ID NO: 514), and TYGMG (SEQ ID NO: 515);
b) CDR2 is selected from the group consisting of RISRSGGRTDYADSVKG (SEQ ID NO: 486), AISWSAGRTYYADSMKG (SEQ ID NO: 487), VISWSGGRTYYADSVKG (SEQ ID NO: 488), AIDLYGRATRYANSVKG (SEQ ID NO: 489), AINLEGYATRYANSVKG (SEQ ID NO: 615), AIDLYGRATRYANSVRG (SEQ ID NO: 616), AINWNGDTALRWNGFATRYADSVKG (SEQ ID NO: 490), SMDWSGGSTYYGDSVKG (SEQ ID NO: 491), SIDWSGGSTYYGDSVKG (SEQ ID NO: 492), SIDWGGGSTYYGDSVKG (SEQ ID NO: 493), SIDWSGKSTYYGDSVKG (SEQ ID NO: 494), SINWSGGSAYYGDSVKG (SEQ ID NO: 495), SMDWTGGSTYYGDSVKG (SEQ ID NO: 496), IMDIGGVTEYADSVKG (SEQ ID NO: 497), LVNSGGQTHYADSVKG (SEQ ID NO: 516), TIYSDGSTYYADSVKG (SEQ ID NO: 517), TIYSDGSTYYADSMKG (SEQ ID NO: 518), LIRGGGSTHYADSVKG (SEQ ID NO: 519), LIRTGGSTHVADSMKG (SEQ ID NO: 520), TISSDGSRTNYAHSVKG (SEQ ID NO: 522), SISSDGSRTNYAHFVKG (SEQ ID NO: 523), QISTGGLTNYADSVKG (SEQ ID NO: 524), QINTGGLTDVYADSVKG (SEQ ID NO: 617), SISTGARDTAYADSVKG (SEQ ID NO: 526), SISTGARDTSYADSVKG (SEQ ID NO: 618), and VITGSGVGTQYADSVKD (SEQ ID NO: 527); and
c) CDR3 is selected from the group consisting of: ATVWEFTDGADQYDY (SEQ ID NO: 498), DPWTSDSDYDRLTMYDY (SEQ ID NO: 499), DPWTSDSDYERLTMYDY (SEQ ID NO: 500), DTSLPLGVLTESQRLYGA (SEQ ID NO: 501), DTSLPLGVLTKSQRMYGA (SEQ ID NO: 502), DTVVSGSYYLAARAEDYEY (SEQ ID NO: 503), GTSGVAAVNLRGFFS (SEQ ID NO: 504), RGL, RYGIDNY (SEQ ID NO: 528), VTGSI (SEQ ID NO: 529), WLGSPGAMSDY (SEQ ID NO: 530), WTGSPGALSDY (SEQ ID NO: 531), PGNS (SEQ ID NO: 532), PGHP (SEQ ID NO: 533), PGHS (SEQ ID NO: 534), GDLRYGPDGYDY (SEQ ID NO: 535), and GHRPGWAVIRADAYEY (SEQ ID NO: 536).
2 . The method of claim 1 , wherein:
a) CDR1 comprises the amino acid sequence NYAAG (SEQ ID NO: 478), CDR2 comprises the amino acid sequence RISRSGGRTDYADSVKG (SEQ ID NO: 486), and CDR3 comprises the amino acid sequence ATVWEFTDGADQYDY (SEQ ID NO: 498);
b) CDR1 comprises the amino acid sequence SYTMG (SEQ ID NO: 479), CDR2 comprises the amino acid sequence AISWSAGRTYYADSMKG (SEQ ID NO: 487), and CDR3 comprises the amino acid sequence DPWTSDSDYDRLTMYDY (SEQ ID NO: 499);
c) CDR1 comprises the amino acid sequence TYTMG (SEQ ID NO: 480), CDR2 comprises the amino acid sequence AISWSAGRTYYADSMKG (SEQ ID NO: 487), and CDR3 comprises the amino acid sequence DPWTSDSDYDRLTMYDY (SEQ ID NO: 499);
d) CDR1 comprises the amino acid sequence SYTMG (SEQ ID NO: 479), CDR2 comprises the amino acid sequence AISWSAGRTYYADSMKG (SEQ ID NO: 487), and CDR3 comprises the amino acid sequence DPWTSDSDYDRLTMYDY (SEQ ID NO: 499);
e) CDR1 comprises the amino acid sequence TYTMG (SEQ ID NO: 480), CDR2 comprises the amino acid sequence AISWSAGRTYYADSMKG (SEQ ID NO: 487), and CDR3 comprises the amino acid sequence DPWTSDSDYDRLTMYDY (SEQ ID NO: 499);
f) CDR1 comprises the amino acid sequence TYTMG (SEQ ID NO: 480), CDR2 comprises the amino acid sequence AISWSAGRTYYADSMKG (SEQ ID NO: 487), and CDR3 comprises the amino acid sequence DPWTSDSDYDRLTMYDY (SEQ ID NO: 499);
g) CDR1 comprises the amino acid sequence SYTMG (SEQ ID NO: 479), CDR2 comprises the amino acid sequence AISWSAGRTYYADSMKG (SEQ ID NO: 487), and CDR3 comprises the amino acid sequence DPWTSDSDYDRLTMYDY (SEQ ID NO: 499);
h) CDR1 comprises the amino acid sequence TYTMG (SEQ ID NO: 480), CDR2 comprises the amino acid sequence AISWSAGRTYYADSMKG (SEQ ID NO: 487), and CDR3 comprises the amino acid sequence DPWTSDSDYDRLTMYDY (SEQ ID NO: 499);
i) CDR1 comprises the amino acid sequence TYTMG (SEQ ID NO: 480), CDR2 comprises the amino acid sequence AISWSAGRTYYADSMKG (SEQ ID NO: 487), and CDR3 comprises the amino acid sequence DPWTSDSDYDRLTMYDY (SEQ ID NO: 499);
j) CDR1 comprises the amino acid sequence SYAMG (SEQ ID NO: 481), CDR2 comprises the amino acid sequence VISWSGGRTYYADSVKG (SEQ ID NO: 488), and CDR3 comprises the amino acid sequence DPWTSDSDYERLTMYDY (SEQ ID NO: 500);
k) CDR1 comprises the amino acid sequence SYAMG (SEQ ID NO: 481), CDR2 comprises the amino acid sequence VISWSGGRTYYADSVKG (SEQ ID NO: 488), and CDR3 comprises the amino acid sequence DPWTSDSDYERLTMYDY (SEQ ID NO: 500);
l) CDR1 comprises the amino acid sequence SYAMG, CDR2 comprises the amino acid sequence VISWSGGRTYYADSVKG (SEQ ID NO: 488), and CDR3 comprises the amino acid sequence DPWTSDSDYERLTMYDY (SEQ ID NO: 500);
m) CDR1 comprises the amino acid sequence SYAMG, CDR2 comprises the amino acid sequence VISWSGGRTYYADSVKG (SEQ ID NO: 488), and CDR3 comprises the amino acid sequence DPWTSDSDYERLTMYDY (SEQ ID NO: 500);
n) CDR1 comprises the amino acid sequence TYNMG (SEQ ID NO: 482), CDR2 comprises the amino acid sequence AIDLYGRATRYANSVKG (SEQ ID NO: 489), and CDR3 comprises the amino acid sequence DTSLPLGVLTESQRLYGA (SEQ ID NO: 501);
o) CDR1 comprises the amino acid sequence TYNMG (SEQ ID NO: 482), CDR2 comprises the amino acid sequence AINLEGYATRYANSVKG (SEQ ID NO: 615), and CDR3 comprises the amino acid sequence DTSLPLGVLTESQRLYGA (SEQ ID NO: 501);
p) CDR1 comprises the amino acid sequence TYNMG (SEQ ID NO: 482), CDR2 comprises the amino acid sequence AIDLYGRATRYANSVKG (SEQ ID NO: 489), and CDR3 comprises the amino acid sequence DTSLPLGVLTESQRLYGA (SEQ ID NO: 501);
q) CDR1 comprises the amino acid sequence TYNMG (SEQ ID NO: 482), CDR2 comprises the amino acid sequence AIDLYGRATRYANSVRG (SEQ ID NO: 616), and CDR3 comprises the amino acid sequence DTSLPLGVLTESQRLYGA (SEQ ID NO: 501);
r) CDR1 comprises the amino acid sequence TYNMG (SEQ ID NO: 482), CDR2 comprises the amino acid sequence AIDLYGRATRYANSVKG (SEQ ID NO: 489), and CDR3 comprises the amino acid sequence DTSLPLGVLTESQRLYGA (SEQ ID NO: 501);
s) CDR1 comprises the amino acid sequence TYNMG (SEQ ID NO: 482), CDR2 comprises the amino acid sequence AIDLYGRATRYANSVKG (SEQ ID NO: 489), and CDR3 comprises the amino acid sequence DTSLPLGVLTKSQRMYGA (SEQ ID NO: 502);
t) CDR1 comprises the amino acid sequence AYAMG, CDR2 comprises the amino acid sequence AINWNGDTALRWNGFATRYADSVKG (SEQ ID NO: 490), and CDR3 comprises the amino acid sequence DTVVSGSYYLAARAEDYEY (SEQ ID NO: 503);
u) CDR1 comprises the amino acid sequence AYAMG, CDR2 comprises the amino acid sequence AINWNGDTALRWNGFATRYADSVKG (SEQ ID NO: 490), and CDR3 comprises the amino acid sequence DTVVSGSYYLAARAEDYEY (SEQ ID NO: 503);
v) CDR1 comprises the amino acid sequence AYAMG, CDR2 comprises the amino acid sequence AINWNGDTALRWNGFATRYADSVKG (SEQ ID NO: 490), and CDR3 comprises the amino acid sequence DTVVSGSYYLAARAEDYEY (SEQ ID NO: 503);
w) CDR1 comprises the amino acid sequence AYAMG, CDR2 comprises the amino acid sequence AINWNGDTALRWNGFATRYADSVKG (SEQ ID NO: 490), and CDR3 comprises the amino acid sequence DTVVSGSYYLAARAEDYEY (SEQ ID NO: 503);
x) CDR1 comprises the amino acid sequence SSGMG (SEQ ID NO: 484), CDR2 comprises the amino acid sequence SMDWSGGSTYYGDSVKG (SEQ ID NO: 491), and CDR3 comprises the amino acid sequence GTSGVAAVNLRGFFS (SEQ ID NO: 504);
y) CDR1 comprises the amino acid sequence SSGMG (SEQ ID NO: 484), CDR2 comprises the amino acid sequence SIDWSGGSTYYGDSVKG (SEQ ID NO: 492), and CDR3 comprises the amino acid sequence GTSGVAAVNLRGFFS (SEQ ID NO: 504);
z) CDR1 comprises the amino acid sequence SSGMG (SEQ ID NO: 484), CDR2 comprises the amino acid sequence SMDWSGGSTYYGDSVKG (SEQ ID NO: 491), and CDR3 comprises the amino acid sequence GTSGVAAVNLRGFFS (SEQ ID NO: 504);
aa) CDR1 comprises the amino acid sequence SSGMG (SEQ ID NO: 484), CDR2 comprises the amino acid sequence SIDWGGGSTYYGDSVKG (SEQ ID NO: 493), and CDR3 comprises the amino acid sequence GTSGVAAVNLRGFFS (SEQ ID NO: 504);
ab) CDR1 comprises the amino acid sequence SSGMG (SEQ ID NO: 484), CDR2 comprises the amino acid sequence SIDWSGGSTYYGDSVKG (SEQ ID NO: 492), and CDR3 comprises the amino acid sequence GTSGVAAVNLRGFFS (SEQ ID NO: 504);
ac) CDR1 comprises the amino acid sequence SSGMG (SEQ ID NO: 484), CDR2 comprises the amino acid sequence SIDWSGKSTYYGDSVKG (SEQ ID NO: 494), and CDR3 comprises the amino acid sequence GTSGVAAVNLRGFFS (SEQ ID NO: 504);
ad) CDR1 comprises the amino acid sequence SSGMG (SEQ ID NO: 484), CDR2 comprises the amino acid sequence SINWSGGSAYYGDSVKG (SEQ ID NO: 495), and CDR3 comprises the amino acid sequence GTSGVAAVNLRGFFS (SEQ ID NO: 504);
ae) CDR1 comprises the amino acid sequence SSGMG (SEQ ID NO: 484), CDR2 comprises the amino acid sequence SMDWSGGSTYYGDSVKG (SEQ ID NO: 491), and CDR3 comprises the amino acid sequence GTSGVAAVNLRGFFS (SEQ ID NO: 504);
af) CDR1 comprises the amino acid sequence SSGMG (SEQ ID NO: 484), CDR2 comprises the amino acid sequence SMDWTGGSTYYGDSVKG (SEQ ID NO: 496), and CDR3 comprises the amino acid sequence GTSGVAAVNLRGFFS (SEQ ID NO: 504);
ag) CDR1 comprises the amino acid sequence VDATT (SEQ ID NO: 485), CDR2 comprises the amino acid sequence IMDIGGVTEYADSVKG (SEQ ID NO): 497), and CDR3 comprises the amino acid sequence RGL;
ah) CDR1 comprises the amino acid sequence INVIG (SEQ ID NO: 505), CDR2 comprises the amino acid sequence LVNSGGQTHYADSVKG (SEQ ID NO: 516), and CDR3 comprises the amino acid sequence RYGIDNY (SEQ ID NO: 528);
ai) CDR1 comprises the amino acid sequence SSFMS (SEQ ID NO: 506), CDR2 comprises the amino acid sequence TIYSDGSTYYADSVKG (SEQ ID NO: 517), and CDR3 comprises the amino acid sequence VTGSI (SEQ ID NO: 529);
aj) CDR1 comprises the amino acid sequence SSFMS (SEQ ID NO: 506), CDR2 comprises the amino acid sequence TIYSDGSTYYADSMKG (SEQ ID NO: 518), and CDR3 comprises the amino acid sequence VTGSI (SEQ ID NO: 529);
ak) CDR1 comprises the amino acid sequence TNVMG (SEQ ID NO: 507), CDR2 comprises the amino acid sequence LIRGGGSTHYADSVKG (SEQ ID NO: 519), and CDR3 comprises the amino acid sequence WLGSPGAMSDY (SEQ ID NO: 530);
al) CDR1 comprises the amino acid sequence TNNMG (SEQ ID NO: 508), CDR2 comprises the amino acid sequence LIRTGGSTHVADSMKG (SEQ ID NO: 520), and CDR3 comprises the amino acid sequence WTGSPGALSDY (SEQ ID NO: 531);
am) CDR1 comprises the amino acid sequence TNNMA (SEQ ID NO: 509), CDR2 comprises the amino acid sequence LIRTGGSTHVADSMKG (SEQ ID NO: 520), and CDR3 comprises the amino acid sequence WTGSPGALSDY (SEQ ID NO: 531);
an) CDR1 comprises the amino acid sequence RVAMN (SEQ ID NO: 510), CDR2 comprises the amino acid sequence TISSDGSRTNYAHSVKG (SEQ ID NO: 522), and CDR3 comprises the amino acid sequence PGNS (SEQ ID NO: 532);
ao) CDR1 comprises the amino acid sequence RVGMN (SEQ ID NO: 511), CDR2 comprises the amino acid sequence SISSDGSRTNYAHFVKG (SEQ ID NO: 523), and CDR3 comprises the amino acid sequence PGNS (SEQ ID NO: 532);
ap) CDR1 comprises the amino acid sequence FVGWG (SEQ ID NO: 512), CDR2 comprises the amino acid sequence QISTGGLTNYADSVKG (SEQ ID NO: 524), and CDR3 comprises the amino acid sequence PGHP (SEQ ID NO: 533);
aq) CDR1 comprises the amino acid sequence FIGWG (SEQ ID NO: 513), CDR2 comprises the amino acid sequence QINTGGLTDYADSVKG (SEQ ID NO: 525), and CDR3 comprises the amino acid sequence PGHS (SEQ ID NO: 534);
ar) CDR1 comprises the amino acid sequence MYSMS (SEQ ID NO: 514), CDR2 comprises the amino acid sequence SISTGARDTAYADSVKG (SEQ ID NO: 526), and CDR3 comprises the amino acid sequence GDLRYGPDGYDY (SEQ ID NO: 535);
as) CDR1 comprises the amino acid sequence MYSMS (SEQ ID NO: 514), CDR2 comprises the amino acid sequence SISTGARDTAYADSVKG (SEQ ID NO: 526), and CDR3 comprises the amino acid sequence GDLRYGPDGYDY (SEQ ID NO: 535);
at) CDR1 comprises the amino acid sequence MYSMS (SEQ ID NO: 514), CDR2 comprises the amino acid sequence SISTGARDTSYADSVKG (SEQ ID NO: 618), and CDR3 comprises the amino acid sequence GDLRYGPDGYDY (SEQ ID NO: 535); or
au) CDR1 comprises the amino acid sequence TYGMG (SEQ ID NO: 515), CDR2 comprises the amino acid sequence VITGSGVGTQYADSVKD (SEQ ID NO: 527), and CDR3 comprises the amino acid sequence GHRPGWAVIRADAYEY (SEQ ID NO: 536).
3 . The VHH antibody of claim 1 , wherein:
a) FR1 comprises the following amino acid sequence:
X 1 X 2 QLX 3 ESGGX 4 VQX 5 GX 6 SX 7 RLX 8 CX 9 X 10 SGX 11 X 12 X 13 X 14 (SEQ ID NO: 604), wherein
X 1 is E or Q;
X 2 is L or V;
X 3 is V or Q;
X 4 is L or S;
X 5 is P or A;
X 6 is A, E, or G;
X 7 is L, R, or V;
X 8 is A or S;
X 9 is A or V;
X 10 is A, T, or V;
X 11 is A, D, F, G, I, P, R, or S;
X 12 is A, D, I, N, P, S, T, or V;
X 13 is A, F, null, S, or V; and
X 14 is I, L, null, or S;
b) FR2 comprises the amino acid sequence:
WX 15 RX 16 APGX 17 X 18 X 19 X 20 X 21 VX 22 (SEQ ID NO: 605), wherein
X 15 is F, V, or Y;
X 16 is H or Q;
X 17 is E or K;
X 18 A, D, E, G, R, or Q;
X 19 is L or R;
X 20 is D or E;
X 21 is F, L, V, or W; and
X 22 is A or S;
c) FR3 comprises the amino acid sequence:
RFX 23 X 24 SRX 25 X 26 X 27 X 28 X 29 X 30 X 31 X 32 LX 33 MX 34 X 35 LX 36 X 37 EDTAX 38 YYCX 39 X 40 (SEQ ID NO: 606), wherein
X 23 is A, I, or T;
X 24 is I or V;
X 25 is D, E, or V;
X 26 is H, I, or N;
X 27 is A or T;
X 28 is D or K;
X 29 is K, M, N, R, S, or T;
X 30 is A, M, or T;
X 31 is A, L, or V;
X 32 is F, H, N, or Y;
X 33 is H or Q;
X 34 is N or S;
X 35 is G, N, S, or T;
X 36 is K or R;
X 37 is A, F, L, P, or V;
X 38 is V or E;
X 39 is A, H, N, or V; and
X 40 is A, E, F, G, I, N, R, T, or V; and/or
d) FR4 comprises the amino acid sequence:
X 40 GX 41 GTX 42 VX 43 VX 44 S (SEQ ID NO: 607), wherein
X 40 is R or W;
X 41 is Q, E, or P;
X 42 is L or Q;
X 43 is S or T; and
X 44 is S or V.
4 . The VHH antibody of claim 1 , wherein:
a) FR1 comprises an amino acid sequence selected from the group consisting of:
(SEQ ID NO: 537)
QVQLVESGGGLVQPGGSLRLSCAASGRTFI,
(SEQ ID NO: 538)
EVQLVESGGGLVQAGGSLRLSCAASGRTFG,
(SEQ ID NO: 543)
QVQLQESGGGLVQAGGSLRLSCAASGRTFG,
(SEQ ID NO: 619)
QVQLVESGGGLVQAGGSLRLSCAASGRTFG,
(SEQ ID NO: 544)
EVQLVESGGGLVQAGGSLRLSCAASGGTVS,
(SEQ ID NO: 545)
EVQLVESGGGLVQAGGSRRLSCAASGGTVS,
(SEQ ID NO: 546)
QVQLVESGGGLVQAGGSLRLSCAASGGTVS,
(SEQ ID NO: 548)
EVQLVESGGGLVQAGASLRLSCAASGRT,
(SEQ ID NO: 549)
QVQLQESGGGLVQAGASLRLSCAASGRA,
(SEQ ID NO: 550)
QVQLQESGGGLVQAGASLRLSCAASGRT,
(SEQ ID NO: 551)
QVQLVESGGGLVQAGASLRLSCAASGRT,
(SEQ ID NO: 554)
QVQLQESGGGSVQAGGSLRLSCAASGRAFS,
(SEQ ID NO: 559)
EVQLVESGGGLVQAGGSLRLSCAASGPAFS,
(SEQ ID NO: 560)
QVQLQESGGGLVQAGGSLRLSCAASGPAFS,
(SEQ ID NO: 561)
QVQLVESGGGLVQAGGSLRLACAASGAAFS,
(SEQ ID NO: 562)
QVQLVESGGGLVQAGGSLRLSCAASGPAFS,
(SEQ ID NO: 569)
QLQLVESGGGLVQPGGSLRLSCAASGSDFL,
(SEQ ID NO: 573)
QVQLQESGGGLVQAGGSLRLSCATSGITSS,
(SEQ ID NO: 577)
EVQLVESGGGLVQPGGSLRLSCAASGFPFS,
(SEQ ID NO: 578)
QVQLVESGGGLVQPGGSLRLSCAASGFNFS,
(SEQ ID NO: 584)
QVQLVESGGGLVQPGGSVRLSCATSGSIFS,
(SEQ ID NO: 587)
EVQLVESGGGLVQPGGSLRLSCAASGSVVS,
(SEQ ID NO: 588)
QVQLVESGGGLVQPGGSLRLSCAASGSDAS,
(SEQ ID NO: 590)
QLQLVESGGGLVQPGESLRLSCAASGFSFS,
(SEQ ID NO: 594)
QLQLVESGGGLVQPGESLRLSCVVSGDIFS,
(SEQ ID NO: 597)
QVQLVESGGGLVQPGESLRLSCVVSGDIFS,
(SEQ ID NO: 599)
QVQLVESGGGLVQPGGSLRLSCAASGFTFS,
and
(SEQ ID NO: 602)
QVQLVESGGGLVQPGGSLRLSCVASGGTFS;
b) FR2 comprises an amino acid sequence selected from the group consisting of:
(SEQ ID NO: 539)
WFRQAPGKEREFVA,
(SEQ ID NO: 620)
WFRQAPGKGREFVA,
(SEQ ID NO: 621)
WFRQAPGREREFVA,
(SEQ ID NO: 552)
WFRHAPGKDREFVA,
(SEQ ID NO: 553)
WFRHAPGEDREFVA,
(SEQ ID NO: 563)
WFRQAPGKARDFVA,
(SEQ ID NO: 567)
WFRQAPGKAREFVA,
(SEQ ID NO: 570)
WFRQAPGNQREFVA,
(SEQ ID NO: 574)
WYRQAPGKQRELVA,
(SEQ ID NO: 579)
WVRQAPGKGLEWVS,
(SEQ ID NO: 580)
WVRQAPGKEVEWVS,
(SEQ ID NO: 585)
WYRQAPGKEREFVA,
(SEQ ID NO: 591)
WYRQAPGKERELVA,
(SEQ ID NO: 595)
WYRQAPGKQREVVA,
and
(SEQ ID NO: 600)
WVRQAPGKRLEWVS;
c) FR3 comprises an amino acid sequence selected from the group consisting of:
(SEQ ID NO: 540)
RFTISRDNAKSTVYLQMNSLRPEDTAVYYCAE,
(SEQ ID NO: 541)
RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAA,
(SEQ ID NO: 547)
RFTISRDNAKNTVNLQMNSLKPEDTAVYYCAA,
(SEQ ID NO: 555)
RFIISRVNAKNTVNLQMNSLKPEDTAVYYCAA,
(SEQ ID NO: 556)
RFTISRVIAKNTVNLQMNSLKPEDTAVYYCAA,
(SEQ ID NO: 558)
RFTISRVNAKNTVNLQMNSLKPEDTAVYYCAA,
(SEQ ID NO: 564)
RFTVSRDNAKNTVHLQMNSLRPEDTAVYYCAR,
(SEQ ID NO: 565)
RFTVSRDNAKNAVHLQMNSLRPEDTAVYYCAR,
(SEQ ID NO: 568)
RFTVSRDNAKMTVHLQMNSLRPEDTAVYYCAR,
(SEQ ID NO: 571)
RFTISRDHTKNTVYLQMNSLKVEDTAVYYCNT,
(SEQ ID NO: 575)
RFTISRDNAKNTVFLQMNSLKPEDTAEYYCHG,
(SEQ ID NO: 581)
RFTISRDNAKKTAYLQMNSLKAEDTAVYYCAT,
(SEQ ID NO: 582)
RFTISRDNAKNTVYLQMSNLKAEDTAVYYCAT,
(SEQ ID NO: 586)
RFIISRENAKTTVYLQMNGLKPEDTAVYYCVI,
(SEQ ID NO: 589)
RFTISRENAKNTVYLQMNSLKPEDTAVYYCVI,
(SEQ ID NO: 592)
RFTISRENAKNMVYLQMNSLKLEDTAVYYCNV,
(SEQ ID NO: 593)
RFTISRDNVKNMVYLQMNSLKLEDTAVYYCNV,
(SEQ ID NO: 596)
RFAISRDNAKRTVYLQMNSLKFEDTAVYYCNV,
(SEQ ID NO: 598)
RFTISRDNAKRTVYLQMNSLKFEDTAVYYCNF,
(SEQ ID NO: 601)
RFTISRDNADNTLYLHMNNLKPEDTAVYYCAN,
and
(SEQ ID NO: 603)
RFTISRENAKNTVYLQMNTLKLEDTAVYYCVS;
and/or
d) FR4 comprises an amino acid sequence selected from the group consisting of:
(SEQ ID NO: 542)
WGQGTQVTVSS,
(SEQ ID NO: 557)
WGOGTQVSVSS,
(SEQ ID NO: 566)
WGPGTQVTVSS,
(SEQ ID NO: 572)
WGQGTLVTVSS,
(SEQ ID NO: 576)
WGEGTQVTVSS,
(SEQ ID NO: 583)
RGQGTQVTVSS,
and
(SEQ ID NO: 622)
RGQGTQVTVVS.
5 . The VHH antibody of claim 1 , wherein:
a) FR1 comprises the amino acid sequence QVQLVESGGGLVQPGGSLRLSCAASGRTFI (SEQ ID NO: 537), FR2 comprises the amino acid sequence WFRQAPGKEREFVA (SEQ ID NO: 539), FR3 comprises the amino acid sequence RFTISRDNAKSTVYLQMNSLRPEDTAVYYCAE (SEQ ID NO: 540), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
b) FR1 comprises the amino acid sequence EVOLVESGGGLVQAGGSLRLSCAASGRTFG (SEQ ID NO: 538), FR2 comprises the amino acid sequence WFRQAPGKEREFVA (SEQ ID NO: 539), FR3 comprises the amino acid sequence RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAA (SEQ ID NO: 541), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
c) FR1 comprises the amino acid sequence EVOLVESGGGLVQAGGSLRLSCAASGRTFG (SEQ ID NO: 538), FR2 comprises the amino acid sequence WFRQAPGKEREFVA (SEQ ID NO: 539), FR3 comprises the amino acid sequence RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAA (SEQ ID NO: 541), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
d) FR1 comprises the amino acid sequence QVQLQESGGGLVQAGGSLRLSCAASGRTFG (SEQ ID NO: 543), FR2 comprises the amino acid sequence WFRQAPGKEREFVA (SEQ ID NO: 539), FR3 comprises the amino acid sequence RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAA (SEQ ID NO: 541), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
e) FR1 comprises the amino acid sequence QVQLQESGGGLVQAGGSLRLSCAASGRTFG (SEQ ID NO: 543), FR2 comprises the amino acid sequence WFRQAPGKEREFVA (SEQ ID NO: 539), FR3 comprises the amino acid sequence RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAA (SEQ ID NO: 541), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
f) FR1 comprises the amino acid sequence QVQLQESGGGLVQAGGSLRLSCAASGRTFG (SEQ ID NO: 543), FR2 comprises the amino acid sequence WFRQAPGKGREFVA (SEQ ID NO: 620), FR3 comprises the amino acid sequence RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAA (SEQ ID NO: 541), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
g) FR1 comprises the amino acid sequence QVQLVESGGGLVQAGGSLRLSCAASGRTFG (SEQ ID NO: 619), FR2 comprises the amino acid sequence WFRQAPGKEREFVA (SEQ ID NO: 539), FR3 comprises the amino acid sequence RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAA (SEQ ID NO: 541), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
h) FR1 comprises the amino acid sequence QVQLVESGGGLVQAGGSLRLSCAASGRTFG (SEQ ID NO: 619), FR2 comprises the amino acid sequence WFRQAPGKEREFVA (SEQ ID NO: 539), FR3 comprises the amino acid sequence RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAA (SEQ ID NO: 541), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
i) FR1 comprises the amino acid sequence QVQLVESGGGLVQAGGSLRLSCAASGRTFG (SEQ ID NO: 619), FR2 comprises the amino acid sequence WFRQAPGREREFVA (SEQ ID NO: 621), FR3 comprises the amino acid sequence RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAA (SEQ ID NO: 541), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
j) FR1 comprises the amino acid sequence EVOLVESGGGLVQAGGSLRLSCAASGGTVS (SEQ ID NO: 544), FR2 comprises the amino acid sequence WFRQAPGKEREFVA (SEQ ID NO: 539), FR3 comprises the amino acid sequence RFTISRDNAKNTVNLQMNSLKPEDTAVYYCAA (SEQ ID NO: 547), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
k) FR1 comprises the amino acid sequence EVOLVESGGGLVQAGGSRRLSCAASGGTVS (SEQ ID NO: 545), FR2 comprises the amino acid sequence WFRQAPGKEREFVA (SEQ ID NO: 539), FR3 comprises the amino acid sequence RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAA (SEQ ID NO: 541), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
l) FR1 comprises the amino acid sequence QVQLVESGGGLVQAGGSLRLSCAASGGTVS (SEQ ID NO: 546), FR2 comprises the amino acid sequence WFRQAPGKEREFVA (SEQ ID NO: 539), FR3 comprises the amino acid sequence RFTISRDNAKNTVNLQMNSLKPEDTAVYYCAA (SEQ ID NO: 547), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
m) FR1 comprises the amino acid sequence QVQLVESGGGLVQAGGSLRLSCAASGGTVS (SEQ ID NO: 546), FR2 comprises the amino acid sequence WFRQAPGKEREFVA (SEQ ID NO: 539), FR3 comprises the amino acid sequence RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAA (SEQ ID NO: 541), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
n) FR1 comprises the amino acid sequence EVOLVESGGGLVQAGASLRLSCAASGRT (SEQ ID NO: 548), FR2 comprises the amino acid sequence WFRHAPGKDREFVA (SEQ ID NO: 552), FR3 comprises the amino acid sequence RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAA (SEQ ID NO: 541), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
o) FR1 comprises the amino acid sequence QVQLQESGGGLVQAGASLRLSCAASGRA (SEQ ID NO: 549), FR2 comprises the amino acid sequence WFRHAPGEDREFVA (SEQ ID NO: 553), FR3 comprises the amino acid sequence RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAA (SEQ ID NO: 541), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
p) FR1 comprises the amino acid sequence QVQLQESGGGLVQAGASLRLSCAASGRT (SEQ ID NO: 550), FR2 comprises the amino acid sequence WFRHAPGKDREFVA (SEQ ID NO: 552), FR3 comprises the amino acid sequence RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAA (SEQ ID NO: 541), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
q) FR1 comprises the amino acid sequence QVQLQESGGGLVQAGASLRLSCAASGRT (SEQ ID NO: 550), FR2 comprises the amino acid sequence WFRHAPGKDREFVA (SEQ ID NO: 552), FR3 comprises the amino acid sequence RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAA (SEQ ID NO: 541), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
r) FR1 comprises the amino acid sequence QVQLVESGGGLVQAGASLRLSCAASGRT (SEQ ID NO: 551), FR2 comprises the amino acid sequence WFRHAPGKDREFVA (SEQ ID NO: 552), FR3 comprises the amino acid sequence RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAA (SEQ ID NO: 541), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
s) FR1 comprises the amino acid sequence QVQLVESGGGLVQAGASLRLSCAASGRT (SEQ ID NO: 551), FR2 comprises the amino acid sequence WFRHAPGKDREFVA (SEQ ID NO: 552), FR3 comprises the amino acid sequence RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAA (SEQ ID NO: 541), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
t) FR1 comprises the amino acid sequence QVQLQESGGGSVQAGGSLRLSCAASGRAFS (SEQ ID NO: 554), FR2 comprises the amino acid sequence WFRQAPGKEREFVA (SEQ ID NO: 539), FR3 comprises the amino acid sequence RFIISRVNAKNTVNLQMNSLKPEDTAVYYCAA (SEQ ID NO: 555), and FR4 comprises the amino acid sequence WGQGTQVSVSS (SEQ ID NO: 557);
u) FR1 comprises the amino acid sequence QVQLQESGGGSVQAGGSLRLSCAASGRAFS (SEQ ID NO: 554), FR2 comprises the amino acid sequence WFRQAPGKEREFVA (SEQ ID NO: 539), FR3 comprises the amino acid sequence RFTISRVIAKNTVNLQMNSLKPEDTAVYYCAA (SEQ ID NO: 556), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
v) FR1 comprises the amino acid sequence QVQLQESGGGSVQAGGSLRLSCAASGRAFS (SEQ ID NO: 554), FR2 comprises the amino acid sequence WFRQAPGKEREFVA (SEQ ID NO: 539), FR3 comprises the amino acid sequence RFTISRVNAKNTVNLQMNSLKPEDTAVYYCAA (SEQ ID NO: 558), and FR4 comprises the amino acid sequence WGQGTQVSVSS (SEQ ID NO: 557);
w) FR1 comprises the amino acid sequence QVQLQESGGGSVQAGGSLRLSCAASGRAFS (SEQ ID NO: 554), FR2 comprises the amino acid sequence WFRQAPGKEREFVA (SEQ ID NO: 539), FR3 comprises the amino acid sequence RFTISRVNAKNTVNLQMNSLKPEDTAVYYCAA (SEQ ID NO: 558), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
x) FR1 comprises the amino acid sequence EVOLVESGGGLVQAGGSLRLSCAASGPAFS (SEQ ID NO: 559), FR2 comprises the amino acid sequence WFRQAPGKARDFVA (SEQ ID NO: 563), FR3 comprises the amino acid sequence RFTVSRDNAKNTVHLQMNSLRPEDTAVYYCAR (SEQ ID NO: 564), and FR4 comprises the amino acid sequence WGPGTQVTVSS (SEQ ID NO: 566);
y) FR1 comprises the amino acid sequence QVQLQESGGGLVQAGGSLRLSCAASGPAFS (SEQ ID NO: 560), FR2 comprises the amino acid sequence WFRQAPGKARDFVA (SEQ ID NO: 563), FR3 comprises the amino acid sequence RFTVSRDNAKNTVHLQMNSLRPEDTAVYYCAR (SEQ ID NO: 564), and FR4 comprises the amino acid sequence WGPGTQVTVSS (SEQ ID NO: 566);
z) FR1 comprises the amino acid sequence QVQLVESGGGLVQAGGSLRLACAASGAAFS (SEQ ID NO: 561), FR2 comprises the amino acid sequence WFRQAPGKARDEVA (SEQ ID NO: 563), FR3 comprises the amino acid sequence RFTVSRDNAKNTVHLQMNSLRPEDTAVYYCAR (SEQ ID NO: 564), and FR4 comprises the amino acid sequence WGPGTQVTVSS (SEQ ID NO: 566);
aa) FR1 comprises the amino acid sequence QVQLVESGGGLVQAGGSLRLSCAASGPAFS (SEQ ID NO: 562), FR2 comprises the amino acid sequence WFRQAPGKARDFVA (SEQ ID NO: 563), FR3 comprises the amino acid sequence RFTVSRDNAKNAVHLQMNSLRPEDTAVYYCAR (SEQ ID NO: 565), and FR4 comprises the amino acid sequence WGPGTQVTVSS (SEQ ID NO: 566);
ab) FR1 comprises the amino acid sequence QVQLVESGGGLVQAGGSLRLSCAASGPAFS (SEQ ID NO: 562), FR2 comprises the amino acid sequence WFRQAPGKARDFVA (SEQ ID NO: 563), FR3 comprises the amino acid sequence RFTVSRDNAKNTVHLQMNSLRPEDTAVYYCAR (SEQ ID NO: 564), and FR4 comprises the amino acid sequence WGPGTQVTVSS (SEQ ID NO: 566);
ac) FR1 comprises the amino acid sequence QVQLVESGGGLVQAGGSLRLSCAASGPAFS (SEQ ID NO: 562), FR2 comprises the amino acid sequence WFRQAPGKARDFVA (SEQ ID NO: 563), FR3 comprises the amino acid sequence RFTVSRDNAKNTVHLQMNSLRPEDTAVYYCAR (SEQ ID NO: 564), and FR4 comprises the amino acid sequence WGPGTQVTVSS (SEQ ID NO: 566);
ad) FR1 comprises the amino acid sequence QVQLVESGGGLVQAGGSLRLSCAASGPAFS (SEQ ID NO: 562), FR2 comprises the amino acid sequence WFRQAPGKARDFVA (SEQ ID NO: 563), FR3 comprises the amino acid sequence RFTVSRDNAKNTVHLQMNSLRPEDTAVYYCAR (SEQ ID NO: 564), and FR4 comprises the amino acid sequence WGPGTQVTVSS (SEQ ID NO: 566);
ae) FR1 comprises the amino acid sequence QVQLVESGGGLVQAGGSLRLSCAASGPAFS (SEQ ID NO: 562), FR2 comprises the amino acid sequence WFRQAPGKARDEVA (SEQ ID NO: 563), FR3 comprises the amino acid sequence RFTVSRDNAKNTVHLQMNSLRPEDTAVYYCAR (SEQ ID NO: 564), and FR4 comprises the amino acid sequence WGPGTQVTVSS (SEQ ID NO: 566);
af) FR1 comprises the amino acid sequence QVQLVESGGGLVQAGGSLRLSCAASGPAFS (SEQ ID NO: 562), FR2 comprises the amino acid sequence WFRQAPGKAREFVA (SEQ ID NO: 567), FR3 comprises the amino acid sequence RFTVSRDNAKMTVHLQMNSLRPEDTAVYYCAR (SEQ ID NO: 568), and FR4 comprises the amino acid sequence WGPGTQVTVSS (SEQ ID NO: 566);
ag) FR1 comprises the amino acid sequence QLQLVESGGGLVQPGGSLRLSCAASGSDFL (SEQ ID NO: 569), FR2 comprises the amino acid sequence WFRQAPGNQREFVA (SEQ ID NO: 570), FR3 comprises the amino acid sequence RFTISRDHTKNTVYLQMNSLKVEDTAVYYCNT (SEQ ID NO: 571), and FR4 comprises the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 572);
ah) FR1 comprises the amino acid sequence QVQLQESGGGLVQAGGSLRLSCATSGITSS (SEQ ID NO: 573), FR2 comprises the amino acid sequence WYRQAPGKQRELVA (SEQ ID NO: 574), FR3 comprises the amino acid sequence RFTISRDNAKNTVFLQMNSLKPEDTAEYYCHG (SEQ ID NO: 575), and FR4 comprises the amino acid sequence WGEGTQVTVSS (SEQ ID NO: 576);
ai) FR1 comprises the amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFPFS (SEQ ID NO: 577), FR2 comprises the amino acid sequence WVRQAPGKGLEWVS (SEQ ID NO: 579), FR3 comprises the amino acid sequence RFTISRDNAKKTAYLQMNSLKAEDTAVYYCAT (SEQ ID NO: 581), and FR4 comprises the amino acid sequence RGQGTQVTVSS (SEQ ID NO: 583);
aj) FR1 comprises the amino acid sequence QVQLVESGGGLVQPGGSLRLSCAASGENES (SEQ ID NO: 578), FR2 comprises the amino acid sequence WVRQAPGKEVEWVS (SEQ ID NO: 580), FR3 comprises the amino acid sequence RFTISRDNAKNTVYLQMSNLKAEDTAVYYCAT (SEQ ID NO: 582), and FR4 comprises the amino acid sequence RGQGTQVTVSS (SEQ ID NO: 583);
ak) FR1 comprises the amino acid sequence QVQLVESGGGLVQPGGSVRLSCATSGSIFS (SEQ ID NO: 584), FR2 comprises the amino acid sequence WYRQAPGKEREFVA (SEQ ID NO: 585), FR3 comprises the amino acid sequence RFIISRENAKTTVYLQMNGLKPEDTAVYYCVI (SEQ ID NO: 586), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
al) FR1 comprises the amino acid sequence EVOLVESGGGLVQPGGSLRLSCAASGSVVS (SEQ ID NO: 587), FR2 comprises the amino acid sequence WYRQAPGKEREFVA (SEQ ID NO: 585), FR3 comprises the amino acid sequence RFTISRENAKNTVYLQMNSLKPEDTAVYYCVI (SEQ ID NO: 589), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
am) FR1 comprises the amino acid sequence QVQLVESGGGLVQPGGSLRLSCAASGSDAS (SEQ ID NO: 588), FR2 comprises the amino acid sequence WYRQAPGKEREFVA (SEQ ID NO: 585), FR3 comprises the amino acid sequence RFTISRENAKNTVYLQMNSLKPEDTAVYYCVI (SEQ ID NO: 589), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
an) FR1 comprises the amino acid sequence QLQLVESGGGLVQPGESLRLSCAASGFSFS (SEQ ID NO: 590), FR2 comprises the amino acid sequence WYRQAPGKERELVA (SEQ ID NO: 591), FR3 comprises the amino acid sequence RFTISRENAKNMVYLQMNSLKLEDTAVYYCNV (SEQ ID NO: 592), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
ao) FR1 comprises the amino acid sequence QLQLVESGGGLVQPGESLRLSCAASGFSFS (SEQ ID NO: 590), FR2 comprises the amino acid sequence WYRQAPGKERELVA (SEQ ID NO: 591), FR3 comprises the amino acid sequence RFTISRDNVKNMVYLQMNSLKLEDTAVYYCNV (SEQ ID NO: 593), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
ap) FR1 comprises the amino acid sequence QLQLVESGGGLVQPGESLRLSCVVSGDIFS (SEQ ID NO: 594), FR2 comprises the amino acid sequence WYRQAPGKQREVVA (SEQ ID NO: 595), FR3 comprises the amino acid sequence RFAISRDNAKRTVYLQMNSLKFEDTAVYYCNV (SEQ ID NO: 596), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
aq) FR1 comprises the amino acid sequence QVQLVESGGGLVQPGESLRLSCVVSGDIFS (SEQ ID NO: 597), FR2 comprises the amino acid sequence WYRQAPGKQRELVA (SEQ ID NO: 574), FR3 comprises the amino acid sequence RFTISRDNAKRTVYLQMNSLKFEDTAVYYCNF (SEQ ID NO: 598), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542);
ar) FR1 comprises the amino acid sequence QVQLVESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 599), FR2 comprises the amino acid sequence WVRQAPGKRLEWVS (SEQ ID NO: 600), FR3 comprises the amino acid sequence RFTISRDNADNTLYLHMNNLKPEDTAVYYCAN (SEQ ID NO: 601), and FR4 comprises the amino acid sequence RGQGTQVTVSS (SEQ ID NO: 583);
as) FR1 comprises the amino acid sequence QVQLVESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 599), FR2 comprises the amino acid sequence WVRQAPGKRLEWVS (SEQ ID NO: 600), FR3 comprises the amino acid sequence RFTISRDNADNTLYLHMNNLKPEDTAVYYCAN (SEQ ID NO: 601), and FR4 comprises the amino acid sequence RGQGTQVTVVS (SEQ ID NO: 622);
at) FR1 comprises the amino acid sequence QVQLVESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 599), FR2 comprises the amino acid sequence WVRQAPGKRLEWVS (SEQ ID NO: 600), FR3 comprises the amino acid sequence RFTISRDNADNTLYLHMNNLKPEDTAVYYCAN (SEQ ID NO: 601), and FR4 comprises the amino acid sequence RGQGTQVTVSS (SEQ ID NO: 583); or
au) FR1 comprises the amino acid sequence QVQLVESGGGLVQPGGSLRLSCVASGGTFS, FR2 comprises the amino acid sequence WFRQAPGKEREFVA (SEQ ID NO: 539), FR3 comprises the amino acid sequence RFTISRENAKNTVYLQMNTLKLEDTAVYYCVS (SEQ ID NO: 603), and FR4 comprises the amino acid sequence WGQGTQVTVSS (SEQ ID NO: 542).
6 . The VHH antibody of claim 1 , wherein the VHH antibody comprises an amino acid sequence having at least 85% sequence identity to an amino acid sequence selected from the group consisting of:
(SEQ ID NO: 431)
QVQLVESGGGLVQPGGSLRLSCAASGRTFINYAAGWFRQAPGKEREFVARISRSGGRTDYADSV
KGRFTISRDNAKSTVYLQMNSLRPEDTAVYYCAEATVWEFTDGADQYDYWGQGTQVTVSS;
(SEQ ID NO: 432)
EVQLVESGGGLVQAGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFVAAISWSAGRTYYADSM
KGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADPWTSDSDYDRLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 433)
EVQLVESGGGLVQAGGSLRLSCAASGRTFGTYTMGWFRQAPGKEREFVAAISWSAGRTYYADSM
KGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADPWTSDSDYDRLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 434)
QVQLQESGGGLVQAGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFVAAISWSAGRTYYADSM
KGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADPWTSDSDYDRLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 435)
QVQLQESGGGLVQAGGSLRLSCAASGRTFGTYTMGWFRQAPGKEREFVAAISWSAGRTYYADSM
KGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADPWTSDSDYDRLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 436)
QVQLQESGGGLVQAGGSLRLSCAASGRTFGTYTMGWFRQAPGKGREFVAAISWSAGRTYYADSM
KGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADPWTSDSDYDRLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 437)
QVQLVESGGGLVQAGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFVAAISWSAGRTYYADSM
KGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADPWTSDSDYDRLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 438)
QVQLVESGGGLVQAGGSLRLSCAASGRTFGTYTMGWFRQAPGKEREFVAAISWSAGRTYYADSM
KGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADPWTSDSDYDRLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 439)
QVQLVESGGGLVQAGGSLRLSCAASGRTFGTYTMGWFRQAPGREREFVAAISWSAGRTYYADSM
KGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADPWTSDSDYDRLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 440)
EVQLVESGGGLVQAGGSLRLSCAASGGTVSSYAMGWFRQAPGKEREFVAVISWSGGRTYYADSV
KGRFTISRDNAKNTVNLQMNSLKPEDTAVYYCAADPWTSDSDYERLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 441)
EVQLVESGGGLVQAGGSRRLSCAASGGTVSSYAMGWFRQAPGKEREFVAVISWSGGRTYYADSV
KGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADPWTSDSDYERLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 442)
QVQLVESGGGLVQAGGSLRLSCAASGGTVSSYAMGWFRQAPGKEREFVAVISWSGGRTYYADSV
KGRFTISRDNAKNTVNLQMNSLKPEDTAVYYCAADPWTSDSDYERLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 443)
QVQLVESGGGLVQAGGSLRLSCAASGGTVSSYAMGWFRQAPGKEREFVAVISWSGGRTYYADSV
KGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADPWTSDSDYERLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 444)
EVQLVESGGGLVQAGASLRLSCAASGRTTYNMGWFRHAPGKDREFVAAIDLYGRATRYANSVKG
RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADTSLPLGVLTESQRLYGAWGQGTQVTVSS;
(SEQ ID NO: 445)
QVQLQESGGGLVQAGASLRLSCAASGRATYNMGWFRHAPGEDREFVAAINLEGYATRYANSVKG
RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADTSLPLGVLTESQRLYGAWGQGTQVTVSS;
(SEQ ID NO: 446)
QVQLQESGGGLVQAGASLRLSCAASGRTTYNMGWFRHAPGKDREFVAAIDLYGRATRYANSVKG
RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADTSLPLGVLTESQRLYGAWGQGTQVTVSS;
(SEQ ID NO: 447)
QVQLQESGGGLVQAGASLRLSCAASGRTTYNMGWFRHAPGKDREFVAAIDLYGRATRYANSVRG
RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADTSLPLGVLTESQRLYGAWGQGTQVTVSS;
(SEQ ID NO: 448)
QVQLVESGGGLVQAGASLRLSCAASGRTTYNMGWFRHAPGKDREFVAAIDLYGRATRYANSVKG
RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADTSLPLGVLTESQRLYGAWGQGTQVTVSS;
(SEQ ID NO: 449)
QVQLVESGGGLVQAGASLRLSCAASGRTTYNMGWFRHAPGKDREFVAAIDLYGRATRYANSVKG
RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADTSLPLGVLTKSQRMYGAWGQGTQVTVSS;
(SEQ ID NO: 450)
QVQLQESGGGSVQAGGSLRLSCAASGRAFSAYAMGWFRQAPGKEREFVAAINWNGDTALRWNGF
ATRYADSVKGRFIISRVNAKNTVNLQMNSLKPEDTAVYYCAADTVVSGSYYLAARAEDYEYWGQ
GTQVSVSS;
(SEQ ID NO: 451)
QVQLQESGGGSVQAGGSLRLSCAASGRAFSAYAMGWFRQAPGKEREFVAAINWNGDTALRWNGF
ATRYADSVKGRFTISRVIAKNTVNLQMNSLKPEDTAVYYCAADTVVSGSYYLAARAEDYEYWGQ
GTQVTVSS;
(SEQ ID NO: 452)
QVQLQESGGGSVQAGGSLRLSCAASGRAFSAYAMGWFRQAPGKEREFVAAINWNGDTALRWNGF
ATRYADSVKGRFTISRVNAKNTVNLQMNSLKPEDTAVYYCAADTVVSGSYYLAARAEDYEYWGQ
GTQVSVSS;
(SEQ ID NO: 453)
QVQLQESGGGSVQAGGSLRLSCAASGRAFSAYAMGWFRQAPGKEREFVAAINWNGDTALRWNGF
ATRYADSVKGRFTISRVNAKNTVNLQMNSLKPEDTAVYYCAADTVVSGSYYLAARAEDYEYWGQ
GTQVTVSS;
(SEQ ID NO: 454)
EVQLVESGGGLVQAGGSLRLSCAASGPAFSSSGMGWFRQAPGKARDFVASMDWSGGSTYYGDSV
KGRFTVSRDNAKNTVHLQMNSLRPEDTAVYYCARGTSGVAAVNLRGFFSWGPGTQVTVSS;
(SEQ ID NO: 455)
QVQLQESGGGLVQAGGSLRLSCAASGPAFSSSGMGWFRQAPGKARDFVASIDWSGGSTYYGDSV
KGRFTVSRDNAKNTVHLQMNSLRPEDTAVYYCARGTSGVAAVNLRGFFSWGPGTQVTVSS;
(SEQ ID NO: 456)
QVQLVESGGGLVQAGGSLRLACAASGAAFSSSGMGWFRQAPGKARDFVASMDWSGGSTYYGDSV
KGRFTVSRDNAKNTVHLQMNSLRPEDTAVYYCARGTSGVAAVNLRGFFSWGPGTQVTVSS;
(SEQ ID NO: 457)
QVQLVESGGGLVQAGGSLRLSCAASGPAFSSSGMGWFRQAPGKARDFVASIDWGGGSTYYGDSV
KGRFTVSRDNAKNAVHLQMNSLRPEDTAVYYCARGTSGVAAVNLRGFFSWGPGTQVTVSS;
(SEQ ID NO: 458)
QVQLVESGGGLVQAGGSLRLSCAASGPAFSSSGMGWFRQAPGKARDFVASIDWSGGSTYYGDSV
KGRFTVSRDNAKNTVHLQMNSLRPEDTAVYYCARGTSGVAAVNLRGFFSWGPGTQVTVSS;
(SEQ ID NO: 459)
QVQLVESGGGLVQAGGSLRLSCAASGPAFSSSGMGWFRQAPGKARDFVASIDWSGKSTYYGDSV
KGRFTVSRDNAKNTVHLQMNSLRPEDTAVYYCARGTSGVAAVNLRGFFSWGPGTQVTVSS;
(SEQ ID NO: 460)
QVQLVESGGGLVQAGGSLRLSCAASGPAFSSSGMGWFRQAPGKARDFVASINWSGGSAYYGDSV
KGRFTVSRDNAKNTVHLQMNSLRPEDTAVYYCARGTSGVAAVNLRGFFSWGPGTQVTVSS;
(SEQ ID NO: 461)
QVQLVESGGGLVQAGGSLRLSCAASGPAFSSSGMGWFRQAPGKARDFVASMDWSGGSTYYGDSV
KGRFTVSRDNAKNTVHLQMNSLRPEDTAVYYCARGTSGVAAVNLRGFFSWGPGTQVTVSS;
(SEQ ID NO: 462)
QVQLVESGGGLVQAGGSLRLSCAASGPAFSSSGMGWFRQAPGKAREFVASMDWTGGSTYYGDSV
KGRFTVSRDNAKMTVHLQMNSLRPEDTAVYYCARGTSGVAAVNLRGFFSWGPGTQVTVSS;
(SEQ ID NO: 463)
QLQLVESGGGLVQPGGSLRLSCAASGSDFLVDATTWFRQAPGNQREFVAIMDIGGVTEYADSVK
GRFTISRDHTKNTVYLQMNSLKVEDTAVYYCNTRGLWGQGTLVTVSS;
(SEQ ID NO: 464)
QVQLQESGGGLVQAGGSLRLSCATSGITSSINVIGWYRQAPGKQRELVALVNSGGQTHYADSVK
GRFTISRDNAKNTVFLQMNSLKPEDTAEYYCHGRYGIDNYWGEGTQVTVSS;
(SEQ ID NO: 465)
EVQLVESGGGLVQPGGSLRLSCAASGFPFSSSFMSWVRQAPGKGLEWVSTIYSDGSTYYADSVK
GRFTISRDNAKKTAYLQMNSLKAEDTAVYYCATVTGSIRGQGTQVTVSS;
(SEQ ID NO: 466)
QVQLVESGGGLVQPGGSLRLSCAASGFNFSSSFMSWVRQAPGKEVEWVSTIYSDGSTYYADSMK
GRFTISRDNAKNTVYLQMSNLKAEDTAVYYCATVTGSIRGQGTQVTVSS;
(SEQ ID NO: 467)
QVQLVESGGGLVQPGGSVRLSCATSGSIFSTNVMGWYRQAPGKEREFVALIRGGGSTHYADSVK
GRFIISRENAKTTVYLQMNGLKPEDTAVYYCVIWLGSPGAMSDYWGQGTQVTVSS;
(SEQ ID NO: 468)
EVQLVESGGGLVQPGGSLRLSCAASGSVVSTNNMGWYRQAPGKEREFVALIRTGGSTHVADSMK
GRFTISRENAKNTVYLQMNSLKPEDTAVYYCVIWTGSPGALSDYWGQGTQVTVSS;
(SEQ ID NO: 469)
QVQLVESGGGLVQPGGSLRLSCAASGSDASTNNMAWYRQAPGKEREFVALIRTGGSTHVADSMK
GRFTISRENAKNTVYLQMNSLKPEDTAVYYCVIWTGSPGALSDYWGQGTQVTVSS;
(SEQ ID NO: 470
QLQLVESGGGLVQPGESLRLSCAASGFSFSRVAMNWYRQAPGKERELVATISSDGSRTNYAHSV
KGRFTISRENAKNMVYLQMNSLKLEDTAVYYCNVPGNSWGQGTQVTVSS);
(SEQ ID NO: 471)
QLQLVESGGGLVQPGESLRLSCAASGFSFSRVGMNWYRQAPGKERELVASISSDGSRTNYAHFV
KGRFTISRDNVKNMVYLQMNSLKLEDTAVYYCNVPGNSWGQGTQVTVSS;
(SEQ ID NO: 472)
QLQLVESGGGLVQPGESLRLSCVVSGDIFSFVGWGWYRQAPGKQREVVAQISTGGLTNYADSVK
GRFAISRDNAKRTVYLQMNSLKFEDTAVYYCNVPGHPWGQGTQVTVSS;
(SEQ ID NO: 473)
QVQLVESGGGLVQPGESLRLSCVVSGDIFSFIGWGWYRQAPGKQRELVAQINTGGLTDYADSVK
GRFTISRDNAKRTVYLQMNSLKFEDTAVYYCNFPGHSWGQGTQVTVSS;
(SEQ ID NO: 474)
QVQLVESGGGLVQPGGSLRLSCAASGFTFSMYSMSWVRQAPGKRLEWVSSISTGARDTAYADSV
KGRFTISRDNADNTLYLHMNNLKPEDTAVYYCANGDLRYGPDGYDYRGQGTQVTVSS;
(SEQ ID NO: 475)
QVQLVESGGGLVQPGGSLRLSCAASGFTFSMYSMSWVRQAPGKRLEWVSSISTGARDTAYADSV
KGRFTISRDNADNTLYLHMNNLKPEDTAVYYCANGDLRYGPDGYDYRGQGTQVTVVS;
(SEQ ID NO: 476)
QVQLVESGGGLVQPGGSLRLSCAASGFTFSMYSMSWVRQAPGKRLEWVSSISTGARDTSYADSV
KGRFTISRDNADNTLYLHMNNLKPEDTAVYYCANGDLRYGPDGYDYRGQGTQVTVSS;
and
(SEQ ID NO: 477)
QVQLVESGGGLVQPGGSLRLSCVASGGTFSTYGMGWFRQAPGKEREFVAVITGSGVGTQYADSV
KDRFTISRENAKNTVYLQMNTLKLEDTAVYYCVSGHRPGWAVIRADAYEYWGQGTQVTVSS.
7 . The VHH antibody of claim 1 , wherein the VHH antibody comprises an amino acid sequence selected from the group consisting of:
(SEQ ID NO: 431)
QVQLVESGGGLVQPGGSLRLSCAASGRTFINYAAGWFRQAPGKEREFVARISRSGGRTDYADSV
KGRFTISRDNAKSTVYLQMNSLRPEDTAVYYCAEATVWEFTDGADQYDYWGQGTQVTVSS;
(SEQ ID NO: 432)
EVQLVESGGGLVQAGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFVAAISWSAGRTYYADSM
KGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADPWTSDSDYDRLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 433)
EVQLVESGGGLVQAGGSLRLSCAASGRTFGTYTMGWFRQAPGKEREFVAAISWSAGRTYYADSM
KGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADPWTSDSDYDRLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 434)
QVQLQESGGGLVQAGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFVAAISWSAGRTYYADSM
KGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADPWTSDSDYDRLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 435)
QVQLQESGGGLVQAGGSLRLSCAASGRTFGTYTMGWFRQAPGKEREFVAAISWSAGRTYYADSM
KGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADPWTSDSDYDRLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 436)
QVQLQESGGGLVQAGGSLRLSCAASGRTFGTYTMGWFRQAPGKGREFVAAISWSAGRTYYADSM
KGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADPWTSDSDYDRLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 437)
QVQLVESGGGLVQAGGSLRLSCAASGRTFGSYTMGWFRQAPGKEREFVAAISWSAGRTYYADSM
KGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADPWTSDSDYDRLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 438)
QVQLVESGGGLVQAGGSLRLSCAASGRTFGTYTMGWFRQAPGKEREFVAAISWSAGRTYYADSM
KGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADPWTSDSDYDRLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 439)
QVQLVESGGGLVQAGGSLRLSCAASGRTFGTYTMGWFRQAPGREREFVAAISWSAGRTYYADSM
KGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADPWTSDSDYDRLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 440)
EVQLVESGGGLVQAGGSLRLSCAASGGTVSSYAMGWFRQAPGKEREFVAVISWSGGRTYYADSV
KGRFTISRDNAKNTVNLQMNSLKPEDTAVYYCAADPWTSDSDYERLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 441)
EVQLVESGGGLVQAGGSRRLSCAASGGTVSSYAMGWFRQAPGKEREFVAVISWSGGRTYYADSV
KGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADPWTSDSDYERLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 442)
QVQLVESGGGLVQAGGSLRLSCAASGGTVSSYAMGWFRQAPGKEREFVAVISWSGGRTYYADSV
KGRFTISRDNAKNTVNLQMNSLKPEDTAVYYCAADPWTSDSDYERLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 443)
QVQLVESGGGLVQAGGSLRLSCAASGGTVSSYAMGWFRQAPGKEREFVAVISWSGGRTYYADSV
KGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADPWTSDSDYERLTMYDYWGQGTQVTVSS;
(SEQ ID NO: 444)
EVQLVESGGGLVQAGASLRLSCAASGRTTYNMGWFRHAPGKDREFVAAIDLYGRATRYANSVKG
RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADTSLPLGVLTESQRLYGAWGQGTQVTVSS;
(SEQ ID NO: 445)
QVQLQESGGGLVQAGASLRLSCAASGRATYNMGWFRHAPGEDREFVAAINLEGYATRYANSVKG
RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADTSLPLGVLTESQRLYGAWGQGTQVTVSS;
(SEQ ID NO: 446)
QVQLQESGGGLVQAGASLRLSCAASGRTTYNMGWFRHAPGKDREFVAAIDLYGRATRYANSVKG
RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADTSLPLGVLTESQRLYGAWGQGTQVTVSS;
(SEQ ID NO: 447)
QVQLQESGGGLVQAGASLRLSCAASGRTTYNMGWFRHAPGKDREFVAAIDLYGRATRYANSVRG
RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADTSLPLGVLTESQRLYGAWGQGTQVTVSS;
(SEQ ID NO: 448)
QVQLVESGGGLVQAGASLRLSCAASGRTTYNMGWFRHAPGKDREFVAAIDLYGRATRYANSVKG
RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADTSLPLGVLTESQRLYGAWGQGTQVTVSS;
(SEQ ID NO: 449)
QVQLVESGGGLVQAGASLRLSCAASGRTTYNMGWFRHAPGKDREFVAAIDLYGRATRYANSVKG
RFTISRDNAKNTVYLQMNSLKPEDTAVYYCAADTSLPLGVLTKSQRMYGAWGQGTQVTVSS;
(SEQ ID NO: 450)
QVQLQESGGGSVQAGGSLRLSCAASGRAFSAYAMGWFRQAPGKEREFVAAINWNGDTALRWNGF
ATRYADSVKGRFIISRVNAKNTVNLQMNSLKPEDTAVYYCAADTVVSGSYYLAARAEDYEYWGQ
GTQVSVSS;
(SEQ ID NO: 451)
QVQLQESGGGSVQAGGSLRLSCAASGRAFSAYAMGWFRQAPGKEREFVAAINWNGDTALRWNGF
ATRYADSVKGRFTISRVIAKNTVNLQMNSLKPEDTAVYYCAADTVVSGSYYLAARAEDYEYWGQ
GTQVTVSS;
(SEQ ID NO: 452)
QVQLQESGGGSVQAGGSLRLSCAASGRAFSAYAMGWFRQAPGKEREFVAAINWNGDTALRWNGF
ATRYADSVKGRFTISRVNAKNTVNLQMNSLKPEDTAVYYCAADTVVSGSYYLAARAEDYEYWGQ
GTQVSVSS;
(SEQ ID NO: 453)
QVQLQESGGGSVQAGGSLRLSCAASGRAFSAYAMGWFRQAPGKEREFVAAINWNGDTALRWNGF
ATRYADSVKGRFTISRVNAKNTVNLQMNSLKPEDTAVYYCAADTVVSGSYYLAARAEDYEYWGQ
GTQVTVSS;
(SEQ ID NO: 454)
EVQLVESGGGLVQAGGSLRLSCAASGPAFSSSGMGWFRQAPGKARDFVASMDWSGGSTYYGDSV
KGRFTVSRDNAKNTVHLQMNSLRPEDTAVYYCARGTSGVAAVNLRGFFSWGPGTQVTVSS;
(SEQ ID NO: 455)
QVQLQESGGGLVQAGGSLRLSCAASGPAFSSSGMGWFRQAPGKARDFVASIDWSGGSTYYGDSV
KGRFTVSRDNAKNTVHLQMNSLRPEDTAVYYCARGTSGVAAVNLRGFFSWGPGTQVTVSS;
(SEQ ID NO: 456)
QVQLVESGGGLVQAGGSLRLACAASGAAFSSSGMGWFRQAPGKARDFVASMDWSGGSTYYGDSV
KGRFTVSRDNAKNTVHLQMNSLRPEDTAVYYCARGTSGVAAVNLRGFFSWGPGTQVTVSS;
(SEQ ID NO: 457)
QVQLVESGGGLVQAGGSLRLSCAASGPAFSSSGMGWFRQAPGKARDFVASIDWGGGSTYYGDSV
KGRFTVSRDNAKNAVHLQMNSLRPEDTAVYYCARGTSGVAAVNLRGFFSWGPGTQVTVSS;
(SEQ ID NO: 458)
QVQLVESGGGLVQAGGSLRLSCAASGPAFSSSGMGWFRQAPGKARDFVASIDWSGGSTYYGDSV
KGRFTVSRDNAKNTVHLQMNSLRPEDTAVYYCARGTSGVAAVNLRGFFSWGPGTQVTVSS;
(SEQ ID NO: 459)
QVQLVESGGGLVQAGGSLRLSCAASGPAFSSSGMGWFRQAPGKARDFVASIDWSGKSTYYGDSV
KGRFTVSRDNAKNTVHLQMNSLRPEDTAVYYCARGTSGVAAVNLRGFFSWGPGTQVTVSS;
(SEQ ID NO: 460)
QVQLVESGGGLVQAGGSLRLSCAASGPAFSSSGMGWFRQAPGKARDFVASINWSGGSAYYGDSV
KGRFTVSRDNAKNTVHLQMNSLRPEDTAVYYCARGTSGVAAVNLRGFFSWGPGTQVTVSS;
(SEQ ID NO: 461)
QVQLVESGGGLVQAGGSLRLSCAASGPAFSSSGMGWFRQAPGKARDFVASMDWSGGSTYYGDSV
KGRFTVSRDNAKNTVHLQMNSLRPEDTAVYYCARGTSGVAAVNLRGFFSWGPGTQVTVSS;
(SEQ ID NO: 462)
QVQLVESGGGLVQAGGSLRLSCAASGPAFSSSGMGWFRQAPGKAREFVASMDWTGGSTYYGDSV
KGRFTVSRDNAKMTVHLQMNSLRPEDTAVYYCARGTSGVAAVNLRGFFSWGPGTQVTVSS;
(SEQ ID NO: 463)
QLQLVESGGGLVQPGGSLRLSCAASGSDFLVDATTWFRQAPGNQREFVAIMDIGGVTEYADSVK
GRFTISRDHTKNTVYLQMNSLKVEDTAVYYCNTRGLWGQGTLVTVSS;
(SEQ ID NO: 464)
QVQLQESGGGLVQAGGSLRLSCATSGITSSINVIGWYRQAPGKQRELVALVNSGGQTHYADSVK
GRFTISRDNAKNTVFLQMNSLKPEDTAEYYCHGRYGIDNYWGEGTQVTVSS;
(SEQ ID NO: 465)
EVQLVESGGGLVQPGGSLRLSCAASGFPFSSSFMSWVRQAPGKGLEWVSTIYSDGSTYYADSVK
GRFTISRDNAKKTAYLQMNSLKAEDTAVYYCATVTGSIRGQGTQVTVSS;
(SEQ ID NO: 466)
QVQLVESGGGLVQPGGSLRLSCAASGFNFSSSFMSWVRQAPGKEVEWVSTIYSDGSTYYADSMK
GRFTISRDNAKNTVYLQMSNLKAEDTAVYYCATVTGSIRGQGTQVTVSS;
(SEQ ID NO: 467)
QVQLVESGGGLVQPGGSVRLSCATSGSIFSTNVMGWYRQAPGKEREFVALIRGGGSTHYADSVK
GRFIISRENAKTTVYLQMNGLKPEDTAVYYCVIWLGSPGAMSDYWGQGTQVTVSS;
(SEQ ID NO: 468)
EVQLVESGGGLVQPGGSLRLSCAASGSVVSTNNMGWYRQAPGKEREFVALIRTGGSTHVADSMK
GRFTISRENAKNTVYLQMNSLKPEDTAVYYCVIWTGSPGALSDYWGQGTQVTVSS;
(SEQ ID NO: 469)
QVQLVESGGGLVQPGGSLRLSCAASGSDASTNNMAWYRQAPGKEREFVALIRTGGSTHVADSMK
GRFTISRENAKNTVYLQMNSLKPEDTAVYYCVIWTGSPGALSDYWGQGTQVTVSS;
(SEQ ID NO: 470)
QLQLVESGGGLVQPGESLRLSCAASGFSFSRVAMNWYRQAPGKERELVATISSDGSRTNYAHSV
KGRFTISRENAKNMVYLQMNSLKLEDTAVYYCNVPGNSWGQGTQVTVSS;
(SEQ ID NO: 471)
QLQLVESGGGLVQPGESLRLSCAASGFSFSRVGMNWYRQAPGKERELVASISSDGSRTNYAHFV
KGRFTISRDNVKNMVYLQMNSLKLEDTAVYYCNVPGNSWGQGTQVTVSS;
(SEQ ID NO: 472)
QLQLVESGGGLVQPGESLRLSCVVSGDIFSFVGWGWYRQAPGKQREVVAQISTGGLTNYADSVK
GRFAISRDNAKRTVYLQMNSLKFEDTAVYYCNVPGHPWGQGTQVTVSS;
(SEQ ID NO: 473)
QVQLVESGGGLVQPGESLRLSCVVSGDIFSFIGWGWYRQAPGKQRELVAQINTGGLTDYADSVK
GRFTISRDNAKRTVYLQMNSLKFEDTAVYYCNFPGHSWGQGTQVTVSS;
(SEQ ID NO: 474)
QVQLVESGGGLVQPGGSLRLSCAASGFTFSMYSMSWVRQAPGKRLEWVSSISTGARDTAYADSV
KGRFTISRDNADNTLYLHMNNLKPEDTAVYYCANGDLRYGPDGYDYRGQGTQVTVSS;
(SEQ ID NO: 475)
QVQLVESGGGLVQPGGSLRLSCAASGFTFSMYSMSWVRQAPGKRLEWVSSISTGARDTAYADSV
KGRFTISRDNADNTLYLHMNNLKPEDTAVYYCANGDLRYGPDGYDYRGQGTQVTVVS;
(SEQ ID NO: 476)
QVQLVESGGGLVQPGGSLRLSCAASGFTFSMYSMSWVRQAPGKRLEWVSSISTGARDTSYADSV
KGRFTISRDNADNTLYLHMNNLKPEDTAVYYCANGDLRYGPDGYDYRGQGTQVTVSS;
and
(SEQ ID NO: 477)
QVQLVESGGGLVQPGGSLRLSCVASGGTFSTYGMGWFRQAPGKEREFVAVITGSGVGTQYADSV
KDRFTISRENAKNTVYLQMNTLKLEDTAVYYCVSGHRPGWAVIRADAYEYWGQGTQVTVSS.
8 . A chimeric antigen receptor polypeptide comprising the VHH antibody of claim 1 , or an antigen-binding fragment thereof.
9 . An immunoconjugate comprising the VHH antibody of claim 1 .
10 . A polynucleotide encoding the VHH antibody of claim 1 .
11 . A vector comprising the polynucleotide of claim 10 .
12 . A cell expressing the VHH antibody of claim 1 .
13 . A lipid nanoparticle comprising the VHH antibody of claim 1 .
14 . The lipid nanoparticle of claim 13 , wherein the lipid nanoparticle is conjugated to the VHH antibody.
15 . The lipid nanoparticle of claim 14 , wherein the VHH antibody is covalently bound to a polyethylene glycol (PEG) molecule of the lipid nanoparticle.
16 . The lipid nanoparticle of claim 14 , wherein the VHH antibody is covalently bound to a PEG portion of a PEG-modified lipid of the lipid nanoparticle.
17 . The lipid nanoparticle of claim 13 , wherein the lipid nanoparticle comprises a polynucleotide encoding a chimeric antigen receptor.
18 . The lipid nanoparticle of claim 13 , wherein the chimeric antigen receptor comprises an antigen binding domain capable of binding a marker associated with a neoplasia.
19 . A composition comprising the VHH antibody of claim 1 , and a carrier or excipient.
20 . A method for treating a neoplasia in a subject in need thereof, the method comprising administering to the subject the lipid nanoparticle of claim 17 .
21 . The method of claim 20 , wherein the neoplasia is a B cell lymphoma or a T cell lymphoma.