CA3181996A1 - Sars-cov-2 inhibitors - Google Patents

Abstract

Polypeptide inhibitors of SARS-CoV-2 are disclosed comprising an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-17, 19-21, 23-34 and 100-101, and their use for treating and limiting development of SARS-CoV-2 infection.

Description

SARS-COV-2 inhibitors Cross reference This application claims priority to U.S. Provisional Patent Application Serial Nos.
63/051,474 filed July 14, 2020 and 63/067,593 filed August 19, 2020, each incorporated by reference herein in its entirety.
Federal Funding Statement This invention was made with government support under Grant No. FA8750-17-C-0219, awarded by the Defense Advanced Research Projects Agency and Grant Nos.
HHSN272201700059C and ROI GM120553, awarded by the National Institutes of Health.
The government has certain rights in the invention.
Sequence Listing Statement:
A computer readable form of the Sequence Listing is filed with this application by electronic submission and is incorporated into this application by reference in its entirety. The Sequence Listing is contained in the file created on May 25, 2021, having the file name "20-1074-WO SegList ST25" and is 1,112kb in size.
Background SARS -CoV-2 infection is thought to often start in the nose, with virus replicating there for several before spreading to the broader respiratory system. Delivery of a high concentration of a viral inhibitor into the nose and into the respiratory system generally could therefore potentially provide prophylactic protection, and therapeutic efficacy early in infection, and could be particularly useful for health care workers and others coming into frequent contact with infected individuals.
Summary In a first aspect the disclosure provides polypeptides comprising an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:1-17, 19-21, 23-34 and 100-101, wherein the polypeptide binds to SARS-CoV-2 Spike glycoprotein receptor binding domain (RBD). In one embodiment, amino acid substitutions relative to the reference polypeptide amino acid sequence are selected from the exemplary amino acid substitutions provided in Table 1. In another embodiment, interface residues are identical to those in the reference polypeptide or are conservatively substituted relative to interface residues in the reference polypeptide. In a further embodiment the polypeptides comprise two or more copies of the amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-17, 19-21, 23-34 and 100-101. In one embodiment, the polypeptide comprises the formula Z1-Z2-Z3, wherein:
Z1 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-17, 19-21, 23-34 and 100-164;
Z2 comprises an optional amino acid linker; and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-17, 19-21, 23-34 and 100-164;
wherein Z1 and Z3 may be identical or different.
In another embodiment, the polypeptides comprises the formula B1-B2-Z1-Z2-Z3-B3-B4, wherein:
Z1, Z2, and Z3 are as defined;
B2 and B3 comprise optional amino acid linkers; and one or both of B1 and B4 independently comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-17, 19-21, 23-34 and 100-164, wherein one of B1 and B4 may be absent.
In one embodiment, the polypeptides comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:47-60, 193-355 and 454-588, and a genus selected from those recited in the right hand column of Table 8 wherein genus positions Xl, X2, X3, and X4 may be present or absent, and when present may be any sequence of 1 or more amino acids.

2 In another embodiment, the polypeptide comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 356-453 and 595-692, and a genus selected from those recited in the middle column of Table 9 wherein genus positions Xi, X2, X3, and X4 may be present or absent, and when present may be any sequence of 1 or more amino acids.
In a further embodiment, the polypeptide comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 65-96, wherein in embodiments where a secretion signal is present (MARAWIFFLLCLAGRALA; SEQ ID NO:63) it can be replaced with any other secretion signal.
In other aspects, the disclosure provides nucleic acids encoding the polypeptide of the disclosure, expression vectors comprising the nucleic acids operatively linked to a promoter, host cell comprising a polypeptide, nucleic acid, and/or expression vector of the disclosure, oligomers of the polypeptides of the disclosure, compositions comprising 2, 3, 4, or more copies of the polypeptide any embodiment of the disclosure attached to a support, including but not limited to a polypeptide particle support, and pharmaceutical compositions, comprising a polypeptide, nucleic acid, expression vector, host cell, oligomer, and/or composition of the disclosure, and a pharmaceutically acceptable carrier.
In another aspect, the disclosure provides methods for treating or limiting development of a severe acute respiratory syndrome (SARS) coronavirus infection (including SARS-Co-V and SARS-CoV-2), comprising administering to a subject in need thereof an amount of the polypeptide, the nucleic acid, the expression vector, the host cell, the oligomer, the composition, and/or the pharmaceutical composition of the disclosure, effective to treat or limit development of the infection.
Description of the Figures Figure 1. Designed Minibinder Proteins For the SARS-CoV-2 Spike Receptor Binding Domain Designs for approach 1, and approach 2, were encoded in long oligonucleotides, and screened for binding to fluorescently tagged RED on the yeast cell surface. Deep sequencing identified 3 Ace2 helix scaffolded designs (approach 1), and 150 de novo interface designs (approach 2) that were clearly enriched following FACS sorting for RBD binding. Designs were expressed in E. coil and purified, and many were found to have

3 soluble expression, to bind RBD in biolayer interferometry experiments, and could effectively compete with ACE-2 for binding to RBD (example shown in Figure 2).
Based on BLI data (e.g. See Figure 2) the RBD binding affinities of minbinders are:
LCB1 <1M, LCB3 <1M. The affinities of LCB2, LCB4, LCB5, LCB6, LCB7 ,LCB8 range from 1-20nM, with relative strength of different binders being LCB4 > LCB2 > LCB9 =
LCB5 >
LCB6 > LCB7.
Figure 2. High Affinity Binding of De novo Designed Minibinder to SARS-CoV-2 Spike RBD. Biotinylated Spike RBD protein was loaded to a streptavidin biolayer interferometry (BLI) tip (ForteBio Octet) and after washing, the tip was dipped into purified Combo 1 anti-RBD minibinder at different concentrations. After loading the tips were placed into buffer alone. (Left and middle) Response curves indicate ¨Kd of 300 pM
affinity. (Right) If ACE-2 is loaded to RBD tips and then Combo 1 is added, the minibinder rapidly displaces ACE-2 off of the BLI tip.
Figure 3. De novo Designed Minibinder to SARS-CoV-2 Spike RBD is Heat Stable. Purified Combo 1 minibinder was measured for in a circular dichroism spectrometer at 25C, 95C and at 25C after heating to 95C. The CD spectra were all very similar in shape indicating that the protein remains folded in all conditions.
Figure 4. De novo Designed Minibinder to SARS-CoV-2 Spike RBD are Potent in Virus Neutralization Assays. SARS-CoV-2 strain 2019 n-CoV/USA WA1/2020 was obtained from the Centers for Disease Control and Prevention (gift of Natalie Thornburg).
Virus stocks were produced in Vero CCL81 cells (ATCC) and titrated by focus-forming assay on Vero E6 cells. Serial dilutions of mAbs or minibinder were incubated with 102 focus-forming units (FFU) of SARS-CoV-2 for 1 h at 37C. RBD minibinder (or mAb)-virus complexes were added to Vero E6 cell monolayers in 96-well plates and incubated at 37C for 1 h. Subsequently, cells were overlaid with 1% (w/v) methylcellulose in MEM
supplemented with 2% FBS. Plates were harvested 30 h later by removing overlays and fixed with 4% PFA
in PBS for 20 min at room temperature. Plates were washed and sequentially incubated with 11..tg/mL of CR3022 ([l]) anti-S antibody and HRP-conjugated goat anti-human IgG in PBS
supplemented with 0.1% saponin and 0.1% BSA. SARS-CoV-2-infected cell foci were visualized using TrueBlueTm peroxidase substrate (KPL) and quantitated on an ImmunoSpotTm microanalyzer (Cellular Technologies). Data were processed using Prism software (GraphPad PrismTM 8.0).
Figure 5(A-J). LCB1-Fc prophylaxis protects against SARS-CoV-2 infection. (A) Molecular surface representation of three LCB1v1.3 miniproteins bound to individual

4 protomers of the SARS-CoV-2 spike protein trimer (left: side view; right: top view). (B) Binding curves of purified LCB1v1.3 and LCB1-Fc to SARS-CoV-2 RBD as monitored by biolayer interferometry (one experiment performed in technical duplicate). (C) Neutralization curves of LCB1v1.3, LCB1-Fc, or control binder against a SARS-CoV-2 WA1/2020 isolate (EC50 values: 14.4 pM, 7L8 pM, and >10,000 nM respectively; average of two experiments, each performed in duplicate). (D-J) 7 to 8-week-old female and male K18-hACE2 transgenic mice received 250 lig of LCB1-Fc or control binder by i.p. injection one day prior to in.
inoculation with 103 PFU of SARS-CoV-2. Tissues were collected at 4 and 7 dpi.
(D) Weight change following LCB1-Fc administration (mean SEM; n = 8, two experiments:
two-way ANOVA with Sidak's post-test: *** P < 0.001, **** P < 0.0001). (E) Infectious virus measured by plaque assay at 4 or 7 dpi in the lung (n = 8, two experiments:
Mann-Whitney test; *** P < 0.001). (F-J) Viral RNA levels at 4 or 7 dpi in the lung, heart, spleen, brain, or nasal wash (n = 8, two experiments: Mann-Whitney test: ns, not significant, *
P < 0.05, ** P
< 0 .01,*** P <0.001, **** P <0.0001).
Figure 6(A-C). LCB1-Fc prophylaxis prevents SARS-CoV-2-mediated lung disease. (A) Respiratory mechanics parameters: inspiratory capacity, resistance, elastance tissue damping, quasi-static compliance, and pressure-volume loops measured at 7 dpi (n = 3-6, two experiments: two-way ANOVA with Tukey's post-test: ns, not significant, * P < 0.05, ** P < 0.01, *** P < 0.001 between indicated groups). (B) Hematoxylin and eosin staining of lung sections from mice treated at D-1 and collected at 7 dpi with SARS-CoV-2.
Images show low (left) and high (right; boxed region from left) magnification. Scale bars for all images, 100 jim. Representative images from n = 3 mice per group. (C) Heat-map of cytokine mRNA levels from lung tissues of SARS-CoV-2 infected mice at 4 dpi.
For each cytokine, the fold-change was calculated relative to age-matched naïve control animals after normalization to Gapdh and the Log2(fold change) was plotted (n = 8 mice/group relative to n = 3 naïve controls).
Figure 7(A-J). Post-exposure delivery of anti-RBD binders reduces SARS-CoV-2 burden. (A-G) 7 to 8-week-old female and male K18-hACE2 transgenic mice received 250 !As of LCBI-Fc or control binder by i.p. injection one day after i.n.
inoculation with 103 PFU
of SARS-CoV-2. Tissues were collected at 4 or 7 dpi. (A) Weight change following LCB1-Fc administration (mean SEM; n = 6, two experiments: two-way ANOVA with Sidak's post-test: ** P < 0.01, **** P < 0.0001). (B) Infectious virus in the lung measured by plaque assay at 4 or 7 dpi in the lung (n = 6, two experiments: ** P < 0.01). (C-G) Viral RNA levels

5 at 4 or 7 dpi in the lung, heart, spleen, brain, or nasal wash (n = 6, two experiments: Mann-Whitney test: ns, not significant, * P < 0.05, ** P < 0.01). (H) Hematoxylin and eosin staining of lung sections from mice treated at D+1 and collected at 7 dpi with SARS-CoV-2.
Images show low (left) and high (right; boxed region from left) magnification.
Scale bars for all images, 100 um Representative images from n = 3 mice per group. (I-J) 7 to 8-week-old male K18-hACE2 transgenic mice received a single 50 jig i.n. dose of LCB1v1.3 or control binder at one- or two-days post-inoculation with iO3 PFU of SARS-CoV-2. Viral RNA levels at 7 dpi in the lung (I) or nasal wash (J) (n = 6, two experiments: one-way ANOVA: ns, not significant, * P <0.05, **** P < 0.0001).
Figure 8(A-K). Intranasal administration of LCB1v1.3 reduces viral infection even when given 5 days prior to SARS-CoV-2 exposure. (A-D) 7 to 8-week-old female K18-hACE2 transgenic mice received a single i.n. 50 us dose of LCB1v1.3 or control binder at the indicated time prior to i.n. inoculation with 103 PFU of SARS-CoV-2.
Tissues were collected at 4 or 7 dpi and viral RNA levels were determined (n = 5-6 animals per group, two-experiments: two-way ANOVA with Sidak's post-test: ns, not significant, *
P < 0.05, **
P < 0.01, *** P < 0.001, **** P < 0.0001). (E-J) 7 to 8-week-old female K18-hACE2 transgenic mice received the indicated i.n. dose of LCB1v1.3 or control binder at one day prior to i.n. inoculation with 103 PFU of SARS-CoV-2. (E) Weight change following LCB1v1.3 or control binder administration (mean + SEM; n = 6, two experiments:
two-way ANOVA with Sidak's post-test compared to the control binder treated group: **
P < 0.01, **** P < 0.0001). (F-J) Viral RNA levels at 7 dpi in the lung, heart, spleen, brain, or nasal wash (n = 6, two experiments: Kruskal-Wallis ANOVA with Dunn's post-test: * P
< 0.05, **
P < 0.01, *** P < 0.001). (K) Hematoxylin and eosin staining of lung sections from mice treated with a single i.n. 50 jig dose of LCB1v1.3 or control binder at D-1 and collected at 7 dpi with SARS-CoV-2. Images show low (left) and high (right; boxed region from left) magnification. Scale bars for all images, 100 um. Representative images from n = 3 mice per group.
Figure 9(A-H). Immunogenicity of LCB1v1.3 and protection from challenge. (A) Scheme of experimental details. K18-hACE2 transgenic mice (n = 10 to 12 per group) were treated every 3 days with 50 jig of LCB1v1.3 or control binder by i.n.
administration. On day 18 post-treatment, animals were bled and anti-LCB1v1.3 antibodies were measured. The following day, animals were challenged with 103 PFU of SARS-CoV-2, and tissues were collected at 7 dpi. (B) Binding of serum antibodies to LCB1v1.3 as measured by ELISA

6 (three experiments). Dashed line indicated limit of detection of the assay.
(C) Weight change following LCB1v1.3 or control binder administration (mean SEM; two experiments: two-way ANOVA with Sidak's post-test: **** P< 0.0001). (D-H) Viral RNA levels at 7 dpi in the lung, heart, spleen, brain, or nasal wash (two experiments: Mann-Whitney test: * P<
0.05, ** P< 0.01, **** P< 0.0001).
Figure 10(A-M). LCB1v1.3 protects mice against B.1.1.7 variant and WA1/2020 E484K/N501Y/D614G strains. (A) Neutralization of LCB1v1.3 against B.1.1.7 or WA1/2020 E484K/N501Y/D614G SARS-CoV-2 (EC50 values: 802 pM and 667 pM, respectively; mean of two experiments, each performed in duplicate). (B-G) 7 to 8-week-old female K18-hACE2 transgenic mice were treated with a single 50 in. dose of LCB1v1.3 or control binder at 1 day prior to i.n. inoculation with 103 PFU of B.1.1.7.
(B) Weight change following LCB1v1.3 or control binder administration (mean SEM; n = 6, two experiments: two-way ANOVA with Sidak's post-test: *** P< 0.001, **** P<
0.0001). (C-G) Viral RNA levels at 6 dpi in the lung, heart, spleen, nasal wash, or brain (n = 6, two experiments: Mann-Whitney test: * /' < 0.05, ** /' < 0.01). (H-M) 8-week-old male K18-hACE2 transgenic mice were treated with a single 50 j.ig i.n, dose of LCB1v1.3 or control binder at 1 day prior to i.n. inoculation with 103 PFU of WA1/2020 E484K/N501Y/D614G.
(H) Weight change following LCB1v1.3 or control binder administration (mean SEM; n =
6, two experiments: two-way ANOVA with Sidak's post-test: * P< 0.05, **** P<
0.0001).
(I-M) Viral RNA levels at 6 dpi in the lung, heart, spleen, nasal wash, or brain (n = 6, two experiments: Mann-Whitney test: * P< 0.05, ** P< 0.01).
Figure 11. Cytokine and chemokine induction following SARS-CoV-2 infection.
Individual plots for cytokine and chemokine RNA levels in the lungs of SARS-CoV-2 infected mice at 4 dpi following treatment with control or LCB1-Fc binders (n = 8 per group, two experiments: Mann-Whitney test: ns, not significant, * P< 0.05, ** P<
0.01, *** P<
0.001). Data were used to generate the heat-map in Figure 6C.
Figure 12(A-C). Intranasal delivery of LCB1v1.3 at 1 or 2 days post-SARS-CoV-2 infection reduces viral burden, Related to Fig 7. (A-C) 7 to 8-week-old male hACE2 transgenic mice received a single 50 j.ig i.n. dose of LCB1v1.3 or control binder at one- or two-days post-inoculation with 103 PFU of SARS-CoV-2. Viral RNA levels at 7 dpi in the heart (A), spleen (B), or brain (C) (n = 6, two experiments: one-way ANOVA: * P<
0.05, ** P< 0.01).

7

8 Figure 13. Intranasal prophylaxis of LCB1v1.3 reduces weight loss, Related to Fig 8. 7 to 8-week-old female K18-hACE2 transgenic mice received a single 50 tig in. dose of LCB1v1.3 or control binder at the indicated time prior to i.n. inoculation with 103 PFU of SARS-CoV-2. Weight change was recorded daily (mean + SEM; n = 6, two experiments:
two-way ANOVA with Sidak's post-test: * P < 0.05, ** P < 0 .01, *** P < 0.001, **** P <
0.0001).
Figure 14(A-B). Multivalent minibinders simultaneously engage multiple epitopes on the pre-fusion SARS-CoV-2 spike protein resulting in extremely slow dissociation rates.
(A,B) Dissociation of the minibinder construct and the receptor binding domain (RBD) (A) or the hexapro spike protein (S6P) (B) complex was monitored via competition with 100-fold molar excess of untagged M1 using AlphaLISAI'm (Mean SEM, n=3).
Figure 15(A-F). Cryo-EM structures of multivalent minibinders in complex with the SARS-CoV-2 S glycoprotein. (A) Ribbon diagram representations of all three minibinders bound to the RBD. (B) Cryo-EM map of F31-G10 in complex with two RBDs. (C) Cryo-EM
map of F231-P24 in complex with three RBDs. (D) Design model of H2-1 bound to the S
glycoprotein. (E) Cryo-EM map of H2-1 in complex with the S glycoprotein in two orthogonal orientations. (F) Cryo-EM map showing the interacting residues of the H2-1 and S glycoprotein interface.
Figure 16(A-F). Multivalency enhances both the breadth and potency of neutralization against SARS-CoV-2 variants by minibinders. (A) Dissociation of minibinder constructs from S6P variants after 24 hours was measured via competition with untagged H2-0 using AlphaLISA (mean, n=3). Cells containing an X indicate insufficient signal in the no competitor condition to quantify the fraction of protein bound. (B) Competition of minibinder constructs with ACE2 for S6P was measured via ELISA (mean, n=2). (C) Neutralization curves of minibinder constructs against SARS-CoV-2 pseudovirus variants (mean, n=2) (D) Table summarizing neutralization potencies of multivalent minibinder constructs against SARS-CoV-2 pseudovirus variants. N/A indicates an IC50 value above the tested concentration range and an IC50 greater than 50,000 pM. (E) Neutralization curves of minibinder constructs against authentic SARS-CoV-2 isolates (mean, n=2). (F) Table summarizing neutralization potencies of multivalent minibinder constructs against authentic SARS-CoV-2 isolates.
Figure 17(A-C). Top multivalent minibinder candidates are escape resistant and protect mice from SARS-CoV-2 infection via pre-exposure intranasal administration. (A) Plaque assays were performed to isolate VSV-SARS-CoV-2 chimera virus escape mutants against a control neutralizing antibody (2B04) and the F231-P12 and H2-1 multivalent minibinders. Images are representative of 35 replicate wells per multivalent minibinder.
Large plaques, highlighted by black arrows, are indicative of escape. (B, C) K18-hACE2-transgenic mice (n=6/timepoint) were dosed with 50ug H2-0 by intranasal administration (i.n., 2 x 25 Ill doses per nostril, 100 pi total) 24h prior (T-24h) to infection with 103 plaque forming units of SARS-CoV-2 Variants B.1.1.7, B1.351, B.1.1.24 intranasally at Day 0. (B) Daily weight change following infection (mean I SEM; n = 6, two-way ANOVA with Sidak's post-test: * P < 0.05, *** P < 0.001, **** P < 0.0001). (C) After days post infection (6dpi) animals (n=6/timepoint) were sacrificed and analyzed for the presence of SARS-CoV-2 viral RNA by quantitative real time RT-PCR in the lung, heart, spleen, brain, or nasal wash (n = 6: Mann-Whitney test: ns, not significant, * P <0.05, ** P <0.01).
Detailed Description All references cited are herein incorporated by reference in their entirety.
Within this application, unless otherwise stated, the techniques utilized may be found in any of several well-known references such as: Molecular Cloning: A Laboratory Manual (Sambrook, et al., 1989, Cold Spring Harbor Laboratory Press), Gene Expression Technology (Methods in Enzymology, Vol. 185, edited by D. (iioeddel, 1991. Academic Press, San Diego, CA), "Guide to Protein Purification" in Methods in Enzymology (M.P. Deutshcer, ed., (1990) Academic Press, Inc.); PCR Protocols: A Guide to Methods and Applications (Innis, et al.
1990. Academic Press, San Diego, CA), Culture of Animal Cells: A Manual of Basic Technique, 2nd Ed. (R.I. Freshney. 1987. Liss, Inc. New York, NY), Gene Transfer and Expression Protocols, pp. 109-128, ed. E.J. Murray, The Humana Press Inc., Clifton, N.J.), and the Ambion 1998 Catalog (Ambion, Austin, TX).
As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.
As used herein, the amino acid residues are abbreviated as follows: alanine (Ala; A), asparagine (Asn; N), aspartic acid (Asp; D), arginine (Arg; R), cysteine (Cys;
C), glutamic acid (Glu; E), glutamine (Gln; Q), glycine (Gly; G), hi stidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe;
F), proline (Pro;
P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr;
Y), and valine (Val; V).

9 In all embodiments of polypeptides disclosed herein, an N-terminal methionine residue is optional (i.e.: may be present or absent).
All embodiments of any aspect of the disclosure can be used in combination, unless the context clearly dictates otherwise.
Unless the context clearly requires otherwise, throughout the description and the claims, the words 'comprise', 'comprising', and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to". Words using the singular or plural number also include the plural and singular number, respectively. Additionally, the words "herein,"
"above," and "below" and words of similar import, when used in this application, shall refer to this application as a whole and not to any particular portions of the application.
In a first aspect, the disclosure provides polypeptides comprising an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-17, 19-21, 23-34 and 100-101, wherein the polypeptide binds to SARS-CoV-2 Spike glycoprotein receptor binding domain (RBD).
>LCB1-1 DKEWTLQKTYFTMRLLDFMGHAFASMRVSDDTYFFMKKGDFPLLFFAFRLLFFVFR (SEQ ID NC): 1) >LCB1-2 DKEEILNKIYEIMRLLDELGNAEASMRVSDLILEFMKKGDERLLEEAERLLEEVER (SEQ ID NO:2) >LCB1-3 DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKQGDERLLEEAERLLEEVER (SEQ ID NO: 3) >LCB1-4 DKENILQKIYEIMKTLDQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVER (SEQ ID NO: 4) >LCB1-5 DKENILQKIYEIMKTLDQLGHAEASMNVSDLIYEFMKQGDERLLEEAERLLEEVER (SEQ ID NO: 5) LCB1_v1.1 Cys DKENILQKIYEIMKTLDQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEFVERC(SEQ ID NO: 6) >LCB1 v1.2 DKENILQKIYEIMKTLDQLGHAEASMYVSDLIYEFMKQGDERLLEEAERLLEEVER (SEQ ID NO: 7) >LCB1 v1.3 DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVER (SEQ ID NO: 8) >LCB1 v1.4 DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEFMKQGDENLLEEAEQLLQEVER (SEQ ID NO: 9) >LCB1 v1.5 (LCB1 v1.3 with N-link Glycosylation) DKENILQKIYEIMKTLEQLGHAEASMNVSDLIYEFMKQGDERLLEEAERLLEEVER (SEQ ID NO: 10) >LCB2-1 SDDEDSVRYLLYMAELRYEQGNPEKAKKILEMAEFIAKRNNNEELERLVREVKKRL (SEQ ID NO: 11) >LCB2-2 SUDEDAVRYLLYMAELLYKQGNPLEAKKLLhLAL.h1AKRNNNLELLRLVRLVKKRL (ShQ 11) NO: 12) >LCB3-1 NDDELHMLMTDLVYEALHFAKDEEIKKRVFQLFELADKAYKNNDRQKLEKVVEELKELLERLLS (SEQ ID
NO: 13) >LCB3-2 NDDELLMLVTDLVAEALLFAKDEEIKKRVFTLFELADKAYKNNDRDTLSKVVSELKELLERLQ (SEQ ID
NO: 14) > LCB3 v1.2 NDDELHMQMTDLVYEALHFAKDEEIQKHVFQLFEKATKAYKNKDRQKLEKVVEELKELLERLLS (SEQ ID
NO: 15) >LCB3-4 NDDELHMQMTDLVYEALHFAKDEEIQKHVFQLFENATKAYKNKDRQKLEKVVEELKELLERLLS (SEQ ID
NO:16) >LCB3 v1.1 NDDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNNDRQKLEKVVEELKELLERLLS (SEQ ID
NO: 17) >LCB3 v1.3 NDDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKELLERLLS (SEQ ID
NO: 19) >LCB3 v1.4 NDDELHMQMTDLVYEALHKAKDEEFQKHVFQLFEKATKARKNKDRQKLEKVVEELKELLERLLS (SEQ ID
NO:20) >LCB3 v1.5 NDDELHMQMTDLVYEALHKAKDEEMQKRVFQLFEQADKAYKTKDRQKLEKVVEELKELLERLLS (SEQ ID
NO: 21) >LCB4-1 QREKRLKOLEMLLEYAIERNDPYLMFDVAVEMERLAEENNDERIIERAKRILEEYE (SEQ ID NO:23) >LCB4-2 DREERLKYLEMLLELAVERNDPYLIEDVAIELLRLAEENNDERIYERAKRILEEVE (SEQ ID NO:24) >LCB5-1 SLEELKEQVKELKKELSPEMRRLIEEALRFLEEGNPAMAMMVLSDLVYQLGDPRVIDLYMLVTKT (SEQ ID
NO:25) >LCB5-2 SLEEVKEILKELKKELSPEDRRLIEEALRLLEEGNPAMASMVLSDLVFLLGDPRVIELLMLVTKT (SEQ ID
NO:26) >LCB6-1 DREQRLVRELVRLASKENLSPEQILQLFEVLEELLERGVSEEEIRKQLEEVAKELG (SEQ ID NO:27) >LCB6-2 DREQRLVRFLVRLASKFNLSMEQILILFDVLEELLERGVSEEEIRKILEEVAKEL (SEQ ID NO:28) >LCB7-1 DDDIRYLIYMAKLRLEQGNPEEAEKVLEMARFLAERLGMEELLKEVRELLRKIEELR (SEQ ID NO: 29) >LCB7-2 DDDVRYEIYMAKLELEQGNPEEAEKVLESARFAAELEGNEELEKEVRELERKIEELR (SEQ ID NO: 30) >LCB8-1 PIIELLREAKEKNDEFAISDALYLVNELLQRTGDPRLEEVLYLIWRALKEKDPRLLDRAIELFER (SEQ ID
NO:31) >LCB8-2 PVTELLREAKEKNDPMAISDALFLVFELAQRTGDPRLEEVLFLIWRALKEKDPRELDRAIELFER (SEQ ID
NO: 32) >AHB1-1 DEDLEELERLYRKAEEVAKEAKDASRRGDDERAKEQMERAMRLFDQVFELAQELQEKQTDGNRQKATHLDKAVKE
AADELYQRVR(SEQ ID NO:33) >AHB1-2 DEDLEELERLYRKAEEVAKEAEEASRRGDKERAKELLERALHLFDQVFELAQELQEKLIDEKRQKATHLDKAVHE
AADELYQRVR (SEQ ID NO:34) >AHB2-1 ELEERVMHLLDQVSELAHELLHKETGEELQRATBEDKWANEAILELIKSDDEREIREIEEEARRILEHLEELARK
(SEQ ID NO: 100) >AHB2-2 ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIREIEEEARRILEHLEELARK
(SEQ ID NO: 101) As detailed in the examples that follows, the polypeptides bind with high affinity to the SARS-CoV-2 Spike glycoprotein receptor binding domain (RBD).
In all of embodiments herein, the percent identity requirement does not include any additional functional domain that may be incorporated in the polypeptide. In one embodiment, 1, 2, or 3 amino acids may be deleted from the N and/or C
terminus.
The polypeptides have been subjected to extensive mutational analysis as described in the examples that follow, permitting determination of allowable substitutions at each residue within the polypeptide. Exemplary substitutions are as shown in Table 1 (The number denotes the residue number, and the letters denote the single letter amino acids that can be present at that residue). Thus, in one embodiment, amino acid substitutions relative to the reference polypeptide amino acid sequence (i.e.: one of SEQ ID NOS: 1-17, 19-21, 23-34 and 1)0-101) are selected from the exemplary amino acid substitutions provided in Table 1.
Table 1: Exemplary substitutions:
LCB1 (SEQ ID NOS:1-10 and 102-136) 1 -- ArC,D,E,F,G,H,I,K,L,M,N,P,Q,R,S,T,V,WrY
2 -- A,D,E,F,G,H,I,K,L,M,N,P,Q,R,S,T,V,WrY
3 -- A,D,E,F,G,H,K,L,M,N,P,Q,R,S,T,V,WrY
4 -- A,C,D,E,F,G,H,I,K,L,M,N,P,Q,R,S,T,V,W,Y
5 -- A,C,D,E,F,G,H,I,K,L,M,N,P,Q,R,S,T,V,W,Y
6-- ArCrI,L,M,Q,T,V
7 -- ArC,D,E,F,G,H,M,N,P,Q,R,S,V,WrY
8 -- A,C,D,E,F,G,H,I,K,L,M,N,Q,R,S,T,V,W,Y
9 -- C,I,L,M,N,Q,T,V

10 -- C,F,V,WrY

11 -- A,C,D,E,F,G,H,I,K,L,M,N,Q,R,S,T,V,WrY

12 -- ArC,D,H,I,L,M,N,S,T,VrY

13 --

14 -- ArC,D,E,F,G,H,I,K,L,M,N,Q,R,S,T,V,WrY

15 -- A,C,D,E,F,G,H,I,K,L,M,N,Q,R,S,T,V,W,Y

16 -- C,F,I,L,M,T,V

17 -- ArC,D,F,E,G,H,T,K,L,M,N,Q,R,S,T,V,W,Y

18 -- A,C,D,E,F,G,H,I,K,L,M,N,Q,R,S,T,V,WrY

19 -- A,C,D,E,F,G,H,I,K,L,M,N,Q,R,S,T,V,W,Y

20 -- A,C,D,E,F,G,H,K,L,M,N,Q,R,S,T,W

21 -- A, C,D, E, F,G, H, K,L,M,N,Q, R, S,T,V,W,Y

22 -- A, C,D, F, G,H, I,L,M,N, P,Q, S, T,V,W,Y

23 C, E,M,N, P,Q, S,T,V

24 -- A, C,D, E, F,G, H,K, L,M,N, P,Q, R, S, T,V,W, Y

25-- A, C,G,M,N,Q, S,T,V

26 M,N,V

27 -- A, C,D, E, F,G, H, I, K,L,M,N,Q, R, S,T,V,W,Y

28-- A, C,G, L, S, T,V

29 -- C,S,V,W

30--D

31 -- A, C,D, I,K, L,M,N,Q,R, S,T,V,W,Y

32 C, F,H, I, L,M,N, P, T,V

33 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, S,T,V,W,Y

34 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, S,T,V,W,Y

35 -- A, C,D, F, H,M, Q,V,W,Y

36 -- A, C,D, E,G,H, I,L,M,N,Q,R, S, T,V,W,Y

37 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, S,T,V,W,Y

38 -- A, C,D, E, F,G, H, I, K,L,M,N,Q, R, S,T,V,W,Y

39 -- A, C,D, E, F, G, H, K, L,M, N, P, Q, R, S, T, V, W, Y

40 --

41 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, S,T,V,W,Y

42 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, S,T,V,W,Y

43 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, S,T,V,W,Y

44 -- A, C, D, E, F, G, H, I, K, L,M, Q, R, S V, W, Y

45 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y

46 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, S,T,V,W,Y

47-- A, C,G, P, S,T,V

48 -- A, C,D, E, F,G, H, I, K,L,M,N,Q, R, S,T,V,W,Y

49 -- A, C,D, E, F,G, H, I, K,L,M,N,Q, R, S,T,V,W,Y

50 -- A, C,D, E, F,G, H, K,L,M,N,Q, S,T,V,W,Y

51 -- A, C,E, F, G,H, I,K, L,M,N,Q,R, S,T,V,W,Y

52 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, S,T,V,W,Y

53 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, S,T,V,W,Y

54 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, S,T,V,W,Y

55 -- A,C,D,E,F,G,H,I,K,L,M,N,P,Q,R,S,T,V,W,Y

56 -- A,C,D,E,F,G,H,I,K,L,M,N,P,Q,R,S,T,V,W,Y
LCB2 (SEQ ID NOS:11-12) 1 -- A,C,D,E,G,N,P,S,T
2 D,M,P,Q,Y
3 A,D,E,N,Q

4 -- C,D,E,V
-- D
6 -- A, C,D, E,G,N,Q, S,T,V
7 -- A, C,G, I, L,M, P, S, T,V
5 8 -- A, C,E, F,G, Fir I, K, L,M,N,Q, Rr S, T,V,W, Y
9 -- D,N,Y
-- I,L,T
7_1 -- C, E,G, L,M,W
12 -- F,H,Y
10 13 -- E,M,Q,R,V
14 -- A, C,E, F,G,H, I,K,L,M,N,Q,R, S,T,V,W,Y
-- A, C,D,E,G,H, I,K,L,M,N,Q,R, S, T,V
16 -- C,H,L,T
17 -- A, C,D, Er F,G,H,I, K,L,M,N, P, Q, R, S,T,V,W,Y
15 18-- A, C,D, E, F,G, H, I, K,L,M,N,Q, R, S,T,V,W,Y
19 -- A, C,D, Er F,G,H,I, Kr L,M,N,P,Q,R, S,T,V,W,Y
-- A, C,E, F, G,H, I,K,L,M,N,P,Q,R, S, T,V, Y
21 -- A, C,D, E, F,G,H,I, K,L,M,N, P, Q, R, S,T,V,W,Y
22 -- A, C,D, E, G, I, K,L,N,P,Q,R, S, T,V
20 23 -- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, S,T,V,W,Y
24 -- A, C,D, Er F,G,H,I, K,L,M,N, P, Q, R, S,T,V,W,Y
-- A, C,E, G,H, I, K,N, P,Q, R, S,T,Y
26 -- A, C,D, E, F,G,H,I, K,L,M,N, P, Q, R, S,T,V,W,Y
27 -- A, C,D, Er F,G,H,I, K,L,M,N, Q, R, S,T,V,W,Y
25 28 -- H,K,R,T, Y
29 -- C, N, E, H, I, K, L,M, N, P, Q, R, S, T,V, Y
-- A, C,D, Er F,G,H,I, K,L,M,N, P,Q, S,T,V,W,Y
31 -- A, C,D, E, F, G, H, I, K,L,M,N, D, Q, R, S,T,V,Y
32-- F, H, I, K, L,M, P,Q,R,Y
30 33 -- A,C,G,P,S,T
34 -- A, C,D, E, F,G,H,I, K,L,M,N,Q, R, S,T,V,W,Y
-- F, H, Y
36-- A, C,E,Hr I,L,M,S,V
37-- A, C,E, G,H,L,M,Q,R,S,T,V,W
35 38 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
39 -- A, C,D, Er G,H, I,K,L,M,N,P,Q,R, S,T,V
-- A, C,D, Er G,H, I,K,L,M,N,P,Q,R, S,T,V,W,Y
/11 -- A, C,D, Er F,G,H,I, K,L,M,N, P,Q,R, S,T,V,W,Y
42 -- A, C,D, Er F,G,H,I, K,L,M,N, P, Q, R, S,T,V,W,Y
40 42 -- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, S,T,V,W,Y
44 -- A, C,D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T V, W, Y

45-- A, C,E, F, I,L,M,P, S,T,V,W,Y
46 -- A, C,D, E, F,G, H, K,L,M,N, P,Q,R, S,T,V,W,Y
47 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
48 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
49-- A, C,E, F, G,H, I,K, L,M,N, P,Q, R, S,T,V,W,Y
50 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
51 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
52 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
53 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
54 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
55 -- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, S,T,V,W,Y
56 -- A, C,D, E, F,G, H, I, K,L,M,N, P, 0, R, S,T,V,W,Y
LCB3 ( SEQ ID NOS : 13-17 19-21 and 137-163) 1-- C, E, F, I,M,N,T,W
2 -- A, C,D, E,F, G,H, I, K, L,M,N, P,Q, R, S,T,V,W,Y
3 -- D,G,L,M,N, S,Y
4 -- A, C,E, F,H,K,Q,T
5 -- C,E, F,G, H, I, K, L,M, N,Q, R, S,T,V,W,Y
6 -- A, C,D, E,F, G,H, K, L,M,N, P,Q, R, S,T,V,W,Y
7-- A, C,D, F, I, L,M, P,R, S,V,W
8 -- A, C,D, E,F, G,H, K, L,M,N,Q,R, S,T,V,W,Y
9 A,C,E,F,G,H,I,L,M,N,Q,R,S,T,V,Y
10-- A,C,F,G,H,K,M,N,Q,R,S,T,Y
11 -- D, F,H, L,M,N,Q
12 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
13 -- A, F, L,M,N,Q,S,T,V
14 -- A, C, F, G, H,I,K,L,M,N,P ,Q,R,S,T ,V,W ,Y
15 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y

18 -- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, S,T,V,W,Y
19 -- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, S,T,V,W,Y
20 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
21 -- A,C,D,E,F,G,H,I,K,L,M,N,P,Q,R,S,T,V,W,Y
22 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
23 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
24 -- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, S,T,V,W,Y
25 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y

27 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y

28 -- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, S,T,V,W,Y
29 -- A, C,D, E, F,G, I,L,M,N, P, S,T,V,W,Y
30 -- C, E,F,H,L,N, S,W,Y
31 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
32 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
33-- A, C,E, F, I,K, P,Q, S,V,W,Y
34 -- A, D,E, F,G,H,M,N, P,Q, R, S,V,W,Y
35 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
36-- A, C,E, G,H,I,M,N,Q,S,T,V
37 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
38 -- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, S,T,V,W,Y
39 -- A, C,D, E, F,G, H, I, K,L,M,N, P, 0, R, S,T,V,W,Y
40 -- A, C,D, E, F,G, H,K, L,M,N, P,Q, R, S,T,V,W,Y
41 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
42-- A, C,D, E, F,G,H,I, K,L,M,N, P, Q,R, S,T,V,W,Y
43 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
44 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
45 -- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, S,T,V,W,Y
46 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
47 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
48 -- A, C, E, F, G, I, K, L,M,N, P, Q, S,T,V,W
49 -- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, S,T,V,W,Y
50 -- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, S,T,V,W,Y
51 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
52 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
53 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
54 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
55 -- A, C,E, F, G,H, I,K, L,M,N,Q, S,T,V,W,Y
56 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y

57 -- A, C,D, E, F,G, H, K,L,M,N, P, R, S,T,V,W,Y

58 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y

59 -- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, S,T,V,W,Y

60 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y

61 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y

62 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y

63 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y

64 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
LCB4 ( SEQ ID NO:23-24) 1 -- A, C,D, E,F, G,H, K, L,M,N, P,Q, R, S,T,V,W,Y
2 -- A, C,D, E,F, G,H, I, K, L,M,N, P,Q, R, S,T,V,W,Y

3 -- A, C,D, E,F, G,H, K, L,M,N, P,Q, R, S,T,V,W,Y
4 -- A, C,D, E,F, G,H, K, L,M,N, P,Q, R, S,T,V,W,Y
5-- C,D,H,K,N,Q,R,Y
6 -- A, C, F, G, I, K,L,M, P, Q, R, S,T,V,Y
7 -- A, C,D, E, F, G,H, I, K, L,M,N, P,Q,R, S,T,V,W,Y
8 -- A, C,H, I,M,N,Q,R, S,T,V,Y
9 -- A, C,D, G,H, I,K,L,M,N,Q,R, S,T,V,Y
-- A, C,D, E,M,N, P,Q, S,T,V
11-- C, D,G,H,I,K, L,M,N,P,R, S,T,V
10 12 -- F,G,I,L
13 -- F, I,L,M, S,V, Y
14 -- A, C,D, E,G,L,M,N,Q,R, S,T,V
-- C, E,F, G,H, I, L,M, S,V,W,Y
16 -- A, G,T,Y
15 17-- A, C, D, E, F, G, H, I, K,L,M,N,Q, R, S,T,V,W,Y
18 -- A, C,D, E, F,G, H, I, K,L,M,N,Q, R, S,T,V,W,Y
19 -- A, C,D, E, F,G, H, I, K,L,M,N,Q, R, S,T,V,W,Y
-- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, S,T,V,W,Y
21 -- C, D, Q, Y
20 22 -- A, C,D, E, F,G, H, K,L,M,N, P,Q,R, S,T,V,W,Y
23 E, F,H, Y
24 -- A, F,G, L,M,W
-- A, C, K, G, H, I, K,L,M,N,Q, R, S, T,V, Y
26 -- C, F,H, L,N, S,T,V,W
25 27 -- D,Q,W,Y
28-- A, C,D, I, L,V, Y
29-- A, C,E, G,K,L,N,Q, R,S,T
30-- C, I,L,M, P,T,V
31 -- C, D,E
32 -- A, C,E, L,M, Q, S, Y
33 -- A, C,E, F, G,H, I,K, L,M,Q,R, S, T,V, Y
34 C, D,F, G,H,L,M,N, P,R, S, T,W, Y
-- A, C,E, F,G,H, I,K, L,N, P,R,T,V,W
36 -- A, C,G, S,T,V
35 37-- A, C,D, E, G,H, I,K, L,M,N, P,Q, R, S, T,V, Y
38 -- A, C,D, F, F,G, H, K,L,M,N, P,Q,R, S,T,V,W,Y
39 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, S,T,V,W,Y
/10 -- A, C,D, E, F,G, H, I, K,L,M,N,Q, R, S,T,V,Y
41 -- A, C,D, E,G,H,K,N,Q,S,W
42 -- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, S,T,V,W,Y
43 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S, T,V, Y

44 -- A, E, F, G, H, I, K, L,M,N, Q, R, S, T,V
45 -- A, C,E, F, G,H, I,K, L,M,N,Q,R, S,T,V,W,Y
46 -- A, C,D, E, F,G, H, I, K,L,M,N,Q, R, S,T,V,W,Y
47 -- A, C,D, E, F, G, H, I, K, L, M, N, Q, R, S, T, V, W, Y
48 -- A, C,M, S, T,V
49 -- A, H, I, K, R, S, T,V,W, Y
50 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
51 -- A, F, K, L,M, Y
52 -- F, I,K, L,M,V
53 -- A, C,D, E, F,G, H, I, K,L,M,N,Q, S,T,V,W,Y
54 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
55 -- A, C, F, G, H, I, K, L,M,N, 0,R, S,T,V,W,Y
56 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
LCB5 ( SEQ ID NO : 25-26) 1 -- A, C,D, E,F, G,H, I, K, L,M,N, P,Q, R, S,T,V,W,Y
2 -- A, C,D, E,F, G,H, I, K, L,M,N, P,Q, R, S,T,V,W,Y
3 -- A, C,D, E,F, G,H, I, K, L,M,N, P,Q, R, S,T,V,W,Y
4 -- A, C, D, E, F, G, H, I, K, L,M,N, P, Q, R, S, T, V, W, Y
5 -- A, C,D, E,F, G,H, K, L,M,N, P,Q, R, S,T,V,W,Y
6 -- A, C,D, E,F, G,H, I, K, L,M,N, P,Q, R, S,T,V,W,Y
7 -- A, C,D, E,F, G,H, I, K, L,M,N, P,Q, R, S,T,V,W,Y
8 -- A, C,D, E,F, G,H, I, K, L,M,N, P,Q, R, S,T,V,W,Y
9 -- A, C,E, F,G, H, I, L,M,N, Q, S, T,V,W, Y
10 -- A, C,D, E, F,G, H, K,L,M,N, P, R, S,T,V,W,Y
11 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
12 -- A, C,D, E, F,G, H, I, L,M,N, P,Q, R, S,T,V,W,Y
13 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
14 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
15 -- A, C,D, E, F,G, H, K,L,M,N, P, R, S,T,V,W,Y
16 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
17 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
18 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
19 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
20 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
21 -- A, C,D, E, F,G, H, K,L,M,N, P, R, S,T,V,W,Y
22 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
23 -- A, C,D, E, F,G, H, I, L,M,N, P,Q, R, S, T,W, Y
24 -- A, C,D, E, F,G, H, I, L,M,N, P,Q, S,T,V,W,Y
25 -- A,C,D,E,F,G,H,I,K,L,M,N,P,Q,R,S,T,V,W,Y
26 -- A, C,D, E, F,G,H,I, K,L,M,N, P,Q,R, S,T,V,W,Y

27-- A,C,G,H,I,S,T,V
28 -- A, C,D, E, F,G, H, K,L,M,N,Q, R, S,T,V,W,Y
29 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
30 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q,R, S,T,V,W,Y
31-- A, C,E, F,H, I, K,L,M,N,Q, S,T,V,W,Y
32 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
33 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
34 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
35 -- A, C,D, E, F,G, H, I, K,L,M,N,Q, R, S,T,V,W,Y
36 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
37 -- A, C,D, E, F,G, H, L,M,N, P,Q, R, S,T,V,W,Y
36 -- A, C,D, E, G, L,M,N,P,Q, S,T,V,W
39 -- A, C,F, G,L,M,N,S,T,V,W
40 -- A, C,E, F, G,H, I,K, L,M,N,Q,R, T,V, Y
41-- C,H,I,L,M,P,R
42 -- A, C,E, G,H, L,M, P,T,V,Y
43-- C, I,L,M,Q,T,V
44 -- A, C,D, F, G,H, I,M, S,T
45 -- D, Y
46 -- A, C, D, E, , L, R,V
47 -- C, E,G, I,V
48 -- F, I,V,W,Y
49 -- A, C,D, E, F,G, H, K,L,M,N,Q, R, S,T,V,W,Y
50 -- A, C,E, F, G,H, I,K, L,M,N,Q,R, S,T,V,W,Y
51 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y

53 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
54 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
55 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
56-- F, I,L,M,T,V,W
57 -- A, C,D, E, F,G, H,N, P,Q, R, S, T,W, Y
58 -- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, S,T,V,W,Y
59 -- A, C,F, L,M, T,V, Y
60 -- C, F,M,N,V,Y
61 -- A, C,D, E, F,G, H, I, K,L,M,N,Q, R, S,T,V,W,Y
62-- A, C,F, G,I,L,M,S,T,V,W
63 -- A, C,E, E,G,H, I,K, S,T,V,W,Y
64 -- A, C, E, F, G, H, K,L,N, P, R, S, T, W, Y

65 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
LCB6 (SEQ ID NO:27-28) 1 -- A, C,D, E,F, G,H, K, L,M,N, P,Q, R, 2 -- A, C,D, E,F, G,H, K, L,M,N, P,Q, R, 3 E,W
4 -- A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, Y
5 -- A, C,D, E, F, G,H, I, K, L,M,N, P,Q,R, S,T,V,W,Y
6 -- F,L,M,R,S
7 H,T,V
8 -- A, C,D, E,F, G,H, K, L,M,N, P,Q, R, 9 -- E,M
10 -- A, K,L,W
-- D, 12 -- A, C,D, E, F,G, H, I, K,L,M,N, P, 0, R, S,T,V,W,Y

14 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
15-- A, C,D, E, F,G, H, I, K,L,M,N, P, Q,R, S,T,V,W,Y
16 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, 17 -- F,N,P, S
18 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, 20 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, 21 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, S,T,V,W,Y
22 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, 23 C, D,P,Q,R,W
24 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, S,T,V,W,Y
25 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, 26 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, 27 -- D,H,L, S,W
28 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, 29 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, 31 -- K,L, S
32 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, S,T,V,W,Y
33 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, 34 -- A, F,L,T,V
35 C, 36 -- A, C,D, F, F,G, H, I, K,L,M,N, P, Q, R, 37 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, 38 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, 39 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, 40 -- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, 41 -- A, C,D, E, F,G, H, I, K,L,M,N, P,Q,R, S,T,V,W,Y

42 -- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, S,T,V,W,Y
43 -- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, S,T,V,W,Y
44 -- F, I
45 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q,R, S,T,V,W,Y
46-- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
47 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
48 -- L, Q,R, T
49 -- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, S,T,V,W,Y
50 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
51 -- C,V,Y
52 -- A, E,H, K
53 -- A, C,D, E, F,G, H, I, K,L,M,N, P, 0, R, S,T,V,W,Y
54 -- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, S,T,V,W,Y
55-- C, F,H,L,P,W,Y
56-- A, C,D, E, F,G, H, I, K,L,M,N, P, Q,R, S,T,V,W,Y
LCB7 (SEQ ID NO : 29-30) 1 -- A, C,D, E, F, G,H, I, K, L,M,N, P,Q, R, S,T,V,W,Y
2 -- A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, Y
3 -- A, C,D, E, F, G,H, K, L,M,N, P,Q, R, S,T,V,W,Y
4 -- I,T,V
5 -- A, C,D, E, F, G,H, I, K, L,M,N, P,Q, R, S,T,V,W,Y
6 -- A, C,D, E, F, G,H, I, K, L,M,N, P,Q, R, S,T,V,W,Y
7 -- L,P,Y
8 -- A, C,D, E, F, G,H, K, L,M,N, P,Q, R, S,T,V,W,Y
9 -- A, C,D, E, F, G,H, I, K, L,M,N, P,Q, R, 10 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y

12 -- A, C,D, E, F,G, H, I, P, R, S,T,V,W,Y
13 -- A, L, P
14 H, L,R, T, Y
15 -- A, C,D, E, F,G, H, K,L,M,N, P, Q, R, S,T,V,W,Y
16 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
17 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
18 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
19 -- A, C,D, E, F,G, H, K,L,M,N, P, R, S,T,V,W,Y
20 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
21 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
22 -- A, C,D, E, F,G, H, I, K,L,M,N, P, R, S,T,V,W,Y
22 -- A, S
24 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y

25 -- A, C,D, E, F,G, H,I, K,L,M,N, P, Q,R, S,T,V,W,Y
26 C,G,S,V,Y
27 -- K, L,M,W
28 -- A, C,D, E, F, G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
29 -- A, C,D, E, F,G, H,I, K,L,M,N, P, Q,R, S,T,V,W,Y
30 -- A, Y
31 -- A, C,D, E, F,G, H,I, K,L,M,N, P, Q,R, S,T,V,W,Y
32 -- A, C,D, E, F,G, H,I, P, Q,R, S,T,V,W,Y
33 -- A, C, F, I,K,L,V,W
34 -- A, H,L
35 -- A, C,D, E, F,G, H,I, K,L,M,N, P, Q,R, S,T,V,W,Y
36 -- A, C,D, E, F,G, H,I, K,L,M,N, P, 0,R, S,T,V,W,Y
37 -- A, C,D, E, F,G, H,I, K,L,M,N, P, Q,R, S,T,V,W,Y
38 -- A, C,D, E, F,G, H,I, K,L,M,N, P, Q,R, S,T,V,W,Y
39 -- A, C,K, L,M,N
40 -- A, C,D, E, F,G, H,I, K,L,M,N, P, Q,R, S,T,V,W,Y
41 -- A, C,D, E, F,G, H,I, K,L,M,N, P, Q,R, S,T,V,W,Y
42 -- A, C,D, L,V
43 -- A, C,D, E, F, G, H, K,L,M,N, P, Q, R, S,T,V,W,Y
44 -- A, C,D, E, F,G, H,I, K,L,M,N, P, Q,R, S,T,V,W,Y
45 -- A, C,D, E, F,G, H,I, K,L,M,N, P, Q,R, S,T,V,W,Y
46 Q, S,V
47 -- A, C,D, E, F,G, H,I, K,L,M,N, P, Q,R, S,T,V,W,Y
48 -- A, C,D, E, F,G, H,I, K,L,M,N, P, Q,R, S,T,V,W,Y
49 -- E, L
50 -- A, C,D, E, F,G, H,I, P, Q,R, S,T,V,W,Y
51 -- A, C,D, E, F,G, H,I, K,L,M,N, P, Q,R, S,T,V,W,Y
52 -- A, C,D, E, F,G, H,I, K,L,M,N, P, Q,R, S,T,V,W,Y

54 -- A, C,D, F,G, H,I, P, Q,R, S,T,V,W,Y
55 -- A, C,D, E, F,G, H,I, K,L,M,N, P, Q,R, S,T,V,W,Y
56 L,M,N,R
57 -- A, C,D, E, F,G, H,I, K,L,M,N, P, Q,R, S,T,V,W,Y
LCB8 SEQ ID NO: 31-32) 1 -- A, C,D, E,F, G,H, I,K, L,M,N, P,Q,R,S,T,V,W,Y
2 -- C,F,I,L,M, S,V,W,Y
3 -- A, C,E, F,G,H,I,K,L,M,N,P,Q,R,S,T,V,W,Y
4 -- A, C,D, E,F, G,H, I,K, L,M,N,Q,R, S,T,V,W,Y
5 -- A, C,F, G, K,L,M, Q, S, T,V,W,Y
6 -- H,I,K,L,M

7 -- A,H, I, K,L,M,N, P,Q,R,W,Y
8 -- A, C,D, E,F, G,H, I, K, L,M,N,Q,R, S,T,V,W,Y
9 -- A, C, F, G, I, L,M, S, Y
-- A, F,H, K, L,M, Q,R, S
5 11 - - A, C,D, E, F,G, H, I, K,L,M,N,Q, R, S,T,V,W,Y
12 -- A, C,D, E, G,H, I,K, L,M,N,Q,R, S,T,V,W,Y
13-- A, C,D, E, F,G,H,M,N,Q, S,W, Y
14 -- C, D,E,H,N,Q, S
-- A, D,E, F,H, I, L,M,N,P,Q, S,T,V,W,Y
10 16 -- C, F,M,N,R,Y
17 -- A, C, I, L,M,Q, R,V
18 -- A, C,F,11, I,L,M,T,V,Y
19 -- I, Q, S
-- D,N
15 21 -- A, C,G, S,V
22 -- A, C, I, L,M,V
23 -- C, F,R,T,W,Y
24 -- A, C,D, E, F,G, H, I, L,M,N,Q,R, S,T,V,W,Y
25-- C, E, S, T,V,Y
20 26 -- A, C,D, E, F,G,H,N,Q,S,T
27 -- A, C,D, E, G,H, I,K, L,M,N,Q,R, S, T,V
28 - - C, E,F, G,H, I, K,L,M,Q, R,W, Y
29 -- A, C, F, G, H, I, K, L,M,N, Q, R, S, T,V, Y
30-- A, C,E, G,H,K,M,N, P,Q, R, T
31-- A, C,D, E, F,G, H, I, K,L,M,N,Q, R, S, T,V, Y
32-- A, C,D, E, G,H, I,K,N,Q,R, S,T,W
33 -- A, C,E, G,H,K,M,N, P,Q, R, S,W, Y
34 -- C, D,E, F,H,M,N,W,Y
-- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S, T,V, Y
30 36 -- A, C,D, E, F,G, H,K, L,M,N,Q,R, S,T,V,W,Y
37-- F, G,H, I, L,M, S,T,Y
38 -- D, E,H,Q,W,Y
39 -- C, D,E, F,G,H,K,L,M,N, P,Q, R, S,T,V,W,Y
-- A, C,E, G,H, I, K,M, P,V,Y
35 41-- C, F,H, I, K,L,M,R, S,T,V
42 -- E, F, I, T,W,Y
43 -- A, C,D, E, F,H, I,L,M,N,Q,R, S, T,V,W,Y
44 -- C, G, I, K, L,M, T,V, Y
-- G, S,W,Y
40 46-- C, I,K, L,M,N,Q,R, S,T
47-- A, C,E,N,Q,S, T,V

48 -- C, D,E, F, H, L,M,W
49-- C, D,F,H,K,L,M,N, Q,R,T
50-- A, C,D, E,N,Y
51 -- A, C,D, E, F,G, H, I, K,L,M,N, P, Q, R, S, T,V,W, Y
52-- A, C,D, E,G,H, K,L,M,N,Q,R, S, T
53 -- A, C,D, E, F, G, H, I, L,M,N, P,Q, S,T,V,W,Y
54 -- A, C,D, E, F, G, H, I, K,L,M,N, P, Q,R, S,T,V,W,Y
55 -- A, C,D, E, F, G, H, K,L,M,N, P, Q, S,T,V,W,Y
56 -- C, I,L,M
57-- A, C,D,E,G,I,N,Q, S,T
58 -- A, C,D, E, F, G, H, I, K,L,M,N, P, Q, R, S,T,V,W,Y
59 -- A,C,G,P,S
60 -- A, C,E, F,G,I, L,M,N,Q, S,T,V
61 -- A, C,D, E, F, G, H, I, K,L,M,N, P, Q,R, S,T,V,W,Y
62-- A, C,D, E, F,G,H,I, K,L,M,N,Q, R, S,T,V,W,Y
63 -- A, C,E, F,G,H, I,L,M,N,Q, S,T,V,W,Y
64 -- A, C,D, E,G,H, I,K,L,M,N,P,Q,S,T,V
65 -- A, C,D, E,G,H, I,K, L,M,N, P,Q, R, S,T,W,Y
AHB1 (SEQ ID NOS : 33-34 ) 1 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y
2 -- A, C, D, E, F, G, H, I, K, L,M, N, P,Q,R, S,T,V,W,Y
3 -- A, C, D, E, F, G, H, I, K, L,M, N, P,Q,R, S,T,V,W,Y
4 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y
5 -- C, D,E, F, G, H, K, L,M,N, P, Q, R, S,T,V,W,Y
6 -- A, C, D, E, F, G, H, I, K, L,M, N, P,Q,R, S,T,V,Tar Y
7 -- A, C, D, E, F ,G,H,I, K, L,M, NT, P,Q,R, S,T,V,W,Y
8 -- A, C, D, E, F ,G,H,I,K, L,M, NT, P, Q, R, S,T,V,W,Y
9 -- A, C, D, E, F, G, H, I, K, L,M, N, P,Q,R, S,T,V,W,Y
10 -- A, C, F,H, I,K, S,T,V,W,Y
11 -- F,N,Y
12 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y
13 -- A, C, D, E, F, G, H, I, K, L,M, N, P,Q,R, S,T,V,W,Y
14 -- A, D,G
15 -- A, C, D,E, G,H, I,K,L,M,N, Q,R, S, T,V
16 -- A, C, D, E, F, G, H, I, K, L,M, N, P,Q,R, S,T,V,W,Y
17 -- A, C, D,E, F, G, H, K, L,M,N, Q, R, S,T,V,W,Y
18 -- A, C, D,E, F, G, H, I, L,M,N, S,T,V,W,Y
19 -- A, C, D, E, F, G, H, I, K, L,M, N, P,Q,R, S,T,V,W,Y
20 -- A, C, D,E, F, G, H, K, L,M,N, P, Q, R, S,T,V,W,Y
21 -- A, C, E, G, S,V

22 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y
23 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y
24 -- A, C, D,E, F,H, K,L,M,N,Q, R, S, T,V, Y
25 -- A, C, D, F, G,H, L,M, N, Q, R, S, T, V, W, Y
26 -- A, C, D,E, F,G, H, I , K, L,M, N, P, Q, R, S,T,V,W,Y
27 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y
28 -- A, C, D,E, F,G, H,K, L,M,N, P, Q, R, S,T,Y
29 -- A, C, D,E, F,G, H, I , K, L,M,N,Q,R, S,T,V,W,Y
30 -- A, D, E, E, G,H, I, K, L,M,N, P, Q, R, S,T,V,W,Y
31 -- A, C, D,E, F,G, H, I , K, L,M, N, P, Q, R, S,T,V,W,Y
32 -- A, C, D,E, F,G, H, I , K, L,M, N, P, Q, R, S,T,V,W,Y
33 -- A, G, S
34 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y
35 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y
36 -- A, C, D, E, F, G, H,K, L, M, N, P, 0, R, S, T, V, W, Y
37 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y
38 -- A, C, E,G, H,M, P,Q
39 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y
40 -- A, C, D, E, G,K, N,Q, R, S, T
41 -- A, C, D,E, F,G, H, I , L,M,N, P,Q, S,T,V,W,Y
42 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y
43 -- A, C, D, E, F, G, H, I, K, L,M,N,Q, S,T,V,W,Y
44 -- E, F, H,Q, S,W, Y
45 -- D,N
46 -- A, C, D,E, F,G, H, I , K, L,M, N, P, Q, R, S,T,V,W,Y
47 -- C,T,V
48 -- F, S,W, Y
49 -- A, C, D,E, F,G, H, I , K, L,M,N,Q,R, S,T,V,W,Y
50 -- A, C, F,H, I , K, L,M,N,Q,R, S,T,V,W,Y
51 -- A, ID, G,H, N, S
52 -- H, K,Q,R
53 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y
54 -- A, C, H, I, K,L,M,N, P, Q, R, S, T,V
55 -- A, C, E,G, H,K,N,Q,R, S, T
56 -- A, C, D,E, F,G, H, I , K, L,M, N, P, Q, R, S,T,V,W,Y
57 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y
58 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y
59 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y
60 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y
61 -- A, ID, E,F, G,H, I, K, L,M,N, P, Q, R, S,T,V,W,Y
62 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y

63 -- A, C, D, E, F,G, H, , K, L,M, N, P, Q, R, S,T,V,W,Y
64 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y
65 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y

66 -- A, C, D,E, F,G,H,I, K, L,M, N, P, Q, R, S, T, V,W, Y

67 -- A, C, D, E, F,G, H, I , K, L,M, P, Q, R, S,T,V,W,Y

68 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y

69 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, 5, T,V,W, Y

70 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y

71 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y

72 -- A, C, D, E, F,G, H, I , K, L,M, P, Q, R, S,T,V,W,Y

73 -- A, C,D,E, F, G, H, I, K, L,M, N, P,Q,R, S,T,V,W,Y

74 -- A, C, D, E, F, G, H, I, K, L,M, N, P, 0,R, S,T,V,W,Y

75 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y

76 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y

77 -- A, C, D,E, F,G,H,I, K, L,M, N, P, Q, R, S, T, V,W, Y

78 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y

79 -- A, C, D, E, F, G, H, I, K, L,M, N, P,Q,R, S,T,V,W,Y
BO -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, 5, T,V,W, Y
61 -- D, E, F, G, H, K, L,M,N, P, Q, R, 5, T, V,W, Y
B2 -- Cr D,E, F,G, H, , K, L,M, N, P, Q, R, S,T,V,Wr Y
33 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y
34 -- A, C, D, E, F, G, H, I, K, L,M, N, P, Q, R, S,T,V,W,Y
85 -- A, C, D, E, F, G, H, I, K, L,M, N, P,Q,R, S,T,V,W,Y
AHB2 (SEQ ID NO:101-102 and 164) 1 C, G,A,V, R,K
2 -- C, P, G,V, I ,M, L,F,Y,W, S,N,Q,D,E,R,H
3 -- C, C,A,V, I , F, S,T,D,E,K
4 -- C, P, G,A, V, I,M, L, F, Y,W, S,T,N,Q,D,E,R,K,H
5 -- C, P, G,A, V,M, S,N, Q,D,E,R,K,H
6 -- G,A,V, I, F, S, T,D,H
7 -- C, P, G,V, ,M, L, F,W, S,T,N,Q,E,R,K,H
8 -- C, P, G,A, V,M, L,Y,W, S, T, 1\T, Q, D, E, R, K, H
9 -- C, P, G,A, V, L, F,W, S, T,N,Q,D,E,R,K,H
10 C, P, G,A, V, I, L,Y,W, S,T,N,E,R,K
11 C, P, G,A, I,M, L, F, Y,W, S,T,N,Q,D,E,R,H
12 -- C, P, G,A, V, I, L,F,Y,W, S, T,N,Q,D,E,R,K,H
13 -- C, F,W, S,T,N, E,H
14 -- C, P,G,A,V,I,Y,S,T,N,D,E,R,H
15 -- C, G,A,V, ,M, L, F, Y,W, S, T,N, Q, D, E, R, K
16 -- C, P, G,A, V, L, F, Y,W, S,T,N,Q,D,E,R,K,H

17 -- C, P,G,A,V,L, Y,W, S,T,Q, D, E, R
18 -- C, P,A,V, I,M, F,Y,N,Q,R, K,H
19 -- C, P,G,A,V,I,M,L, F, Y,W, S,T,N,Q,D,E,R,K,H
20 -- C, P, G,A, V,M, L,Y,W,N,Q, E, R, K, H
21 C, P,G,A,V,I,M,L, F, Y,W, S,N,Q,E,R,K,H
22 C, P,G,A,V,M, L, F, Y, S,T,N,Q,D,E,R,K,H
23 -- C, F, Y,W, S,T,N,Q,E,R,K
24 -- C, F, Y,W, S,Q,E,R,H
25 -- C, P,G,A,V,I,M,L, F, Y,W, S,T,N,Q,D,R,H
26 -- C, G,A,V, L,Y, S,N,D,R,K,H
27 -- C, P,G,A,V,I,M,L, F, Y,W, S,T,N,Q,D,E,R,K,H
28 -- C, P,G,A,V,I,M,L, F, Y,W, S,T,N,Q,D,E,R,K,H
29 -- C, P, G,V, I,M, L,F,Y,W, S, T,N,Q,D,R,K,H
30 -- C, P,G,A,V,I,M,L, F, Y,W, S,T,N,Q,D,E,R,K,H
31 -- C, G,A,V, I,M, L, F,Y ,W ,S, T, 0, E, R, K, H
32 -- P, G,A,V, I,L,W,S,T,D,R,H
33 -- C, F, Y,W, S,T,N,Q,E,R,K,H
34 -- C, G,A,V, I,M, L,F,Y,W, S, T,N,Q,D,E,R,K,H
35 -- C, P, G,A, V, I,M,L, F, Y,W, S, T,N, Q, D, E, R,K,H
36 -- C, P, G,A,V, L, F, Y, S,T,N,Q,D,E,R,H
37 -- C, G,A,V, I,M, L,F,Y,W, S, T,N,Q,D,E,R,K,H
38 -- C, P,G,A,V,I,M,L, F, Y,W, S,T,Q,E,R,K
39 -- C, P,G,A,V,I,W,S,Q,E,R,H
40 -- C, P, G,A,V, I, L,Y,W, S,T,N,D,E,R,K,H
41 -- C, P,G,A,V,I,M,L,Y,W, S, T,N,Q,D,E,R,K,H
42 -- C, P,G,A,V,M, S,T,N,Q,D,E,R,K,H
43 -- C, G,A,V, I,M, L,F,Y,W, S, T,N,Q,D,E,R,K,H
44 -- C, P,G,A,V,I,M,L, F,W, S, T,Q,D,E,R,H
45 -- C, G,A,V, I,M, L,F,Y,W, S, T,N,Q,D,E,R,K,H
46 -- C, F, S,T,Q,E,R,K
47 -- C, G,A,V, I,M, L, F,W, S,T,N,Q,D,E,R,H
48 -- C, P,G,A,V,I,M,L, F, Y,W, S,N,Q,E,R,K
49 C, P,G,A,V,M, L,F,Y,W, S, T,N,Q,D,E,R,K,H
50 -- C, F, Y,W, S,T,N,Q,D,E,R,K,H
51 -- C, G,A,V, I,M, L,F,Y,W, S, T,N,Q,D,E,R,K,H
52 -- C, P,G,A,V,I,M,L, F, Y,W, S,T,N,Q,D,E,R,K,H
53 -- C, F, Y,W, S,T,N,D,E,R,K,H
54 -- C, P,G,A,V,I,M,L, F, Y,W, S,T,N,Q,D,E,R,K,H
55 -- C, P,G,A,V,I,M,L, F,Y, S, T,N,Q,D,E,R,K,H
56 -- C, P,G,A,V,I,M,L, F, Y,W, S,T,N,Q,D,E,R,K,H
57 C, F, Y,W, S,T,N,Q,D,E,R,K,H

58 C, G,A,V, I,M,L,F,Y,W,S,T,N,E,R,K,H
59 -- C, P,G,A,V,I,M,L,F,Y,W,S,T,N,Q,D,E,R,K,H
60 -- C, G,A,V, I,M,L,F,Y,W,S,T,Q,D,E,R,K
61 -- C, P, G,A, V, I,M, L, F, Y,W, S,N,Q,D,E,R,K,H
62 C, G,A,V,L,S,T,N,D,E,K,H
63 -- C, P, G,A,V, I, L, F, Y,W, S, T,N,Q, D, E, R, K,H
64 C, 65 C, G,A,V, I ,M, L, F, Y, S, T, N, R, K, H
66 -- C, P,G,A,V,I,M,L,W,T,Q,E,R
67 -- C, P,G,A,V,I,M,L,F,Y,W,S,T,N,Q,D,E,R,K,H
68 -- C, P, G,A,V, I, L, F, Y,W, S, T,N,Q, D, E, R,H
69 P, G,V,I,M,L,Y,W,S,T,Q,R,K
70 -- C, P,G,A,V,I,M,L,F,Y,W,S,T,N,Q,D,E,R,K,H
71 -- C, G,A,V,L,F,W,S,Q,D,E,R,K
72 -- C,V, I, L, S
73 -- P, G,A.,V, S,T,E
74 -- C,A,L,F,Y,S,T,R,H
75 C, P,G,V, I,L, F,W,S,N,D,E,R,K
The residue numbers of the interface residues which are within 8A to the RBD
target are listed in Table 2 for the various design types. In another embodiment, amino acid residues at the interface residues listed in Table 2 are either identical at that residue to the reference sequence, or may be substituted by a conservative amino acid substitution. Such conservative amino acid substitutions involve replacing a residue by a residue having similar physiochemical characteristics, e g , substituting one aliphatic residue for another (such as Ile, Val, Leu, or Ala for one another), or substitution of one polar residue for another (such as between Lys and Arg; Glu and Asp; or Gin and Asn). Other such conservative substitutions, e.g., substitutions of entire regions having similar hydrophobicity characteristics, are known.
Amino acids can be grouped according to similarities in the properties of their side chains (in A. L. Lehninger, in Biochemistry, second ed., pp. 73-75, Worth Publishers, New York (1975)): (1) non-polar: Ala (A), Val (V), Leu (L), Ile (I), Pro (P), Phe (F), Trp (W), Met (M);
(2) uncharged polar: Gly (G), Ser (S), Thr (T), Cys (C), Tyr (Y), Asn (N), Gln (Q); (3) acidic:
Asp (D), Glu (E); (4) basic: Lys (K), Arg (R), His (H). Alternatively, naturally occurring residues can be divided into groups based on common side-chain properties: (1) hydrophobic:
Norleucine, Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that influence chain orientation: Gly, Pro; (6) aromatic: Trp, Tyr, Phe. Non-conservative substitutions will entail exchanging a member of one of these classes for another class. Particular conservative substitutions include, for example; Ala into Gly or into Ser; Arg into Lys; Asn into Gln or into H is; Asp into Glu; Cys into Ser; Gln into Asn; Glu into Asp; Gly into Ala or into Pro;
His into Asn or into Gln; Ile into Leu or into Val; Leu into Ile or into Val; Lys into Arg, into Gln or into Glu;
Met into Leu, into Tyr or into Ile; Phe into Met, into Leu or into Tyr; Ser into Thr; Thr into Ser; Trp into Tyr; Tyr into Trp; and/or Phe into Val, into Ile or into Leu.
Table 2: Interface residues 'LCB [3, 6, 7, 10, 13, 17, 20, 22, 23, 25, 26, 29, 32, 33, 36], 'LCB2': [1, 2, 5, 6, 9, 12, 13, 16, 20, 32, 35, 39], 'LCB3': [1, 3,4, 6, 7, 10, 11, 13, 14, 15, 18, 27, 30, 33, 34, 37], 'LCB4': [8, 11, 12, 15, 23, 24, 26, 27, 28, 30, 31, 34, 56], 'LCB5': [35, 37, 38, 40, 41, 44, 47, 48, 53, 56, 60, 63], 'LCB6': [3, 4, 7, 8, 11, 12, 14, 15, 21, 24, 25, 28, 31, 32, 35], 'LCB7': [2, 3, 6, 7, 9, 10, 13, 17, 29, 32, 33, 36], 'LCB8': [14, 15, 16, 19, 22, 23, 26, 29, 30, 38, 41, 42, 45], `AHB1', [34, 38, 41, 45, 48, 49, 52, 63, 64, 67, 68, 70, 71, 74, 78, 81, 82, 85], 'AELB2', [4,7, 11, 14, 15, 18, 21, 26, 29, 30, 33, 34, 36, 37, 40, 43, 44, 47, 48].
In one embodiment, amino acid residues at the interface residues listed in Table 2 are identical at that residue to the reference sequence.
In another embodiment, the polypeptide comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:1-10, 13-17, 19-21, 33-34, and 100-101.
In one embodiment, the polypeptides comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:1-10 and 102-136 (see Table 3).
Table 3: LOH exemplary variants Name Binder Protein DKENILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER(SEQ
LCB1 4N ID NO: 102) DKEKILQKIYEIMRLLDELGHAEASMRVSDLIYEEMKKGDERLLEEAERLLEEVER(SEQ
LCB1_4K ID NO: 103) LCB1_14K
DKEWILQKIYEIMKLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER(SEQ

ID NO: 104) DKEWILQKIYEIMRTLDELGHAEASMRVSDLIYEEMKKGDERLLEEAERLLEEVER(SEQ
LCB1_15T ID NO: 105) DKEWILQKIYEIMRLLDQLGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER(SEQ
LCB1 18Q ID NO: 106) DKEWILQKIYEIMRLLDKLGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER(SEQ
LCB1_18K ID NO: 107) DKEWILQKIYEIMRLLDELGHAEASMQVSDLIYEFMKKGDERLLEEAERLLEEVER(SEQ
LCB1 27Q ID NO: 108) DKEWILQKIYEIMRLLDELGHAEASMYVSDLIYEFMKKGDERLLEEAERLLEEVER(SEQ
LCB1_27Y ID NO: 109) DKEWILQKIYEIMRLLEELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER(SEQ
LCB1 17E ID NO: 110) DKEWILQKIYEIMRLLRELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER(SEQ
LCB1_17R ID NO: 111) DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDENLLEEAERLLEEVER(SEQ
LCB1 42N ID NO: 112) DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAEQLLEEVER(SEQ
LCB1 49Q ID NO: 113) DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLQEVER(SEQ
LCB1_52Q ID NO: 114) DKEWILQKIYEIMRLLDELGHAEASMRVSDLLYEFMKKGDERLLEEAERLLEEVER(SEQ
LCB1 32L ID NO: 115) DKEWILQKIYEIMRLLDELGHAEASMRASDLIYEFMKKGDERLLEEAERLLEEVER(SEQ
LCB1_28A ID NO: 116) DKENILQKIYEIMKTLEQLGHAEASMYVSDLIYEFMKQGDERLLEEAERLLEEVER(SEQ
LCB1 v1.3 ACH1 ID NO: 117) DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEFMKQGDENLLEEAERLLEEVER(SEQ
LCB1_v1.3 ACH2 ID NO: 118) DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEFMKQGDERLLEEAEQLLEEVER(SEQ
LCB1_v1.3 ACH3 ID NO: 119) DKENILQKIYEIMKTLEQLGHAEASMYVSDLIYEFMKQGDENLLEEAEQLLEEVER(SEQ
LCB1_v1.3 ACH4 ID NO: 120) DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEFMKQGDENLLEEAEQLLEEVER(SEQ
LCB1_v1.3 ACH5 ID NO: 121) DRENILQKIYEIMKELEKLGHAEASMQVSDLIYEFMQDKDERLLEEAERLLEEVKR(SEQ
LCB1_v1.3 1 ID NO: 122) DRENILQKIYEIMKELRQLGHAEASMQVSDLIYEFMKTKDKRLLEEAERLLEEVER(SEQ
LCB1_v1.3 2 ID NO: 123) DRENILQKIYEIMKTLRRLGHAEASMQVSDLIYEEMQDKDKRLLEEAERLLEEVQR(SEQ
LCB1 v1.3 3 ID NO: 124) DKENVLQKTYETMKELERLGHAEASMQVSDLTYEFMKTKDERLLEEAERLLEEVKR(SEQ
LCB1_v1.3 4 ID NO: 125) DRENILQKIYEIMKTLEKLGHAEASMOASDLIYEEMKTKDERLLEEAERLLEEVOR(SEQ
LCB1_v1.3 5 ID NO: 126) DKENILQKIYEIMKTLRALGHAEASMQVSDLIYEEMQTKDERLLEEAERLLEEVKR(SEQ
LCB1 v1.3 6 ID NO: 127) DKENVLOKIYEIMKTLEKLGHAEASMOVSDLIYEFMOTKDKRLLEEAERLLEEVOR(SEO
LCB1_v1.3 7 ID NO: 128) DRENILQKIYEIMKELEKLGHAEASMQVSDLIYEFMQDKDENLLEEAERLLEEVKR(SEQ
LCB1_v1.3 15 ID NO: 129) DRENTLQKIYEIMKELRQLGHAEASMQVSDLIYEFMKTKDKNLLEEAERLLEEVKR(SEQ
LCB1_v1.3 16 ID NO: 130) DRENILQKIYEIMKTLRRLGHAEASMQVSDLIYEEMQDKDKNLLEEAERLLEEVQR(SEQ
LCB1 v1.3 17 ID NO: 131) DRENILOKIYEIMKTLEKLGHAEASMOASDLIYEFMKTKDENLLEEAERLLEEVOR(SEC
LCB1_v1.3 19 ID NO: 132) DKENILQKIYEIMKTLRALGHAEASMQVSDLIYEEMQTKDENLLEEAERLLEEVKR(SEQ
LCB1_-\71.3_20 ID NO: 133) DKENVLQKIYEIMKTLEKLGHAEASMQVSDLIYEFMQTKDKNLLEEAERLLEEVQR(SEQ
LCB1_v1.3 21 ID NO: 134) DKENVLOKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEVKR(SEQ
LCB1_v2.2 ID NO: 135) DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEVTR(SEQ
LCB1_v2.2 ompT ID NO: 136) The polypeptides may contain a substantial number of mutations while retaining binding activity, as detailed in the examples that follow. In one embodiment, the polypeptide comprises an amino acid substitution relative to the amino acid sequence of SEQ ID NO:1 at 1,2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18 residues selected from the group consisting of 2, 4, 5, 14, 15, 17, 18, 27, 28, 32, 37, 38, 39, 41, 42, 49, 52, and 55. In another embodiment, the substitutions are selected from the substitutions listed in Table 4, either individually (i.e.: any single mutation listed in the Table) or in combinations in a given row.
Table 4: Exemplary LCB1 substitutions Name Parent Mutations from WT

=1_2 LCB1 W4N R14K L151 El8Q R27Y K38Q
LCB1_3 LCB1 W4N R14K L15T 017E E180 R27Q K38Q

LCB1_4N LCBI W4N
LCB1_4K LCB1 W4K
LCB1_14K LCB1 R14K
LCB1_1ST LCB1 LIST
LCB1_18Q LCB1 El8Q
LCB1_18K LCB1 ElOK
LCB1_27Q LCB1 R27Q
LCB1_27Y LCB1 R27Y

L531_17E LCB1 D17E
LCB1_17R LCBI D17R
LCB1_42N LCB1 R42N
L551_49Q LCB1 R49Q
LOB1_52Q LCB1 E52Q
LCB1_32L LCB1 132L
LCB1_28A LCB1 V28A
LOBS v1.3 LOBS W4N R14K LIST 017E E18Q R27Q K38Q
LCBl_v1.3_A0H1 LOBS v13 W4N R14K LiST 017E El8Q R27Y K38Q
LCBl_v1.3_ACH2 LOBl_v1.3 W4N R14K L150 017E E185 R27Q K38Q R42N
LCB1_v1.3_A0113 La31_v1.3 W4N 5145 LIST 0175 5185 R275 K38Q R495 LCBl_v1.3_ACH4 LCBl_v1.3 W4N R14K L150 017E E18Q R27Y K385 R42N R49Q
LCBl_v1.3_ACHS LCBl_v1.3 W4N 5145 L1ST 017E E18Q R275 5385 542N R495 LCB1v1.31 LCB1_v1.3 525 54N 5145 L155 0175 5185 5275 5375 538D

_ _ 40 5555 LCB1 v1.3_2 LCB1 v1.3 K2R 04N 0140 LSE 0170 El8Q R27Q K3BT

LC31_v1.3_3 LC31_v1.3 K2R 04N 0140 L150 11170 0180 R27Q 037Q 0381) LCB1_v1.3_4 LCB1_v1.3 W4N ISV 0140 L15E 11170 E180 R27Q K3BT G39K E55K
LCE1_v1.3_5 LCB1_v1.3 K2R 04N 0140 L150 317E 0180 027Q V28A 038T

LCE1_v1.3_6 LCB1_v1.3 04N 0140 L150 11170 E18A R27Q K37Q K38T G39K

LC111 v1= 3 7 _ LC31 v1.3 04N ISV 0140 LIST 11170 0180 R27Q 037Q

LCB1 v1.3 15 LCB1 v1.3 K21 0411 0140 L15E 317E E180 R27Q K37Q

LCB1 v1.3_16 LCB1 v1.3 0211 0411 0140 L15E 11170 E18Q 1127Q

LCB1_v1.3_17 LC31_v1.3 0211 fi4N 0140 Ll5T 11170 0180 1127Q K37Q 038D G39K

LCB1_v1.3_19 LCB1_v1.3 0211 81411 014K Ll5T 11170 E18K 1127Q V28A

LCB1 v1.3 20 LCB1 vl.3 814N 0140 LIST 11170 E18A R27Q 037Q K3BT G39K

_ E55K
LCBlv1.32_ LCB1_v1.3 W4N ISV 0140 LIST 11170 0180 027Q K37Q 038T G39K
_ _ 0410 R42N E55Q
LcBl_v2.2 L031 _v1.3 04N 15V 0140 L150 1117E 0180 1127Q

L=1_v2.2_oripT LCBl_v1.3 W4N ISV 0140 L15E 11170 E180 027Q K3BT 11390 042N

In another embodiment, the polypeptides comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS. 13-17, 19-21 and 137-163 (see Table 5) Table 5: LCB3 exemplary variants Name Binder Protein NDDELHMQMTDLVYEALHFAKDEEIKKRVFQLFELADKAYKNNDRQKLEKVVEELKELLE
LCB3 8Q RLLS(SEQ ID NO: 137) NDDELHMTMTDLVYEALHFAKDEEIKKRVFQLFELADKAYKNNDRQKLEKVVEELKELLE
LCB3 8T RLLS(SEQ ID NO: 138) NDDELHMLMTDLVYEALHKAKDEEIKKRVFQLFELADKAYKNNDRQKLEKVVEELKELLE
LCB3_19K RLLS(SEQ ID NO: 139) NDDELHMLMTDLVYEALHIAKDEEIKKRVFQLFELADKAYKNNDRQKLEKVVEELKELLE
LCB3_19I RLLS(SEQ ID NO: 140) NDDELHMLMTDLVYEALHFAKDEEFKKRVFQLFELADKAYKNNDRQKLEKVVEELKELLE
LCB3 25F RLLS(SEQ ID NO: 141) NDDELHMLMTDLVYEALHFAKDEEMKKRVFQLFELADKAYKNNDRQKLEKVVEELKELLE
LCB3_25M RLLS(SEQ ID NO: 142) NDDELHMLMTDLVYEALHFAKDEEIQKRVFQLFELADKAYKNNDRQKLEKVVEELKELLE
LCB3 26Q RLLS(SEQ ID NO: 143) NDDELHMLMTDLVYEALHFAKDEEIKKHVFQLFELADKAYKNNDRQKLEKVVEELKELLE
LCB3_28H RLLS(SEQ ID NO: 144) NDDELHMLMTDLVYEALHFAKDEEIKKRVFQLFEKADKAYKNNDRQKLEKVVEELKELLE
LCB3_35K RLLS(SEQ ID NO: 145) NDDELHMLMTDLVYEALHFAKDEEIKKRVFQLFELATKAYKNNDRQKLEKVVEELKELLE

RLLS(SEQ ID NO: 146) NDDELHMLMTDLVYEALHFAKDEEIKKRVFQLFELADKARKNNDRQKLEKVVEELKELLE
LCB3_40R RLLS(SEQ ID NO: 147) NODELHMLMTDLVYEALHFAKDEEIKKRVFQLFELADKAYKNKDRQKLEKVVEELKELLE
LCB3 43K RLLS(SEQ ID NO: 148) NDDELHMLMTDLVYEALHFAKDEEIKKRVFQLFGLADKAYKNNDRQKLEKVVEELKELLE
LCB3_340 RLLS(SEQ ID NO: 149) NDDELHMLMTDLVYEALHFAKDEEIKKRVFQLFYLADKAYKNNDRQKLEKVVEELKELLE
LCB3 34Y RLLS(SEQ ID NO: 150) NDDELHMLMTDLVYEALHFAKDEEIKKRVFQLFTLADKAYKNNDRQKLEKVVEELKELLE
LCB3_34T RLLS(SEQ ID NO: 151) NDDELHMLMTDLVYEALHFAKDEEIKKRVFQLFELADKAYKNNDRQKLKKVVEELKELLE
LCB3_49K RLLS(SEQ ID NO: 152) LCB3_v1.2 AC NDDELHMQMTDLVYEALHFAKDEEIQKHVFQLFGKATKAYKNKDRQKLEKVVEELKELLE
H1 RLLS(SEQ ID NO: 153) LCB3_v1.2 AC NDDELHMQMTDLVYEALHFAKDEEIQKHVFQLFYKATKAYKNKDRQKLEKVVEELKELLE
H2 RLLS(SEQ ID NO: 154) NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKELLE
LCB3_v2.2 RLLS(SEQ ID NO: 155) NDDELHMQMTDLVYEALHFAKTEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKELLE
LCB3_v1.3 2 RLLS(SEQ ID NO: 156) NDDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKARKAYKNKDRQKLEKVVEELKELLE
LCB3_v1.3 3 RLLS(SEQ ID NO: 157) NDDELHMQMTDLVWEALHFAKDEEFQKHVFQLFEKARKAYKNKDRQKLEKVVEELKELLE
LCB3_v1.3 4 RLLS(SEQ ID NO: 158) NDDELHMQMTDLVWEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKELLE
LCB3 v1.3 5 RLLS(SEQ ID NO: 159) NEDELHMQMTDLVWEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKELLE
LCB3_v1.3 6 RLLS(SEQ ID NO: 160) NDDELHMQMTDLVWEALHFAKTEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKELLE
LCB3_v1.3 7 RLLS(SEQ ID NO: 161) NLDELHMQMTDLVYEALHFAKTEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKELLE
LCB3_v1.3 15 RLLS(SEQ ID NO: 162) NIDELLMQVTDLIYEALHFAKDEEFQKHAFQLFEKATKAYKNKDKQKLEKVVEELKELLE
LCB3_v2.3 RILS(SEQ ID NO: 163) The polypeptides may contain a substantial number of mutations while retaining binding activity, as detailed in the examples that follow. In one embodiment, the polypeptide comprises an amino acid substitution relative to the amino acid sequence of SEQ ID NO:13 at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or all 20 residues selected from the group consisting 2, 6, 8, 9, 13, 14, 19, 22, 25, 26, 28, 29, 34, 35, 37, 40, 43, 45, 49, and 62. In another embodiment, the substitutions are selected from the substitutions listed in Table 6, either individually or in combinations in a given row.
Table 6: Exemplary LCB3 substitutions Name Parent Mutations from WT
LC33_1 LC33 LOQ I25F 1{26Q R2BH L3514 D37T
LC33_2 LCB3 LOQ K26Q R2811 L35K D37T N43K
LC33_3 LC33 L8Q I25F K26Q R2BH L35K D37T N43K

Y4OR, LC334 LCB3 L8Q Fl9K I25F K26Q R2811 L35K 037T
_ LC53_8Q LCB3 L8U
LC33_8T LC33 LET
L033_19K LC33 Fl9K

LC33_25F LC33 I2SF
LC33_25M LCB3 I25M
LC33_26Q LCB3 K26Q
LC33_28H LCB3 R28H
LC33_35K LC33 L35K
LC33_37T LC33 13370 LC33_40R LC33 Y4OR
LC33_43K LC33 N431( LC33_34Y LCB3 134Y
LC33_34T LCB3 E34?
LC33_49K LC33 E49K
LC33_v1.2 LCB3 LEO K260 R2811 L35K 937T N43K
LC33_v1.2_ACH1 LC33_v1.2 LEO K260 R28H E34G L35K D37T N43K
LC33_v1.2_AC112 LC33_v1.2 L8Q K260 R28H E34Y L35K 037T N43K
LC33_v2.2 LC33_v1.3 92L L8Q 1251 K26Q R2811 L35K 037T N43K
LC33 v1.3_2 LC23_v1.3 L8Q 022T I25F K26Q R28H

LC33_v1.3_3 LC33_v1.3 L8Q I2SF K26Q R28H L35K 037R N43K
LC33_v1.3_4 LC33_v1.3 LEO Y14W I25F K26Q R28H L35K 037R N43K
LC33_v1.3_5 LC33_vi.3 L6Q Y140 I25F K26Q R28H L35K 1337T N43K
1337 T, LC33_v1.3_6 LCB3_v1.3 D2E L8Q Y14W 125F K26Q R2811 L35K N43K
D37T, LC33_v1.3 7 LCB3_v1.3 LEO Y1413 322T I25F K26Q

LC33_v1.3 LC33_v1.2 LEO I25F K260 R28H L35K 1337T N43K
LC33v1.315 LCB3 v1.3 02L LEO D22T I25F K26Q
R28H L35K 537T, _ _ _ R28H, V29A, L35K, 1337 T, N43K, R45K, LC33_v2.3 LOSS v2.1 52I H6L LEO M9V V131 I25F

In a further embodiment, the polypeptides comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:33-34 and 100-101 and 164 (see Table 7).

Table 7: AHB2 exemplary variant EEEAARI LEH
v2 LEELART (SEQ ID NO: 164) In one embodiment, the polypeptide comprises an amino acid substitution relative to the amino acid sequence of SEQ ID NO:101 at or both residues selected from the group consisting 63 and 75. In a further embodiment, the substitutions comprise R63A
and/or K75T.
In all embodiments disclosed herein, the polypeptides may comprise one or more additional functional groups or residues as deemed appropriate for an intended use. In one embodiment, the polypeptides may further comprise one or more added cysteine residues at the N-terminus and/or C-terminus. In another embodiment, the polypeptides may further comprise an N-linked glycosylation site (i.e.: NX(S/T), where X is any amino acid).
In another embodiment, the polypeptides may comprise two or more (i.e.: 2, 3, 4, 5, or more) copies of the amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%,

80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-17, 19-21, 23-34 and 100-101. In this embodiment, 2 or more of the binders are linked. In one embodiment, the two or more copies of the polypeptide are all identical; in another embodiment, the two or more copies of the polypeptide are not all identical. In any of these embodiments, the two or more copies of the polypeptide may be separated by amino acid linker sequences, though such linkers are not required. The amino acid linkers may be of any length and amino acid composition as suitable for an intended purpose. In one embodiment, the amino acid linkers are independently between 2-100 or 3-100 amino acids in length.
In another embodiment, the amino acid linker sequences comprise Gly-Ser rich (at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% Gly-Ser residues) amino acid linkers. In a further embodiment, the Gly-Ser rich linkers comprise an amino acid sequence selected from the group consisting of GG and SEQ ID NOs.35-46 and 165-GSGS (SEQ ID NO:35) GGSGGS (SEQ ID NO:36) SGGSGGSGGSG (SEQ ID NO:37) GGSGGSGSGGSG (SEQ ID NO:38) GGSGSSGGSGSGSG (SEC ID NO:39) GGSGSGGSGSGSGGS (SEQ ID NO:40) SGGSGSGSGGSGSGS (SEQ ID NO:41) GGGSGGGSSGGSGGSSGGGSGGGS (SEQ ID NO:42) GGGSGGGGSGGGGSGGGGSGGGGSGGGGSG (SEQ ID NO:43) GGGSGGGSGGSGGSGGGSGGGSGSGGSGGGGSGGGS (SEQ ID NO: 44) GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGsGGGGSGGGGSGGGGSGGGGSGGGGS
(SEQ ID
NO: 45) SGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGS
(SEQ
ID NO:46) GGSGGGGSGGGGSGGGGSGG (SEQ ID NO: 165) GGSGGGGSGGGGSGG(SEO ID NO: 166) GGSGGGGSGG(SEQ ID NO: 167) GGGGSGGGG(SEQ ID NO: 168) GGGSGGG(SEQ ID NO: 169) GGSGG(SEO ID NO: 170) GGSGSSG(SEQ ID NO: 171) In another embodiment, the amino acid linker sequences may comprise Pro-rich (at least 15%, 20%, 25%, or greater Pro residues) amino acid linkers. Non-limiting and exemplary embodiments may comprise an amino acid sequence selected from the group consisting of SEQ ID NOs:97-98 and 172-176.
AGSGGSGGSGGSPVPSTPPTPSPSTETTPSPSPVPSTPPTPSPSTPPTPSPSPVPSTETTPSPSTETTPSPSASC(SEQ
ID
NO:97) GSGGSGGSGGSPVESTEPTPSPSTEPTESPSGGSGNSSGSGGSPVESTEPTPSESTEPTESPSAS(SEQ ID
NO:98) GGASPAAPAPASPAAPAPSAPAGG (SEQ ID NO: 172) GGASPAAPAPASPAGG(SEO ID NO: 173) GGASPAAPAPGG(SEQ ID NO: 114) GGASPAAPAGG(SEQ ID NO: 175) GGSSGPSTPPTPSPSTPPTPSPSPGGSSG(SEQ ID NO: 176) In further non-limiting embodiments, the amino acid linkers may comprise the amino acid sequence selected from the group consisting of SEQ ID NOS: 99 and 177-178.
GGSSAGSPTSTGTSSATPSGSGIGG(SEQ ID NO: 177) GGSSGEAAAKEAAAKEAAAKGSSGG(SEQ ID NO: 178) GGSSGQIFVKILTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGRILSDYNIQKESTLHLVL
RLRGGGGSSG(SEQ ID NO: 99) In one embodiment, the polypeptide comprises the formula Z1-Z2-Z3, wherein:
Z1 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-17, 19-21, 23-34 and 100-164;
Z2 comprises an optional amino acid linker; and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-17, 19-21, 23-34 and 100-164;
wherein Z1 and Z3 may be identical or different. In one embodiment, Z1 and Z3 are identical; in another embodiment Z1 and Z3 are different. In embodiments where Z1 and Z3 differ, each may be a variant of a given starting monomer (ex: Z1 comprises the amino acid sequence of SEQ ID NO:1 (LCB1), and Z3 comprises the amino acid sequence of SEQ ID
NO: 102-136. Any such combination of the monomers disclosed herein may be used. It will further be understood that the polypeptides may comprise 2, 3, 4, 5, or more monomers of any embodiment disclosed herein. In embodiments where there are 3 or more monomers, all 3 monomers may be identical; 2 monomers may be identical and one may differ, or all 3 monomers may be different.
In one embodiment employing LCB1 and variants thereof, Z1 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-10 and 102-136; and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-10 and 102-136.
In another embodiment employing LCB3 and variants thereof, Z1 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 13-17, 19-21 and 137-163; and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 13-17, 19-21 and 137-163.
In another embodiment employing ATIB and variants thereof, Z1 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 33-34, 100-101, and 164; and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 33-34, 100-101, and 164.
In one embodiment, one of Z1 and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 940/s, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-10 and 102-136; and the other of Z1 and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID
NOS: 13-17, 19-21 and 137-163.
In another embodiment, one of Zl and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-10 and 102-136; and the other of Z1 and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID
NOS: 33-34, 100-100, and 164.
In a further embodiment, one of Z1 and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting SEQ ID NOS: 13-17, 19-21 and 137-163; and the other of Z1 and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID
NOS: 33-34, 100-100, and 164.
In another embodiment of any of the other embodiments disclosed herein, the polypeptide comprises at least 3 monomers (i.e.: 3, 4, 5, or more). In one such embodiment, the polypeptide comprises the formula B1-B2-Z1-Z2-Z3-B3-B4, wherein:
Z1, Z2, and Z3 are as defined above;
B2 and B3 comprise optional amino acid linkers; and one or both of B1 and B4 independently comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: SEQ ID NOS: 1-17, 19-21, 23-34 and 100-164, wherein one of B1 and B4 may be absent. In one embodiment, one of B1 and B4 is absent. In another embodiment, both B1 and B4 are present. In one embodiment, B1 and B4 independently comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-17, 19-21, 23-34 and 100-164. In this embodiment, B1 and B4 may be identical or may be different. In one embodiment, B1 when present and B4 when present, are identical to one or both of Z1 and Z3. In another embodiment, B1 when present and B4 when present, are not identical to either of Z1 and Z3.
In one embodiment, B1 when present, and B4 when present, independently comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-10, 13-17, 19-21, 33-34, 100-101, and 102-164.
In another embodiment, B1 when present, and B4 when present, independently comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-10 and 102-136.
In a further embodiment, B1 when present, and B4 when present, independently comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 13-17, 19-21 and 137-163.
In a still further embodiment, B1 when present, and B4 when present, independently comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 33-34, 100-101, and 164.
In various embodiments when both B1 and B4 are present, = one of B1 and B4 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ
ID NOS: 1-10 and 102-136, and the other comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 13-17, 19-21 and 137-163;
= one of B1 and B4 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ
ID NOS: 1-10 and 102-136, and the other comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 33-34, 100-101, and 164, or = one of B1 and B4 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ
ID NOS: 13-17, 19-21 and 137-163, and the other comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 33-34, 100-101, and 164.
In various non-limiting embodiments, the polypeptides comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:47-60, 193-355, and 454-588 and a genus selected from those recited in the right hand column of Table 8 wherein genus positions Xl, X2, X3, and X4 may be present or absent, and when present may be any sequence of 1 or more amino acids. In all embodiments, any N-terminal methionine residues may be present or absent in the polypeptide. In one embodiment, any N-terminal methionine residues are absent in the polypeptide.
>LCB1-60S-LOB1 DKEWILOKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVERGGSGGSDKEWILOKIYEIMRLLD
ELGH
AEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER (SEQ ID NO: 4I
>LCB1-120S-LCB1 DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEEMKKGDERLLEEAERLLEEVERGGSGGSGSGGSGDKEWILQKIYE
IMRL
LDELGRAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER (SEQ ID NO:48) >LCB1-24GS-LCB1 DKEWILOKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLERAERLLEEVERGGGSGGGSSGGSGGSSGGGSGGG
SDKE
WILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER (SEQ ID NO: 49) >LCB1-36GS-LCB1 DKEWILOKIYEIMRLLDELGHAEASMEVSDLIYEFMKKGDERLLEEAERLLEEVERGGGSGGGSGGSGGSGGGSGGGSG
SGGS
GGGGSGGGSDKEWILOKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLFEVER (SEQ. ID
NO: 50) >LCB1_v1.1-0SLCB1_v1.1(1031) DKENILQKIYEIMKILDQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVERGGGGSGGGGSGGGGSGGGGSGGG
GSGG
GGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSDKENILQKIYEIMKTLDOLGHAEASMQVSDL
IYEF
MKQGDERLLEEAERLLEEVER (SEQ ID NO:51) >LCB1_v1.1-PRO-LCB1_v1.1(1PRO1) DKENILQKIYEIMKILDQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVERAGSGGSGGSGGSPVPSTEPTPSP
STPP
TRSPSPVRSTPRIPSPSTPPTPSPSRVPSTPRTRSESTPRIPSRSASGDKENILQKIYEIMKTLDQLGHAEASMQVSDL
IYEF
MKAGDERLLEEAERLLEEVER (SEQ ID NO:52) >LCB3_v1.2-0S3-L083_v1.2(305:3) NDDELHMQMTDLVYEALHEAKDEEIQKHVFQLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGGGGSGGGGSGGGGS
GGGG
SGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSNDDELHMQMTDLVYEALHFAKDE
EIQK
HVFQLFEKATKAYKNKDRQKLEKVVEELKELLERLLS (SEQ ID NO: 53) >LCB3_v1.2-PRO-LCB3_v1.2(3PRO3) NDDELHMQMIDLVYEALHFAKDEEIQKHVFQLFEKATKAYKNKDRQKLEKVVEELKELLERLLSAGSGGSGGSGGSPVP
STPP
TESPSTPFTPSESEVESTEPTESPSTPETPSFSEVESTPFTESFSTFETPSESASGNDDELHMQMTDLVYEALHFAKDE
EIQK
HVFQLFEKATKAYKNKDRQKLEKVVEELKELLERLLS (SEQ ID NO: 54) >LCB1 v1.1-GS-LCB3 v1.2(1053) DKENILQKIYEIMKILDQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVERGGGGSGGGGSGGGGSGGGGSGGG
GSGG
GGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSNDDELHMQMTDLVYEALHFAKDEEIQKHVFQ
LFEK
ATKAYKNKDRQKLEKVVEELKELLERLLS (SEQ ID NO:55) >LCB3_v1.2-G5-LCBi_v1.1(3GS1) NDDELHMQMIDLVYFALHFAKDEEIQKHVFQLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGGGGSGGGGSGGGGS
GGGG
SGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSDKENILQKIYEIMKTLDQLGHAE
ASMQ
VSDLIYEFMKQGDERLLEEAERLLEEVER (SEQ ID NO:56) >LCB3_v1.2-10GS-LCB1_v1.1(LCB3-GS10-LCB1) NDDELHMQMIDLVYFALHFAKDEEIQKHVFQLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGGSGGSGGSGDKENI
LQKI
YEIMKTLDQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVER (SEQ ID NO: 57) >LCB1 v1.1-PRO-LCB3 v1.2(1PRO3) DKENILQKIYEIMKTLDQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVERAGSGGSGGSGGSPVPSTRPTDSP
STPP
TESPSEVESTPETPSPSTEPTPSPSEVPSTPETESESTPETESESASGNDDELHMQMTDLVYEALHEAKDEEIQKHVFQ
LFEK
ATKAYKNKDRQKLEKVVEELKELLERLLS (SEQ ID NO:58) >LCB3 v1.2-PRO-LCB1 v1.1(3PRO1) NDDELHMQMTDEVYEALHFAKDEEIQKHVFQLEEKATKAYKNKDRQKLEKVVEELKELLERLLSAGSGGSGGSGGSPVP
STPP
TRSBSTBRIBSRSPVRSTRPTESBSTBPTBSRSRVPSTRRIFSRSTRRTRSPSASGDKENILQKIYEIMKTLDQLGHAE
ASMQ
VSDLIYEFMKQGDERLLEEAERLLEEVER (SEQ ID NO:59) >36115(b_LCBi_linker14) DKEWILOKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVERGGSGSSGGSGSGSGDKEWILQKI
YEIM
RLLDELGHAEASMRVSDLIYEEMKKGDERLLEEAERLLEEVERGGSGSSGGSGSGSGDKEWILQKIYEIMRLLDELGHA
EASM
RVSDLIYEbMKKGDERLLEEAERLLEEVERGGSGSSGGSGSGSGDKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEF
MKKG

DERLLEEAERLLEEVERGGSGSSGGSGSGSGDKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAE
RLLE
EVER (SEQ ID NO:60) Table 8. Daisy Chain Designs Annotated: Xl, X2, X3, and X4 may be present or absent, and when present may be any sequence of 1 or Name Protein more amino acids MEKKIGSSAWSHPQFEKGGGSGGGSGGSAWSHPQFE

GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSG MKQGDERLLEEAERLLEEVER(SEQ ID NO:4) ENILQKIYEIMKTLDQLGHAEASMQVSDLIYEFMKQ DKENILQKIYEIMKTLDQLGHAEASMQVSDLIYEF
1GS1 GDERLLEEAERLLEEVER (SEQ ID NO: 193) MKQGDERLLEEAERLLEEVER
(SEQ ID NO:4) MEKKIGSSAWSHPQFEKGGGSGGGSGGSAWSHPQFE

MQVSDLIYEFMKQGDERLLEEAERLLEEVERAGSGG DKENILQKIYEIMKTLDQLGHAEASMQVSDLIYEF
SGGSGGSPVPSTPPTPSPSTPPTPSPSPVPSTPPTP MKQGDERLLEEAERLLEEVER(SEQ ID NO:4)-ENILQKIYEIMKTLDQLGHAEASMQVSDLIYEFMKQ DKENILQKIYEIMKTLDQLGHAEASMQVSDLIYEF
1PRO1 GDERLLEEAERLLEEVER(SEQ ID NO: 194) MKQGDERLLEEAERLLEEVER(SEQ
ID NO:4) MEKKIGSSAWSHRQFEKGGGSGGGSGGSAWSHRQFE

QKHVEQLFEKATKAYKNKDRQKLEKVVEELKELLER NDDELHMQMIDLVYEALHFAKDEEIQKHVFQLFEK
LLSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGG ATKAYKNKDROKLEKVVEELKELLERLLS (SEQ
GSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGG ID NO:15)-X2-SGGGGSNDDELHMQMTDLVYEALHFAKDEEIQKHVF NDDELHMOMIDLVYEALHFAKDEEIQKHVFOLFEK
QLFEKATKAYKNKDRQKLEKVVEELKELLERLLS(S ATKAYKNKDRQKLEKVVEELKELLERLLS (SEQ
3G33 EQ ID NO: 195) ID NO:15) MEKKIGSSAWSHPQFEKGGGSGGGSGGSAWSHPQFE
KGGSGSSGGGGNDDELHMQMTDLVYEALHFAKDEEI Xl-QKHVFQLFEKATKAYKNKDROKLEKVVEELKELLER NDDELHMOMIDLVYEALHFAKDEEIOKHVFOLEEK
LLSAGSGGSGGSGGSPVPSTPPTRSPSTPPTPSPSP ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
VPSTPPTPSPSTPPTPSPSPVPSTPPTPSESTPPTP ID NO:15)-X2-SPSASGNDDELHMQMTDLVYEALHFAKDEEIQKHVF NDDELHMQMTDLVYEALHFAKDEEIQKHVFQLFEK
OLFEKATKAYKNKDROKLEKVVEELKELLERLLS(S ATKAYKNKDROKLEKVVEELKELLERLLS(SEQ
3PRO3 EQ ID NO: 196) ID NO:15) MEKKIGSSAWSHPQFEKGGGSGGGSGGSAWSHPQFE

GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSG MKQGDERLLEEAERLLEEVER(SEQ ID NO:4)-DELHMOMTDLVYEALHFAKDEEIQKHVFQLFEKATK NDDELHMOMIDLVYEALHFAKDEEIOKHVFOLFEK
AYKNKDRQKLEKVVEELKELLERLLS(SEQ ID
ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
1G53 NO: 197) ID NO:15) MEKKIGSSAWSHPQFEKGGGSGGGSGGSAWSHPQFE
KGGSGSSGGGGNDDELHMQMTDLVYEALHFAKDEEI

LLSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGG NDDELHMOMIDLVYEALHFAKDEEIQKHVFQLFEK
GSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGG ATKAYKNKDROKLEKVVEELKELLERLLS(SEQ
SGOGGSDKENILQKIYEIMKTLDQLOHAEASMQVSD ID NO:15)-X2-LIYEFMKQGDERLLEEAERLLEEVER(SEQ ID
DKENILQKIYEIMKTLDQLGHAEASMQVSDLIYEF
3GS1 NO: 198) MKQGDERLLEEAERLLEEVER(SEQ
ID NO:4) MEKKIGSSAWSHPQFEKGGGSGGGSGGSAWSHPQFE

MQVSDLIYEFMKQGDERLLEEAERLLEEVERAGSGG DKENILQKIYEIMKTLDQLGHAEASMQVSDLIYEF
SGGSGGSPVPSTPPTPSPSTPPTPSPSPVPSTPPTP MKQGDERLLEEAERLLEEVER(SEQ ID NO:4)-AYKNKDRQKLEKVVEELKELLERLLS(SEQ ID
ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ

NO: 199) ID NO:15) MEKKIGSSAWSHPQFEKGGGSGGGSGGSAWSHPQFE
KGGSGSSGGGGNDDELHMQMTDLVYEALHFAKDEEI

LLSAGSGGSGGSGGSPVPSTPPTPSPSTPPTPSPSP NDDELHMQMIDLVYEALHFAKDEEIOKHVFQLFEK
VPSTDPTDSPSTRPTDSPSPVDSTETTPSDSTPDTP ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
SPSASGDKENILQKIYEIMKTLDQLGHAEASMQVSD ID NO:15)-X2-LIYEFMKQGDERLLEEAERLLEEVER(SEQ ID
DKENILQKIYEIMKTLDQLGHAEASMQVSDLIYEF
3PRO1 NO: 230) MKQGDERLLEEAERLLEEVER(SEQ
ID NO:4) GSGSSGDKEWILQKIYEIMRLLDELGHAEASMRVSD DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEF
CSL- LIYEFMKKGDERLLEFAERLLEEVERGGGGSGGGGS MKKGDERLLEEAERLLEEVER(SEQ
ID NO:
LCB1- GGGGSDKEWILQKIYEIMRLLDELGHAEASMRVSDL 1)-X2-0515- TYFFMKKGDFRTJFFAFRLLFEVER(SFO ID NO: EKE
WILOKITFIMRLLDFLGHAFASMRVSDLTYFF
LCB1 201) MKKGDERLLEEAERLLEEVER(SEQ
ID NO: 1) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG NDDELHMLMTDLVYEALHFAKDEEIKKRVFQLFEL
GSGSSGNDDELHMLMTDLVYEALHFAKDEEIKKRVF ADKAYKNNDRQKLEKVVEELKELLERLLS (SEQ
CSL- QLFELADKAYKNNDRQKLEKVVEELKELLERLLSGG ID NO:13)-X2-0515- EIKKRVFQLFELADKAYKNNDRQKLEKVVEELKELL ADKAYKNNDRQKLEKVVEELKELLERLLS(SEQ
LCB3 ERLLS(SEQ ID NO: 202) ID NO:13) GSGSSGDKEWILQKIYEIMRLLDELGHAEASMRVSD DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEF
CSL- LIYEFMKKGDERLLEEAERLLEEVERGGGGSGGGGS MKKGDERLLEEAERLLEEVER(SEQ
ID NO:
LCB1- GGGGSGGGGSDKEWILOKIYEIMRLLDELGHAEASM 1)-X2-GS20- RVSDLIYEFMKKGDERLLEEAERLLEEVER(SEQ DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEF
LCB1 ID NO: 203) MKKGDERLLEEAERLLEEVER(SEQ
ID NO: 1) Xl-MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG NDDELHMLMIDLVYEALHFAKDEEIKKRVFQLFEL
GSGSSGNDDELHMLMTDLVYEALHFAKDEEIKKRVF ADKAYKNNDRQKLEKVVEELKELLERLLS(SEQ
CSL- QLFELADKAYKNNDRQKLEKVVEELKELLERLLSGG ID NO:13)-X2-GS20- FAKDEEIKKRVFQLFELADKAYKNNDRQKLEKVVEE ADKAYKNNDRQKLEKVVEELKELLERLLS(SEQ
LCB3 LKELLERLLS(SEQ ID NO: 204) ID NO:13) Xl-DKEWILOKIYEIMRLLDELGHAEASMRVSDLIYEF
MEKKISAWSHPQFEKGGSGSSGDKEWILQKIYEIMR MKKGDERLLEEAERLLEEVER(SEQ ID NO:
CSL- LLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERL 1)-X2-GS20- EIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEE MKKGDERLLEEAERLLEEVER(SEQ ID NO:
LCBI- AERLLEEVERGSSSGGSSSGGSSSGGSSSGDKEWIL 1)-X3-LCBI LLEEAERLLEEVER(SEQ ID NO: 205) MKKGDERLLEEAERLLEEVER(SEQ
ID NO: 1) Xl-NDDELHMLMTDLVYEALHFAKDEEIKKRVFQLFEL
MEKKISAWSHPQFEKGGSGSSGNDDELHMLMTDLVY ADKAYKNNDRQKLEKVVEELKELLERLLS(SEQ
EALHFAKDEEIKKRVFQLFELADKAYKNNDRQKLEK ID NO:13)-X2-CSL- VVEELKELLERLLSGSSGSGSSGSGSSGSGSSGSND DDELHMLMTDLVYEALHFAKDEEIKKRVFQLFELA
LCB3- DELHMLMTDLVYEALHFAKDEEIKKRVFQLFELADK DKAYKNNDRQKLEKVVEELKELLERLLS(SEQ ID

GS20- AYKNNDRQKLEKVVEELKELLERLLSGSSSGGSSSG NO:13)-X3-GS20- KRVFQLFELADKAYKNNDRQKLEKVVEELKELLERL ADKAYKNNDRQKLEKVVEELKELLERLLS(SEQ
LCB3 LS(SEQ ID NO: 206) ID NO:13) GSGSSGDKEWILQKIYEIMRLLDELGHAEASMRVSD DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEF
CSL- LIYEFMKKGDERLLEEAERLLEEVERGSAGGSPAGS MKKGDERLLEEAERLLEEVER(SEQ
ID NO:
LCB1- PTSTGTSTSGDKEWILQKIYEIMRLLDELGHAEASM 1)-X2-XTENx RVSDLIYEFMKKGDERLLEEAERLLEEVER(SEO DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEF
2 ID NO: 207) MKKGDERLLEEAERLLEEVER(SEQ
ID NO: 1) CSL- MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG xi-XTENx LIYEFMKKGDERLLEEAERLLEEVERGSAGGSPAGS MKKGDERLLEEAERLLEEVER(SEQ ID NO: 1) PAGSPTSTGTSGSGDNEWILQKIYEIMRLLDELGELA MKKGDERLLEEAERLLEEVER(SEQ ID NO: 1) EASMRVSDDIYEFMKKGDERLDEEAERLDEEVER(S -X3-EQ ID NO: 208) DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEF
MKKGDERLLEEAERLLEEVER(SEQ ID NO: 1) MEKKISAWSHPQFEKGGGSGGGSGGSAWSEPQFEKG NDDELHMLMTDLVYEALHFAKDEEIKKRVFQLFEL
GSGSSGNDDELHMLMTDLVYEALHFAKDEEIKKRVF ADKAYKNNDRQKLEKVVEELKELLERLLS(SEQ
CSL- QLFELADKAYKNNDRQKLEKVVEELKELLERLLSGS ID NO:13) -X2-XTENx EAKDEEIKKRVFQLFELADKAYKNNDRQKLEKVVEE ADKAYKNNDRQKLEKVVEELKELLERLLS(SEQ
2 LKELLERLLS(SEQ ID NO: 209) ID NO:13) Xl-MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG NDDELHMLMIDLVYEALHFAKDEEIKKRVFQLFEL
GSGSSGNDDELHMLMTDLVYEALHFAKDEEIKKRVF ADKAYKNNDRQKLEKVVEELKELLERLLS(SEQ
QLFELADKAYKNNDRQKLEKVVEELKELLERLLSGS ID NO:13) -X2-AGGSPAGSPISTGTSGSGNDDELHMLMIDLVYEALH NDDELHMLMIDLVYEALHFAKDEEIKKRVFQLFEL
FAKDEEIKKRVFQLFELADKAYKNNDRQKLEKVVEE ADKAYKNNDRQKLEKVVEELKELLERLLS(SEQ
CSL- LKELLERLLSGSAGGSPAGSPTSTGTSGSGNDDELH ID NO:13) -X3-XTENx NURQKLEKVVEELKELLERLLS(SEQ ID NO:
ADKAYKNNDRQKLEKVVEELKELLERLLS(SEQ
3 210) ID NO:13) DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEF
MKKGDERLLEEAERLLEEVER(SEQ ID NO: 1) GS20- GSGSSGSGSSGSDKEWILQKIYEIMRLLDELGHAEA MKKGDERLLEEAERLLEEVER(SEQ ID NO: 1) LCB1- HAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER MKKGDERLLEEAERLLEEVER(SEQ ID NO: 1) LS GGSGSSGSAWSHPQFEK(SEQ ID NO: 211) -X4 Xl-NDDELHMLMIDLVYEALHFAKDEEIKKRVFQLFEL
MEKKISSGNDDELHMLMTDLVYEALHFAKDEEIKKR ADKAYKNNDRQKLEKVVEELKELLERLLS(SEQ
C- VFQLFELADKAYKNNDRQKLEKVVEELKELLERLLS ID NO:

GSSGSGSSGSGSSGSGSSGSNDDELHMLMTDLVYEA NDDELHMLMTDLVYEALHFAKDEEIKKRVFQLFEL
GS20- LHFAKDEEIKKRVFQLFELADKAYKNNDRQKLEKVV ADKAYKNNDRQKLEKVVEELKELLERLLS(SEQ
LCB3- EELKELLERLLSGSSSGGSSSGGSSSGGSSSGNDDE ID NO:13)-X3-LCB3- KNNDRQKLEKVVEELKELLERLLSGGSGSSGSAWSH ADKAYKNNDRQKLEKVVEELKELLERLLS(SEQ
LS PQFEK(SEQ ID NO: 212) ID NO:13)-X4 MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG DKEWILQKIYEIMRLLDELGHAEASMPVSDLIYEF
GSGSSGDKEWILQKIYEIMRLLDELGHAEASMRVSD MKKGDERLLEEAERLLEEVER(SEQ ID NO:
LIYEFMKKGDERLLEEAERLLEEVERGGSSAGSPTS 1)-X2-TGTSSATPSGSGTGGDKEWILQKIYEIMRLLDELGH DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEF
CSL- AEASMRVSDLIYEFMKKGDERLLEEAERLLEEVERG MKKGDERLLEEAERLLEEVER(SEQ
ID NO:
LCB3- GSSAGSPTSTGTSSATPSGSGTGGDKEWILOKIYEI 1)-X3 5x3 RLLEEVER(SEQ ID NO: 213) MKKGDERLLEEAERLLEEVER(SEQ
ID NO: 1) GSGSSGNDDELHMLMTDLVYEALHFAKDEEIKKRVF ELADKAYKNNDRQKLEKVVEELKELLERLLS(SEQ
QLFELADKAYKNNDRQKLEKVVEELKELLERLLSGG ID NO:13)-X2-SSAGSPISIGTSSATPSGSGIGGNDDELHMLMIDLV NDDELHMLMTDLVYEALHFAKDEEIKKRVFQLFEL
YEALHFAKDEEIKKRVFQLFELADKAYKNNDRQKLE ADKAYKNNDRQKLEKVVEELKELLERLLS(SEQ
CSL- KVVEELKELLERLLSGGSSAGSPTSTGTSSATPSGS ID NO:

GTGGNDDELHMLMTDLVYEALHFAKDEEIKKRVFQL NDDELHMLMTDLVYEALHFAKDEEIKKRVFQLFEL
XTEN2 FELADKAYKNNDRQKLEKVVEELKELLERLLS(SEQ ADKAYKNNDRQKLEKVVEELKELLERLLS(SEQ
5x3 ID NO: 214) ID NO:13) v1.3_ LIYEFMKQGDERLLEEAERLLEEVERGGSSGGGSSG MKQGDERLLEEAERLLEEVER (SE0 ID

G3_2X GGSSGGGSSGGGSSGDKENILOKIYEIMKTLEOLGH NO:8)-X2-AEASMVSDLIYEFMKOGDERLLEEAERLLEEVER( DKENILAKIYEIMKTLEOLGHAEASMQVSDLIYEF
SEQ ID NO: 215) MKQGDERLLEEAERLLEEVER(SEQ
ID NO:8) GSGSSGDKENILQKIYEIMKTLEQLGRAFASMQVSD DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEF
LCB1_ LIYEFMKQGDERLLEEAERLLEEVERGGSSAGSPTS MKQGDERLLEEAERLLEEVER(SEQ ID NO:

XTEN_ AEASMQVSDLIYEEMEQGDERLLEEAERLLEEVER( DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEF
2X SEQ ID NO: 216) MKQGDERLLEEAERLLEEVER(SEQ
ID NO:8) GSGSSGDKENILQKIYEIMKTLEQLGHAEASMQVSD DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEF
LCB1_ LIYEFMKQGDERLLEEAERLLEEVERGGSSGEAAAK MKQGDERLLEEAERLLEEVER(SEQ ID NO:

FAAAK AFASMOVSDLTYFFMKOGDERLLFEAERLLEEVER( DKENTLOKTYFTMKTLEOLGHAEASMQVSDLTYEF
2X SEQ ID NO: 217) MKQGDERLLEEAERLLEEVER(SEQ
ID NO:8) GSGSSGDKENILQKIYEIMKTLEQLGHAEASMQVSD DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEF
LCB1_ LIYEFMKQGDERLLEEAERLLEEVERGGSSGPSTET MKQGDERLLEEAERLLEEVER(SEQ ID NO:8)-v1.3 TPSPSTPPTPSPSPGGSSGDKENILQKIYEIMKTLE X2-Pro_2 QLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEE DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEF
X VER(SEQ ID NO: 218) MKQGDERLLEEAERLLEEVER(SEQ
ID NO:8) MEKKISAWSHPQFEKGGGSGGGSGGSAWSEPQFEKG
GSGSSGDKENILQKIYEIMKTLEQLGHAEASMQVSD

TLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQR DKENILOKIYEIMKTLEOLGHAEASMQVSDLIYEF
LIFAGKALEDGRTLSDYNIOKESTLHLVLRLRGGGG MKQGDERLLEEAERLLEEVER(SEQ ID NO:8)-LCB1_ SSGDKENILQKIYEIMKTLEQLGHAEASMQVSDLIY X2-v1.3 EFMKQGDERLLEEAERLLEEVER(SEQ ID NO:
DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEF
Ub_2R 219) MKQGDERLLEEAERLLEEVER(SEQ
ID NO:8) MEKKISAWSHPQFEKGGGSGGGSGGSAWSEPQEEKG DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEF
GSGSSGDKENILQKIYEIMKTLEQLGHAEASMQVSD MKQGDERLLEEAERLLEEVER(SEQ ID NO:8)-TGTSSATPSGSGTGGDKENILQKIYEIMKTLEQLGH DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEF
LCH1_ AEASMQVSDLIYEFMKQGDERLLEEAERLLEEVERG MKQGDERLLEEAERLLEEVER(SEQ ID NO:

XTEN_ MKTLEQLGHAEASMQVSDLIYEFMKQGDEPLLEEAE DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEF
3X RLLEEVER(SEQ ID NO: 220) MKQGDERLLEEAERLLEEVER(SEQ
ID NO:8) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEF
GSGSSGDKENILQKIYEIMKTLEQLGHAEASMQVSD MKQGDERLLEEAERLLEEVER(SEQ ID NO:8)-LCB1_ AEASMQVSDLIYEFMKQGDERLLEEAERLLEEVERG MKQGDERLLEEAERLLEEVER(SEQ ID NO:

3X RLLEEVER(SEQ ID NO: 221) MKQGDERLLEEAERLLEEVER(SEQ
ID NO:8) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEF
GSGSSGDKENILQKIYEIMKTLEQLGHAEASMQVSD MKQGDERLLEEAERLLEEVER(SEQ ID NO:0)-LCB1_ QLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEE MKQGDERLLEEAERLLEEVER(SEQ ID NO:

Pro_3 ILQKIYEIMKTLEQLGHAEASMQVSDLIYEFMKQGD DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEF
X ERLLEEAERLLEEVER(SEQ ID NO: 222) MKQGDERLLEEAERLLEEVER(SEQ
ID NO:8) GSGSSGDKENILQKIYEIMKTLEQL0HAEASMQVSD EFMKQGDERLLEEAERLLEEVER(SEQ ID
LIYEFMKQGDERLLEEAERLLEEVERGGSSGQIFVK NO:

v1.3¨ LIFAGKOLEDGRTLSDYNIQKESTLHLVLRLRGGGG MKQGDERLLEEAERLLEEVER(SEQ ID NO:8)-Ub 3X SSGDKENILQKIYEIMKTLEQLGHAEASMQVSDLIY X3-EFMKQGDERLLEEAERLLEEVERGGSSGQIFVKTLT DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEF

GKTITLEVEPSDTIENVKAKIODKEGIPPDWRLIF MKOGDERLLEEAERLLEEVER(SEO ID NO: 8) AGKOLEDGRTLSDYNIOKESTLHLVLRLRGGGGSSG
DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEFM
KQGDERLLEEAERLLEEVER(SEQ ID NO: 223) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHFQFEKG DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
GSGSSGDKENVLQKIYEIMKELERLGHAEASMQVSD MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
LIYEFMKTKDENLLEEAERLLEEVKRGGSSGGGSSG 135)-X2-GGSSGGGSSGGGSSGDKENVLQKIYEIMKELERLGH DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
1GS1_ AEASMQVSDLIYEFMKTKDENLLEEAERLLEEVKR( MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
NTS SEQ ID NO: 224) 135) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
GSqSSGDKENVLOKTYETMKELERLGHAFASMOVSD MKTEDENLLEEAERLLEEVKR(SE0 TD NO:
LIYEFMKTKDENLLEEAERLLEEVKRGGSSGPSTPP 135)-X2-TPSPSTPPTPSPSPGGSSGDKENVLQKIYEIMKELE DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
1Pro1 RLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEE MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
NTS VKR(SEQ ID NO: 225) 135) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
GSGSSGNLDELHMQMTDLVYEALHFAKDEEFQKHVF ATKAYKNKDRQKLEKVVEELKELLERLLS (SEQ
QLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGG ID NO: 155)-X2-SSGGGSSGGGSSGGGSSGGGSSGNLDELHMQMTDLV NLDELHMQMTDLVYEALHFAKDEEFOKHVFOLFEK
3G53_ YEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLE ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
NTS KVVEELKELLERLLS(SEQ ID NO: 226) ID NO: 155) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
GSGSSGNLDELHMQMTDLVYEALHFAKDEEFQKHVF ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
QLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGG ID NO: 155)-X2-3Pro3 TDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDR ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
NTS QKLEKVVEELKELLEPLLS(SEQ ID NO: 227) ID NO: 155) Xl-MEKKIDKENVLQKIYEIMKELERLGHAEASMQVSDL DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
IYEFMKTKDENLLEEAERLLEEVKRGGSSGGGSSGG MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
GSSGGGSSGGGSSGDEENVLQKIYEIMKELERLGILA 135)-X2-EASNWSDLIYEFMKTKDENLLEEAERLLEEVKRGG DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
1GS1_ SGSSGSAWSHPQFEKGGGSGGGSGGSAWSHPQFEK( MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
CTS SEQ ID NO: 228) 135)-X3 Xl-MEKKIDKENVLQKIYEIMKELERLGHAEASMQVSDL DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
IYEFMKTKDENLLEEAERLLEEVKRGGSSGPSTPPT MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
PSPSTPPTPSPSPGGSSGDKENVLQKIYEIMKELER 135)-X2-LGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEV DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
1Pro1 KRGGSGSSGSAWSHPQFEKGGGSGGGSGGSAWSHPQ MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
CTS FEK(SEQ ID NO: 229) 135)-X3 Xl-MEKKINLDELHMQMTDLVYEALHFAKDEEFQKHVFQ NLDELHMOMTDLVYEALHFAKDEEFOKHVFOLFEK
LFEKATKAYKNKDRQKLEKVVEELKELLERLLSGGS ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
SGSGSSGGGSSGGGSSGGGSSGNLDELHMQMTDLVY ID NO: 155)-X2-EALHEAKDEEFQKHVFQLFEKATKAYKNKDRQKLEK NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
3GS3_ VVEELKELLERLLSGGSGSSGSAWSHPQFEKGGGSG ATKAYKNKDRQKLEKVVEELKELLERLL3(SEQ
CTS GGSGGSAWSHPQFEK(SEQ ID NO: 230) ID NO: 155)-X3 Xl-MEKKINLDELHMOMTDLVYEALHFAKDEEFOKHVFQ NLDELHMOMTDLVYEALHFAKDEEFOKHVFOLFEK
LFEKATKAYKNKDRQKLEKVVEELKELLERLLSGGS ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
SGPSTPPTPSPSTPPTPSPSPGGSSGHLDFLHMOMT ID NO: 155)-X2-DLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQ NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
30ro3 KLEKVVEELKELLERLLSGGSGSSGSAWSEPOFEKG ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
CTS GGSGGGSGGSANSHPQFEK(SEQ ID NO: 231) ID NO: 155)-X3 Si_NT LEEVKRGGSSGGGSSGGGSSGGGSSGGGSSGDKENV MKTKDENLLEEAERLLEEVKR(SEQ ID NO:

LQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDE 135)-X2-NLLEEAERLLEEVKRGGSSGGGSGGGqG11S1G DKENVLAKIYEIMKELERLGHAEASMQVSDLIYEF
GSSGDKENVLQKIYEIMKELERLGHAEASMQVSDLI MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
YEFMKTKDENLLEEAERLLEEVKR(SEQ ID NO: 135)-X3-232) DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
135) DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
MEKKISAWSHPQFEKGGSGSSGDKENVLQKIYEIMK MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
ELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERL 135)-X2-LEEVKRGGSSGPSTPPTPSPSTPPTPSPSPGGSSGD DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
KENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMK MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
TKDENLLEEAERLLEEVKEGGSSGPSTPPIPSPSTP 135)-X3-1Pro1 PTPSPSPGGSSGDKENVLQKIYEIMKELERLGHAEA DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF

Pro1_ SMQVSDLIYEFMKTKDENLLEEAERLLEEVKR(SEQ MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
NTS ID NO: 233) 135) Xl-NEDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEK
MEKKISAWSHPQFEKGGSGSSGNLDELHMQMTDEVY ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
EALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEK ID NO: 155)-X2-VVEELKELLERLLSGGSSGGGSSGGGSSGGGSSGGG NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
SSGNEDELHMQMTDLVYEALHFAKDEEFQKHVFQLF ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
EKATKAYKNKDRQKLEKVVEELKELLERLLSGGSSG ID NO: 155)-X3-S3 NT LHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVV ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
EELKELLERLLS(SEQ ID NO: 234) ID NO: 155) NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
MEKKISAWSHPQFEKGGSGSSGNLDELHMQMTDLVY ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
EALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEK ID NO: 155)-X2-VVEELKELLERLLSGGSSGPSTPPTPSPSTPPTPSP NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
SPGGSSGNLDELHMOMTDIVYEALHFAKDEEFOKHV ATKAYKNKDROKT,F.KWEET.KFT.T.F.RT.T.S(SF.0 FQLFEKATKAYKNKDRQKLEKVVEELKELLERLLSG ID NO: 155)-X3-3Pro3 GSSGPSTPPTPSPSTPPTPSPSPGGSSGNLDELHMQ NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK

Pro 3_ MTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKD ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
NTS RQKLEKVVEELKELLERLLS(SEQ ID NO: 235) .. ID NO: 155) DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
MEKKIDKENVLQKIYEIMKELERLGHAEASMQVSDL MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
IYEFMKTKDENLLERAERLLEEVKRGGSSGGGSSGG 135)-X2-GSSGGGSSGGGSSGDKENVLQKIYEIMKELERLGHA DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
EASMQVSDLIYEFMKTKDENLLEEAERLLEEVKRGG MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
SSGGGSSGGGSSGGGSSGGGSSGDKENVLQKIYEIM 135)-X3-S1 CT LLEEVKRGGSGSSGSAWSHPQFEK(SEQ ID NO: MKTKDENLLEEAERLLEEVKR(SEQ
ID NO:
_ 236) 135)-X4 DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
MEKKIDKENVLQKIYEIMKELERLGHAEASMQVSDL MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
IYEFMKTKDENLLEEAERLLEEVKRGGSSGPSTPPT 135)-X2-PSPSTPPTPSPSPGGSSGDKENVLQKIYEIMKELER DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
LGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEV MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
KRGGSSGPSTPPTPSPSTPPTPSPSPGGSSGDKENV 135)-X3-1Pro1 LQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDE DKENVLOKIYEIMKELERLGHAEASMQVSDLIYEF

Prol_ NL1FEAER1JFEVKRGGSGSSGSAWSHPOFEK(SE0 MKTKDENLLFEAFPLLEEVKR(SE0 TD NO:
CTS ID NO: 237) 135)-X4 SGGGSSGGGSSGGGSSGGGSSGNLDELHMQMTDLVY ATKAYKNKDPQKLEKVVEELKELLERLLS(SEQ
EALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEK ID NO: 155)-X2-VVEELKELLERLLSGGSSGGGSSGGGSSGGGSSGGG NLDELHMOMTDLVYEALHFAKDEEFQKHVFQLFEK
SSGNLDELHMAMTDLVYEALHEAKDEEFOKHVFOLF ATKAYKNKDROKLEKVVEELKELLERLLS(SEO
EKATKAYKNKDRQKLEKVVEELKELLERLLSGGSGS ID NO: 155)-X3-SGSAWSKPQFEK(SEQ ID NO: 238) NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
ID NO: 155)-X4 NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
MEKKINLDELHMQMTDLVYEALHFAKDEEFQKHVFQ ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
LFEKATKAYKNKDRQKLEKVVEELKELLERLLSGGS ID NO: 155)-Z2-SGPSTPPTPSPSTPPTPSPSPGGSSGNLDELHMQMT NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
DLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQ ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
KLEKVVEELKELLERLLSGGSSGPSTPPTPSPSTPP ID NO: 155)-X3-39ro3 TPSPSPGGSSGNLDELHMQMTDLVYEALHFAKDEEF NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK

Pro3_ QKHVFQLFEKATKAYKNKDRQKLEKVVEELKELLER ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
CTS LLSGGSGSSGSAWSHPQFEK(SEQ ID NO: 239) ID NO: 155)-Z4 MEKKISAWSHPQFEKGGGSGGGSGGSAWSEPQFEKG DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
GSGSSGDKENVLQKIYEIMKELERLGHAEASMQVSD MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
LIYEFMKTKDENLLEEAERLLEEVKRGGSSGGGSSG 135)-X2-GGSSGGGSSGGGSSGNLDELHMQMTDLVYEALHFAK NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
15S3_ DEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
NTS LLERLLS(SEQ ID NO: 240) ID NO: 155) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
GSGSSGDKENVLQKIYEIMKELERLGHAEASMQVSD MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
LIYEFMKTKDENLLEEAERLLEEVKRGGSSGPSTFF 135)X-2-TPSPSTPPTPSPSPGGSSGNLDELHMQMTDLVYEAL NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
1Pro3 HFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVE ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
NTS ELKELLERLLS(SEQ ID NO: 241) ID NO: 155) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
GSGSSGNLDELHMQMTDLVYEALHFAKDEEFQKHVF ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
QLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGG ID NO: 155)-X2-SSGGGSSGGGSSGGGSSGGGSSGDKENVLQKIYEIM DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
3GS1_ KELERLGHAEASMQVSDLIYEFMKTKDENLLEEAER MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
NTS LLEEVKR(SEQ ID NO: 242) 135) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
GSGSSGNLDELHMQMTDLVYEALHFAKDEEFQKHVF ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
QLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGG ID NO: 155)-X2-SSGPSTPPTPSPSTPPTPSPSPGGSSGDKENVLOKI DKENVLOKIYEIMKELERLGHAEASMOVSDLIYEF
3Prol YEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLE MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
NTS EAERLLEEVKR(SEQ ID NO: 243) 135) MEKKIDKENVLQKIYEIMKELERLGHAEASMQVSDL DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
IYEFMKTKDENLLEEAERLLEEVKRGGSSGGGSSGG MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
GSSGGGSSGGGSSGNLDELHMQMTDLVYEALHFAKD 135)-X2-EEKOKHVEQLFEKATKAYICI-KDRQKLEKVVEELKEL NLDELHMOMTDLVYEALHFAKDEEFQKHVFQLFEK
1GS3 LERLLSGGSGSSGSAWSHPQFEKGGGSGGGSGGSAW ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
CTS SHPQFEK(SEQ ID NO: 244) ID NO: 155)-X3 xl-MEKKIDKENVLQKIYEIMKELEPLGHAEASMQVSDL DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
IYEFMKTKDENLLEEAERLLEEVKRGGSSGPSTPPT MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
PSPSTRPTPSPSPGGSSGNLDELHMQMTDLVYEALH 135)-X2-FAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEE NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
19ro3 LKELLERLLSCCSCSSCSAWSHPQFEKCCGSCCOSC ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
CTS GSAWSHFQFEK(SEQ ID NO: 245) ID NO: 155)-X3 CTS SGGGSSGGGSSGGGSSGGGSSGDKENVLQKIYEIMK
ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
ELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERL ID NO: 155)-Z2-LEEVKRGGSGSSGSAWSHPQEEKGGGSGGGSGGSAW DKENVLOKIYEIMKELERLGHAEASMQVSDLIYEF
SHROFEK(SEA ID NO: 246) MKTKDENLLEEAERLLEEVKR(SEQ
ID NO:
135)-X3 MEKKINLDELHMQMTDLVYEALHFAKDEEFQKHVFQ NLDELHMQMIDLVYEALHFAKDEEFOKHVFQLFEK
LFEKATKAYKNKDRQMLEKVVEELKELLERLLSGGS ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
SGPSTPPTPSPSTPPTPSPSPGGSSGDKENVLQKIY ID NO: 155)-X2-EIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEE DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
32r01 AERLLEEVKRGGSGSSGSAWSHPQFEKGGGSGGGSG MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
CTS GSAWSHPQFEK(SEQ ID NO: 247) 135)-X3 MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG NLDELHMQMIDLVYEALHFAKDEEFOKHVFQLFEK
GSGSSGNLDELHMQMTDLVYEALHFAKDEEFQKHVF ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
3- OLEEKATKAYKNKDROKLEKVVEELKELLFRLLSGG TD NO: 155)-X2-1- SDLIYEFMKTKDENLLEEAERLLEEVKR(SEQ ID
MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
L_NTS NO: 248) 135) GSGSSGNLDELHMQMTDLVYEALHFAKDEEFQKHVF KATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
QLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGG ID NO: 155)-X2-DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
GS10- SDLIYEFMKTKDENLLEEAERLLEEVKR(SEQ ID MKTKDENLLEEAERLLEEVKR(SEQ
ID NO:
1_NTS NO: 249) 135) MEKKISAWSHPOFEKGGGSGGGSGGSAWSHPOFEKG NLDELHMOMIDLVYEALHFAKDEEFOKHVFALFEK
GSGSSGNLDELHMQMTDLVYEALHFAKDEEFQKHVF ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
QLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGG ID NO: 155)-X2-DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
GS15- ASMQVSDLIYEFMKTKDENLLEEAERLLEEVKR(SE MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
1 NTS Q ID NO: 250) 135) Xl-MEKKISAWSHPQFEKGGGSGGGSGGSAWSEPQFEKG NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEK
GSGSSGNLDELHMQMTDLVYEALHFAKDEEFQKHVF ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
QLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGG ID NO: 155)-X2-DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
GS20- LGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEV MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
1_NTS KR(SEQ ID NO: 251) 135) DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEE
MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
GSGSSGDKENVLQKIYEIMKELERLGHAEASMQVSD 135)-X2-DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
GS10- DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFM MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
1_NTS KTKDENLLEEAERLLEEVKR(SEQ ID NO: 252) 135) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
GSGSSGDKENVLQKIYEIMKELERLGHAEASMQVSD MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
LIYEFMKTKDENLLEEAERLLEEVKRGGSSGGGSSG 135)-X2-DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
G515- IYEFMKTKDENLLEEAERLLEEVKR(SEQ ID NO: MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
1_NTS 253) 135) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
GSGSSGDKENVLOKIYEIMKELERLGHAEASMQVSD MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
LIYEFMKTKDENLLEEAERLLEEVKRGGSSGGGSSG 135)-X2-5S20- QVSDLIYEFMKTKDENLLEEAERLLEEVKR(SEQ MKTKDENLLEEAERLLEEVKR(SEQ
ID NO:
1_NTS ID NO: 254) 135) MSKIKSAWSHPQFEKGGGSGGGSGGSAWSHPQEEKG x1-RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL NWWATEMMLELIKSDDEREIREIEEEARRILEHLE

EHLEELARKGGSSGGGSSGDKENVLQKIYEIMKELE ELARK (SEQ ID NO: 101)-X2-RLGHAEASMCVSDLIYEFMKTKDERLLEEAERLLEE DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
VKR(SEA ID NO: 255) MKTKDERLLEFAERLLEEVKR (SEC-) ID
NO:125) MSKIKSAWSHPQFEKGGGSGGGSGGSAWSHPQFFKG FLEFQVMHVLDQVSFLAHELLHKLTGFELFRAAYF
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
RAAYFNWWATEMMLELIKSDDEREIREIEEFARRIL ELARK (SEQ ID NO:101)-X2-DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
1_GS1 MKELERLGHAEASMQVSDLIYEFMKTKDERLLEEAE MKTKDERLLEEAERLLEEVKR (SEQ ID
RLLEEVKR(SEQ ID NO: 256) NO:125) MSKIKSAWSHPQFFKGGGSGGGSGGSAWSHPQFEKG ELEFQVMHVLDQVSFLAHELLHKLTGEELERAAYF
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
RAAYFNWWATFMMLFTJKSDDFRFTRFTFFFARRTL FTARK (SEQ ID NO:101)-X2-DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
1_GS2 KIYEIMKELERLGHAEASMQVSDLIYEFMKTKDERL MKTKDERLLEEAERLLEEVKR (SEQ ID
LEEAERLLEEVKP(SEQ ID NO: 257) NO:125) MSKIKSAWSHDQFEKGGGSGGGSGGSAWSHDQFEKG

RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
EHLEELARKGGSSGGGSSGELEEQVMHVLDQVSELA NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
HELLHKLTGEELERAAYFNWWATEMMLELIKSDDER ELARK(SEQ ID NO:101)-X2-1_GS1 VLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKD NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
O EPLLEEAERLLEEVKR(SEQ ID NO: 258) ELARK(SEQ ID NO:101)-X3 MSKIKSAWSHPOFEKGGGSGGGGGAWSHPOFFKG
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL Xl-EHLEELARKGGSSGGGSSGGGSSGELEEQVMHVLDQ ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
VSELAHELLHKLTGEELERAAYFNWWATEMMLELIK NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
SDDEREIREIEEEARRILEHLEELARKGGSSGGGSS ELARK(SEQ ID NO:101)-X2-1_GS1 LIYEFMKTKDERLLEEAERLLEEVKR(SEQ ID
NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
5 NO: 259) ELARK(SEQ ID NO:101)-X3 MSKIKSAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE
RAAYENWWATEMMLELIKSDDEREIREIEEEARRIL Xl-EHLEELARKGGSSGGGSSGGGSSGGGSSGELEEQVM ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
HVLDQV-SELAHELLHKLTGEELERAAYFNWWATEMM NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
LELIKSDDEREIPEIEEEARRILEHLEELARKGGSS ELARK(SEQ ID NO:101)-X2-1_GS2 HAEASMCVSDLIYEFMKTKDERLLEEAERLLEEVKR NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
O (SEQ ID NO: 260) ELARK(SEQ ID NO:101)-X3 MSKIKSAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG Xl-GSGSSGELEEQVMHVLDQVSELAHELLHKLIGEELE ELEFQVMHVLDQVSFLAHELLHKLTGEELERAAYF
RAAYPNWWATEMMLELIKSDDEREIREIEEEARRIL NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
EHLEELARKGGSSGGGSSGELEEQVMHVLDQVSELA ELARK(SEQ ID NO:101)-X2-ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
2_GS1 EIREIEEEARRILEHLEELARK(SEQ ID NO:
NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
O 261) ELARK(SEQ ID NO:101) MSKIKSAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG Xl-GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
EHLEELARKGGSSGGGSSGGGSSGELEEQVMHVLDQ ELARK(SEQ ID NO:101)-X2-ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
2_G51 SDDEREIREIEEEARRILEHLEELARK(SEQ ID
NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
NO: 262) ELARK(SEQ ID NO:101) MSKIKSAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG Xl-GSGSSGELEEQVMHVLDQVSELAHELLHKLIGEELE ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF

RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL NWWATEMMLELIKSDDEREIREIEEEARRILEHLE

EHLEELARKGGSSGGGSSGGGSSGGGSSGELEEQVM ELARK(SEQ ID NO:101)-X2-HVLDQVSELAHELLHKLTGEELERAAYFNWWATEMM ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF

LELIKSDDEREIREIEEEARRILEHLEELARK(SEQ NWWATEMMLELIKSDDEREIREIEEEARRILEHLE

ID NO: 263) ELARK(SEQ ID NO:101) MSKIKSAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL ELARK(SEQ ID NO:101)-X2-EHLEELARKGGSSGGGSSGELEEQVMHVLDQVSELA ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
HELLHKLTGEELERAAYFNWWATEMMLELIKSDDER NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
EIREIEEEARRILEHLEELARKGGSSGGGSSGELEE ELARK(SEQ ID NO:101)-X3-2_GS1 EMMLELIKSDDEREIREIEEEARRILEHLEELARK( NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
SEQ ID NO: 264) ELARK(SEQ ID NO:101) GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE YFNWWATEMMLELIKSDDEREIREIEEEARRILEH
PAAYENWWATEMMLELIKSDDERETRFTEFEARRIL LEFLARK(SE0 TD NO:101)-X2-EHLEELARKGGSSGGGSSGGGSSGELEEQVMHVLDQ ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
VSELAHELLHKLTGEELERAAYENWWATEMMLELIK NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
SDDEREIREIEEEARRILEHLEELARKGGSSGGGSS ELARK(SEQ ID NO:101)-X3-EHLEELARK(SEQ ID NO: 265) ELARK(SEQ ID NO:101) MSKIKSAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL ELARK(SEQ ID NO:101)-X2-EHLEELARKGGSSGGGSSGGGSSGGGSSGELEEQVM ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
HVLDQVSELAHELLHHLTGEELERAAYENWWATEMM NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
LELIKSDDEREIREIEEEARRILEHLEELARKGGSS ELARK(SEQ ID NO:101)-X3-2_G52 LHKLTGEELERAAYENWWATEMMLELIKSDDEREIR NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
0 EIEEEARRILEHLEELARK(SEQ ID NO: 266) ELARK(SEQ ID NO:101) GSGSSGELEEQVMHVLDQVSELAHELLHKLIGEELE ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
EHLEELARKGGASPAAPAPASPAAPAPSAPAGGELE ELARK(SEQ ID NO:101)-X2-AHB2_ TEMMLELIKSDDEREIREIEEEARRILEHLEELARK NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
PAS (SEQ ID NO: 267) ELARK(SEQ ID NO:101) MEKKISAWSHRQFEKGGGSGGGSGGSAWSHEQFEKG NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEK
GSGSSGNLDELHMQMTDLVYEALHFAKDEEFQKHVF ATKAYKNKDRQKLEKVVEELKELLERLLS (SEQ
QLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGG ID NO:155)-X2-LCB1_ ELERLGHAEASMQVSDLIYEFMKTKDERLLEEAERL MKTKDERLLEEAERLLEEVKR (SEQ ID
PAS LEEVKR(SEO ID NO: 268) NO:125) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL ELARK (SEQ ID NO:101)-X2-LCB1_ NVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTK MKTKDERLLEEAERLLEEVKR (SEQ ID
PAS DERLLERAERLLEEVER(SEQ ID NO: 269) NO:125) GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
EHLEELARKGGASPAAPAPASPAAPAPSAPAGGELE ELARK(SEQ ID NO:101)-X2-EQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWA ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
TEMMLELIKSDDEREIREIEEEARRILEHLEELARK NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
GGASPAAPAPASPAAPAPSAPAGGELEEQVMHVLDQ ELARK(SEQ ID NO:101)-X3-3x RA SDDEREIREIEEEARRILEHLEELARK(SEQ ID
NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
NO: 210) ELARK(SEQ ID NO:101) GSGSSGNLDELHMQMTDLVYEALHFAKDEEFQKHVF EKATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ

OLFEKATKAYKNKDROKLEKVVEELKELLERLLSGG ID NO: 155)-X2-ASPAAPAPASPAAPAPSAPAGGELEEQVMHVLDOVS ELEEOVMHVLDOVSELAHELLHKLTGEELERAAYF
ELAKELLHKLTGEELERAAYENWWATEMMLELIKSD NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
DEREIREIEEEARRILEHLEFLARKGGASFAAFAFA ELARK(SEQ ID NO:101)-X3 SPAAPAPSAPAGGDKENVLQKIYEIMKELERLGHAE
ASMQVSDLIYEFMKTKDERLLEEAERLLEEVKR(SE
Q ID NO: 271) MEKKISAWSHPQFEKGGGSGGGSGGSAWSEPQFEKG
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE

EHLEELARKGGASPAAPAPASPAAPAPSAPAGGNLD ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
ELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKA NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
YKNKDRQKLEKVVEELKELLERLLSGGASPAAPAPA ELARK(SEQ ID NO:101)-X2-SPAAPAPSAPAGGDKENVLQKIYEIMKELERLGHAE NLDELHMQMIDLVYEALHFAKDEEFQKHVEQLFEK
2-3- ASMQVSDLIYEFMKTKDERLLEEAERLLEEVKR(SE ATKAYKKKDRQKLEKVVEELKELLERLLS(SEQ
1_PAS Q ID NO: 272) ID NO: 155)-X3 DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
GSGSSGDKENVLQKIYEIMKELERLGHAEASMQVSD 135)-X2-LIYEFMKTKDENLLERAERLLEEVKRGGASPAAPAP DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
ASPAARAPSAPAGGDKENVLQKIYEIMKELERLGHA MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
EASMQVSDLIYEFMKTKDENLLEEAERLLEEVKRGG 135)-X3-1_PAS ELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERL MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
24 LEEVKR(SEQ ID NO: 273) 135) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG Xl-GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
RAAYENWWATEMMLELIKSDDEREIREIEEEARRIL NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
EHLEELARKGGASPAAPAPASPAAPAPSAPAGGELE ELARK(SEQ ID NO:101)-X2-EQVMHVLDQVSELAHELLHKLTGEELERAAYENWWA ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
TEMMLELIKSDDEREIREIEEEARRILEHLEELARK NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
GGASPAARAPASPAARAPSAPAGGELEEQVMHVLDQ ELARK(SEQ ID NO:101)-X3-2_PAS SUDEREIREIEEEARRILEHLEELARK(SEQ ID
NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
24 NO: 274) ELARK(SEQ ID NO:101) Xl-MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
GSGSSGHLDELHMQMTDLVYEALHFAKDEEFQKHVF ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
QLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGG ID NO: 155)-X2-ASPAAPAPASPAAPAPSAPAGGNLDELHMQMTDLVY NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEK
EALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEK ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
VVEELKELLERLLSGGASPAAPAPASPAAPAPSAPA ID NO: 155)-X3-3_RAS KATKAYKNKDROKLEKVVEELKELLERLLS(SEQ ATKAYKNKDROKLEKVVEELKELLERLLS(SEQ
24 ID NO: 275) ID NO: 155) Xl-ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
GSGSSGELEEOVMHVLDQVSELAHELLHKLTGEELE ELARK(SEQ ID NO:101)-X2-RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
EHLEELARKGGASPAAPAPASPAAPAPSAPAGGELE NWWATEMMLELIKSDDE-EQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWA REIREIEEEARRILEHLEELARK(SEQ ID
TEMMLELIKSDDEREIREIEEEARRILEHLEELARK NO:101)X3-1_PAS MKELERLGHAEASMQVSDLIYEFMKTKDENLLEEAE MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
24 RLLEEVKR(SEQ ID NO: 276) 135) GSGSSGELEEOVMHVLDQVSELAHELLHKLTGEELE ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
EHLEELARKGGASPAAPAPASPAGGELEEQVMHVLD ELARK(SEQ ID NO:101)-X2-ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
2_PAS KSDDEREIREIEEEARRILEHLEELARK(SEQ ID
NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
16 NO: 277 ELARK(SEQ ID NO:101) GSGSSGELEEAVMHVLDOVSELAHELLHKLTGEELE ELEEOVMHVLDCWSELAHELLHKLTGEELERAAYF
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
EHLEELARKGGASPAAPAGGELEEQVMHVLDQVSEL ELARK(SEQ ID NO:101)-X2-2_PAS REIREIEEEARRILEHLEELARK(SEQ ID NO:
NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
11 278) ELARK(SEQ ID NO:101) MEKKISAWSHPQFEKGGGSGGGSGGSAWSEPQFEKG NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEK
GSGSSGNLDELHMQMTDLVYEALHFAKDEEFQKHVF ATKAYKNKDRQKLEKVVEELKELLERLLS (SEQ
QLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGG ID NO:155)-X2-1_PAS EASMQVSDLIYEFMKTKDERLLEEAERLLEEVKR(S MKTKDERLLEEAERLLEEVKR (SEQ ID
16 EQ ID NO: 279) NO:125) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG NLDELHMQMIDLVYEALHFAKDEEFQKHVEQLFEK
GSGSSGNLDELHMQMTDLVYEALHFAKDEEFQKHVF ATKAYKNKDRQKLEKVVEELKELLERLLS (SEQ
QLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGG ID NO:155)-X2-DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
1_PAS VSDLIYEFMKTKDERLLEEAERLLEEVKR(SEQ ID MKTKDERLLEEAERLLEEVKR (SEQ ID
11 NO: 280) NO:125) MEKKISAWSHPQFEKGGGSGGGSGGSAWSEPQFEKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
RALYFNWWATEMMLELIKSDDEREIREIEEEARRIL ELARK (SEQ ID NO: 101)-X2-DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
I_PAS IMKELERLGHAEASMQVSDLIYEFMKTKDERLLEEA MKTKDERLLEEAERLLEEVKR (SEQ ID
16 ERLLEEVKR(SEQ ID NO: 281) NO:125) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
RAAYENWWATEMMLELIKSDDEREIREIEEEARRIL ELARK (SEQ ID NO: 101)-X2-DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
1_RAS ERLGHAEASMQVSDLIYEFMKTKDERLLEEAERLLE MKTKDERLLEEAERLLEEVKR (SEQ ID
11 EVKR(SEQ ID NO: 282) NO:125) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG
GSGSSGNIDELLMQVTDLIYEALHFAKDEEFQKHAF

ASPAAPAPASPAAPAPSAPAGGELEEQVMHVLDQVS NIDELLMQVIDLIYEALHFAKDEEFQKHAFQLFEK
ELAHELLHKLTGEELERAAYFNWWATEMMLELIKSD ATKAYKNKDKQKLEKVVEELKELLERILS (SEQ
3v2.3 DEREIREIEEEARRILEHLEELARKGGASPAAPAPA ID NO: 163)-X2-l_PAS ASMQVSDLIYEFMKTKDERLLERAERLLEEVKR(SE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
24 Q ID NO: 283) ELARK(SEQ ID NO:101)-X3 GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE

EHLEELARKGGASPAAPAPASPAAPAPSAPAGGNID ELEEOVMHVLDQVSELAHELLHKLTGEELEKAAYF

NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
3v2.3 YKNKDKQKLEKVVEELKELLERILSGGASPAAPAPA ELARK(SEQ ID NO:101)-X2-SPAAPAPSAPAGGDKENVLOKIYEIMKELERLGHAE NIDELLMOVTDLIYEALHFAKDEEFQKHAFQLFEK
l_PAS ASMQVSDLIYEFMKTKDERLLEEAERLLEEVKR(SE ATKAYKNKDKQKLEKVVEELKELLERILS(SEQ
24 Q ID NO: 284) ID NO: 163)-X3 GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
RAAYFNWWATEMMLELIKSDDEREIREIEEEAARIL NWWATEMMLELIKSDDEREIREIEEELARILEHLE
EHLEELARTGGASPAAPAPASPAAPAPSAPAGGELE ELART (SEQ ID NO: 164)-X2-EQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWA ELEEOVMHVLDOVSELAHELLHKLTGEELERAAYF
TEMMLELIKSDDEREIREIEEEAARILEHLEELART NWWATEMMLELIKSDDEREIREIEEEAARILEHLE
2-2- GGASPAAPAPASPAAPAPSAPAGGELEEQVMHVLDO ELART(SEQ ID NO: 164)-X3-2_PAS VSELAHELLHKLTGEELERAAYFNWWATEMMLELIK ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
24_om SDDEREIREIEEEAARILEHLEELART(SEO ID
NWWATEMMLELIKSDDEREIREIEEELARILEHLE
pT NO: 285) ELART(SEQ ID NO: 164) DKENVLAKIYEIMKELERLGHAEASMCWSDLIYEF
MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG MKTKDERLLEEAERLLEEVKR (SEQ ID
GSGSSGDKENVLQKIYEIMKELERLGHAEASMQVSD NO:125)-X2-LIYEFMKTKDENLLEEAERLLEEVTRGGASPAAPAP DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
ASPAAPAPSAPAGGDKENVLQKIYEIMKELERLGHA MKTKDERLLEEAERLLEEVKR (SEQ ID
1-1- EASMQVSDLIYEFMKTKDENLLEEAERLLEEVTRGG NO:125)-X3-24_om ELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERL MKTKDERLLEEAERLLEEVKR (SEQ ID
pT LEEVTR(SEQ ID NO: 286) NO:125) MEKKISAWSHPQFEKGGGSGGGSGGSAWSEPQFEKG
GSGSSGNIDELLMQVTDLIYEALHFAKDEEFQKHAF

ASPAAPAPASPAAPAPSAPAGGELEEQVMHVLDQVS NIDELLMQVIDLIYEALHFAKDEEFQKHAFQLFEK
3v2.3 ELAHELLHKLTGEELERAAYFNWWATEMMLELIKSD ATKAYKNKDKQKLEKVVEELKELLERILS(SEQ
-2- DEREIREIEEEAARILEHLEELARTGGASPAAPAPA ID NO: 163)-X2-24_om ASMQVSDLIYEFMKTEDERLLERAERLLEEVKR(SE NWWATEMMLELIKSDDEREIREIEEEAARILEHLE
pT Q ID NO: 287) ELART(SEQ ID NO: 164)-X3 MEKKISAWSHPQFEKGGGSGGGSGGSAWSEPQFEKG
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE
RAAYFNWWATEMMLELIKSDDEREIREIEEEAARIL Xl-ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
3v2.3 ELLMQVIDLIYEALHFAKDEEFQKHAFQLFEKATKA NWWATEMMLELIKSDDEREIREIEEEAARILEHLE

YKNKDKQKLEKVVEELKELLERILSGGASPAAPAPA ELART(SEQ ID NO: 164)-X2-24_om ASMQVSDLIYEFMKTEDERLLERAERLLEEVKR(SE ATKAYKNKDKQKLEKVVEELKELLERILS(SEQ
pT Q ID NO: 288) ID NO: 163)-X3 Xl-GSGSSGNIDELLMQVTDLIYEALHFAKDEEFQKHAF ATKAYKNKDKQKLEKVVEELKELLERILS (SEQ
QLFEKATKAYKNKDKQKLEKVVEELKELLERILSGG ID NO: 163)-X2-ASPAAPAPASPAAPAPSAPAGGELEEQVMHVLDQVS ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
ELAHELLHKLTGEELERAAYFNWWATEMMLELIKSD NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
3v2.3 DEREIREIEEEARRILEHLEELARKGGASPAAPAPA ELARK(SEQ ID NO:101)-X3-1 PAS ASMQVSDLIYEFMKTKDENLLEEAERLLEEVKR(SE MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
24 0 ID NO: 289) 135) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL ELARK(SEQ ID NO:101)-X2-EHLEELARKGGASPAAPAPASPAAPAPSAPAGGNID NIDELLMQVIDLIYEALHFAKDEEFOKHAFOLFEK

ATKAYKNKDKQKLEKVVEELKELLERILS(SEQ
3v2.3 YKNKDKQKLEKVVEELKELLERILSGGASPAAPAPA ID NO: 163)-X3-SPAAPAPSAPAGGDKENVLQKIYEIMKELERLGHAE DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
1 PAS ASMQVSDLIYEFMKTEDENLLERAERLLEEVKR(SE MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
24 Q ID NO: 290) 135) Xl-MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG NIDELLMQVIDLIYEALHFAKDEEFQKHAFQLFEK
GSGSSGNIDELLMQVTDLIYEALHFAKDEEFQKHAF ATKAYKNKDKQKLEKVVEELKELLERILS(SEQ
QLFEKATKAYKNKDKOKLEKVVEELKELLERILSGG ID NO: 163)-X2-ASPAAPAPASPAAPAPSAPAGGELEEQVMHVLDQVS ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
3v2.3 ELAHELLHKLTGEELERAAYFNWWATEMMLELIKSD NWWATEMMLELIKSDDEREIREIEEEAARILEHLE
-2- DEREIREIEEEAARILEHLEELARTGGASPAAPAPA ELART(SEQ ID NO: 164)-X3-24 om ASMQVSDLIYEFMKTKDENLLEEAERLLEEVKR(SE MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
pT Q ID NO: 291) 135) 3v2 2-.
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF

24 om EHLEELARTGGASPAAPAPASPAAPAPSAPAGGNID ELART(SEQ ID NO: 164)-X2-ELLMQVTDLIYEALHFAKDEEFQKHAFQLFEKATKA NIDELLMQVIDLIYEALHFAKDEEFQKKAFQLFEK
P T
YKNKDKQKLEKVVEELKELLERILSGGASPAAPAPA ATKAYKNKDKQKLEKVVEELKELLERILS(SEQ

SPAAPAPSAPAGGDKENVLQKIYEIMKELERLGHAE ID NO: 163)-X3-ASMnVSDLIYFFMKTKDENLLFEAFRLLEEVKR(SE DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
Q ID NO: 292) MKTKDENLLEEAERLLEEVKR(SEQ
ID NO:
135) Xl-ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
MEKKIHHHHHHSGENLYFQSGGSGSSGELEEQVMHV NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
2- LDQVSELAHELLHKLTGEELERAAYFNWWATEMMLE ELARK(SEQ ID NO:101)-X2-3v2.3 LIKSDDEREIREIEEEARRILEHLEELARKGGASPA NIDELLMQVIDLIYEALHFAKDEEFQKHAFQLFEK
APAPASPAAPAPSAPAGGNIDELLMQVTDLIYEALH ATKAYKNKDKQKLEKVVEELKELLERILS(SEQ
1_PAS EAKDEEFQKHAFQLFEKATKAYKNKDKQKLEKVVEE ID NO: 163)-X3-24_N- LKELLERILSGGASPAAPAPASPAAPAPSAPAGGDK DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
His- ENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKT MKTKDENLLEEAERLLEEVKR(SEQ
ID NO:
TEV KDENLLEEAERLLEEVKR(SEQ ID NO: 293) 135) ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF

NWWATEMMLELIKSDDEREIREIEEEAARILEHLE
3v2.3 LDQVSELAHELLHKLTGEELERAAYFNWWATEMMLE ELART(SEQ ID NO: 164)-K2-LIKSDDEREIREIEERAARILEHLEELARTGGASPA NIDELLMQVIDLIYEALHFAKDEEFQKHAFQLFEK
1_PAS APAPASPAAPAPSAPAGGNIDELLMQVTDLIYEALH ATKAYKNKDKQKLEKVVEELKELLERILS(SEQ
24_om FAKDEEFQKHAFQLFEKATKAYKNKDKQKLEKVVEE ID NO: 163)-X3-pT_N- LKELLERILSGGASPAAPAPASPAAPAPSAPAGGDK DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
His- ENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKT MKTKDENLLEEAERLLEEVKR(SEQ
ID NO:
TEV KUENLLEEAERLLEEVKR(SEQ ID NO: 294) 135) xl-MEKKIDYKDDDDEGSGSSAWSHPQFEKGGGSGGGSG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
GSAWSHPQFEKGGSGSSGELEEQVMHVLDQVSELAH NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
ELLHKLTGEELERAAYFNWWATEMMLELIKSDDERE ELARK(SEQ ID NO:101)-X2-IREIEEEARRILEHLEELARKGGASPAAPAPASPAA NIDELLMQVIDLIYEALHFAKDEEFQKHAFQLFEK
PAPSAPAGGNIDELLMQVTDLIYEALHFAKDEEFQK ATKAYKNKDKQKLEKVVEELKELLERILS(SEQ
2-3- RAFQLFEKATKAYKNKDKQKLEKVVEELKELLERIL ID NO: 163)-X3-1_2AS SGGASPAAPAPASPAAPAPSAPAGGDKENVLQKIYE DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
24_NT IMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEA MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
SF ERLLEEVKR(SEQ ID NO: 295) 135) PQFEKGGGSGGGSGGSAWSHPQFEKGGSGSSGELEE ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
QVMHVLDQVSELAHELLHKLTGEELERAAYENWWAT NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
EMMLELIKSDDEREIREIEEEARRILEHLEELARKG ELARK(SEQ ID NO:101)-X2-GASPAAPAPASPAAPAPSAPAGGNIDELLMQVTDLI NIDELLMQVIDLIYEALHFAKDEEFQKHAFQLFEK
YEALHFAKDEEFQKHAFQLFEKATKAYKNKDKQKLE ATKAYKNKDKQKLEKVVEELKELLERILS(SEQ
2-3- KVVEELKELLERILSGGASPAAPAPASPAAPAPSAP ID NO: 163)-X3-1_PAS AGGDKENVLQKIYEIMKELERLGHAEASMQVSDLIY DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
24_NT EFMKTKDENLLEEAERLLEEVKR(SEQ ID NO: MKTKDENLLEEAERLLEEVKR(SEQ
ID NO:
S3F 296) 135) Xl-MEKKIEQKLISEEDLGSGSSAWSHPQFEKGGGSGGG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
SGGSAWSHPQFEKGGSGSSGELEEQVMHVLDQVSEL NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
AHELLHKLTGEELERAAYFNWWATEMMLELIKSDDE ELARK(SEQ ID NO:101)-X2-REIREIEEEARRILEHLEELARKGGASPAAPAPASP NIDELLMQVIDLIYEALHFAKDEEFQKHAFQLFEK
AAPAPSAPAGGNIDELLMQVTDLIYEALHFAKDEEF ATKAYKNKDKQKLEKVVEELKELLERILS(SEO
2-3- QKHAFQLFEKATKAYKNKDKQKLEKVVEELKELLER ID NO: 163)-X3-1_PAS ILSGGASPAAPAPASPAAPAPSAPAGGDKENVLOKI DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
24_NT YEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLE MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
SM EAERLLEEVKR(SEQ ID NO: 297) 135) MEKKIDYKDHDGDYKDHDIDYKDDDDKGSGSSAWSH ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
PQFEKGGGSGGGSGGSAWSHPQFEKGGSGSSGELEE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
2- QVMHVLDQVSELAHELLHKLTGEELERAAYFNWWAT ELARK(SEQ ID NO:101)-X2--3- aASPAAPAPASPAAPAPSAPAGGNIDELLMQVTDLI ATKAYKNKDKQKLEKVVEELKELLERILS(SEQ
PAS16 YEALHFAKDEEFQKHAFQLFEKATKAYKNKDKOKLE ID NO: 163)-X3-KVVEELKELLERILSGGASPAAPAPASPAGGDKENV DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
1_NTS LQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDE MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
3F NLLEEAERLLEEVKR(SEQ ID NO: 298) 135) MEKKTDYKDHDGMYKDHDTDYKDDDDKGSGSSAWSH ELEEOVMHVLDOVSELAHELLHKLTGEELERAAYF
PQFEKGGGSGGGSGGSAWSHPQFEKGGSGSSGELEE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
2- QVMHVLDQVSELAHELLHKLTGEELERAAYENWWAT ELARK(SEQ ID NO:101)-X2--3- GASPAARAPASPAGGNIDELLMQVTDLIYEALHFAK ATKAYKNKDKQKLEKVVEELKELLERILS(SEQ
PAS16 DEEFQKHAFQLFEKATKAYKNKDKQKLEKVVEELKE ID NO: 163)-X3-LLERILSGGASPAAPAPASPAGGDKENVLQKIYEIM DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
1_NTS KELERLGHAEASMQVSDLIYEFMKTKDENLLEEAER MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
3F LLEEVKR(SEQ ID NO: 299) 135) MEKKIDYKDHDGDYKDHDIDYKDDDDRGSGSSAWSH ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
PQFEKGGGSGGGSGGSAWSHPQFEKGGSGSSGELEE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
2- QVMHVLDQVSELAHELLHKLTGEELERAAYFNWWAT ELARK(SEQ ID NO:101)-X2-ATKAYKNKDKQKLEKVVEELKELLERILS(SEQ
PA316 KHAFQLFEKATKAYKNKDKQKLEKVVEELKELLERI ID NO: 163)-X3-LSGGASPAAPAPASPAGGDKENVLQKIYEIMKELER DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
1_NTS LGHAEASMOVSDLIYEFMKTKDENLLEEAERLLEEV MKTKDENLLEEAERLLEEVKR(SEO ID NO:
3F KR(SEQ ID NO: 300) 135) MEKKIDYKDHDGDYKDHDIDYKDDDDKGSGSSAWSH ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
PQFEKGGGSGGGSGGSAWSHKQFEKGGSGSSGELEE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
2- QVMMVLDQVSELARELLHKLTGEELERAAYENWWAT ELARK(SEQ ID NO:101)-X2--3- GASPAARAPASPAAPAPSAPAGGNIDELLMQVTDLI ATKAYKNKDKQKLEKVVEELKELLERILS(SEQ
PAS11 YEALHFAKDEEFQKHAFQLFEKATKAYKNKDKQKLE ID NO: 163)-X3-KVVEELKELLERILSGGASPAAPAGGDKENVLQKIY DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
1_NTS EIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEE MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
3F AERLLEEVKR(SEQ ID NO: 301) 135) Xl-MEKKIDYKDHDGDYKDHDIDYKDDDDKGSGSSAWSH ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
PQFEKGGGSGGGSGGSAWSHPQFEKGGSGSSGELEE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
2- QVMHVLDQVSELAHELLHKLTGEELERAAYENWWAT ELARK(SEQ ID NO:101)-X2--3- GASPAARAPASPAGGNIDELLMQVTDLIYEALHFAK ATKAYKNKDKQKLEKVVEELKELLERILS(SEQ
PAS11 DEEFQKHAFQLFEKATKAYKNKDKQKLEKVVEELKE ID NO: 163)-X3-LLERILSGGASPAAPAGGDKENVLOKIYEIMKELER DKENVLOKIYEIMKELERLGHAEASMOVSDLIYEF
l_NTS LGRAEASMQVSDLIYEFMKTKDENLLEEAERLLEEV MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
3F KR(SEQ ID NO: 302) 135) MEKKIDYKDHDGDYKDHDIDYKDDDDKGSGSSAWSH ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
PQFEKGGGSGGGSGGSAWSHPQFEKGGSGSSGELEE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
2- QVMHVLDQVSELAHELLHKLTGEELERAAYENWWAT ELARK(SEQ ID NO:101)-X2--3- GASPAAPAGGNIDELLMQVTDLIYEALHFAKDEEFQ ATKAYKNKDKQKLEKVVEELKELLERILS(SEQ
PAS11 KHAFOLFEKATKAYKNKDKOKLEKVVEELKELLERI ID NO: 163)-X3-1_NTS ASMQVSDLIYEFMKTKDENLLEEAERLLEEVKR(SE MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
3F Q ID NO: 303) 135) Xl-MEKKISAWSHFQFEKGGGSGGGSGGSAWSHDOFEKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL ELARK(SEQ ID NO:101)-X2-NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
204 EEARRILEHLEELARK(SEQ ID NO: 304) ELARK(SEQ ID NO:101) MEKKISAWSHPOFEKGGGSGGGSGGSAWSHPOFEKG ELEEOVMHVLDOVSELAHELLHKLTGEELERAAYF
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL ELARK(SEQ ID NO:101)-X2-EHLEELARKGGELEEQVMHVLDQVSELAHELLHKLT ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF

NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
ARRILEHLEELARK(SEQ ID NO: 305) ELARK(SEQ ID NO:101) GSGSSGELEEAVMHVLDOVSELAHELLHKLTGEELE ELEEOVMHVLDOVSELAHELLHKLTGEELERAAYF
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
EHLEELARKGGASPAAPAPASPAAPAPSAPAGGNID ELARK(SEQ ID NO:101)-X2-NIDELLMQVTDLIYEALHFAKDEEFQKHAFQLFEK
3_PAS YKNKDKQKLEKVVEELKELLERILS(SEQ ID NO: ATKAYKNKDKQKLEKVVEELKELLERILS(SEQ
24 306) ID NO: 163) MEKKISAWSHPQFEKGGGSGGGSGGSAWSEPQFEKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL ELARK(SEQ ID NO:101)-X2-NIDELLMQVTDLIYEALHFAKDEEFQKHAFQLFEK
3_PAS LIYEALHFAKDEEFQKHAFQLFEKATKAYKNKDKQK ATKAYKNKDKQKLEKVVEELKELLERILS(SEQ
16 LEKVVEELKELLERILS(SEQ ID NO: 307) ID NO: 163) MEKKISAWSHRQFEKGGGSGGGSGGSAWSHPQFEKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL ELARK(SEQ ID NO:101)-X2-NIDELLMQVTDLIYEALHFAKDEEFQKHAFQLFEK
3_PAS LHFAKDEEFQKHAFQLFEKATKAYKNKDKQKLEKVV ATKAYKNKDKQKLEKVVEELKELLERILS(SEQ
11 EELKELLERILS(SEQ ID NO: 308) ID NO: 163) MEKKISAWSHPQFEKGGGSGGGSGGSAWSEPQFEKG DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
GSGSSGDKENVLQKIYEIMKELERLGHAEASMQVSD MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
LIYEFMKTKDENLLEEAERLLEEVKRGGASPAAPAP 135)-X2-ASPAAPAPSAPAGGELEEQVMHVLDQVSELAHELLH ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
KLTGEELERAAYFNWWATEMMLELIKSDDEREIREI NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
EEEARRILEHLEELARKGGASPAAPAPASPAAPAPS ELARK(SEQ ID NO:101)-X3-l_PAS IYEFMKTKDENLLEEAERLLEEVKR(SEQ ID NO: MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
24 309) 135) Xl-MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL ELARK(SEQ ID NO:101) X2 NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
RA324 ELHMQMTDLVYEALHFAKDEEFOUTVFQLFEKATKA ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
YKNKDRQKLEKVVEELKELLERLLSGGASPAAPAPA ID NO: 155)-X3-ASMQVSDLIYEFMKTKDENLLEEAERLLEEVKR(SE MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
1_NTS Q ID NO: 310) 135) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
PAAYENWWATEMMLELIKSDDEREIREIEEEARRIL ELARK(SEQ ID NO:101)-X2-NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
RAS24 ELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKA ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
-3- YKNKDRQKLEKVVEELKELLERLLSGGASPAAPAPA ID NO: 155)-X3-IYEFMKTKDENLLEEAERLLEEVKR(SEQ ID NO: MKTKDENLLEFAFRLLEEVKR(SEQ ID NO:
l_NTS 311) 135) Xl-ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG ELARK(SEQ ID NO:101)-X2-NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
PAS16 RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL ATKAYKNKDRQKLEKVVEELKELLERLLS (SEQ
-3- EHLEELARKGGASPAAPAPASPAGG(SEQ ID NO: ID NO: 155)-X3-PAS24 155)GGASPAAPAPASPAAPAPSAPAGGDKENVLQK DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
IYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLL MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
1_NTS EEAERLLEEVKR(SEQ ID NO: 312) 135) PAS16 EHLEELARKGGASPAAPAPASPAGGNLDELHMOMTD ELARK(SEQ ID NO:101)-X2-LVYEALHFAKDEEFOKHVFOLFEKATKAYKNKDROK NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
1_NTS LEKVVEELKELLERLLSGGASDAADAPASPAGGDKE ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
NVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTK ID NO: 155)-X3-DENLLEEAERLLEEVER(SEQ ID NO: 313) DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
135) ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE ELARK(SEQ ID NO:101)-X2-NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
PAS11 EHLEELARKGGASPAAPAGGNLDELHMQMTDLVYEA ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
-3- LHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVV ID NO: 155)-X3-IYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLL MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
1_NTS EEAERLLEEVKR(SEQ ID NO: 314) 135) Xl-ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE ELARK(SEQ ID NO:101)-X2-NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
aAS24 EHLEELARKGGASPAAPAPASPAAPAPSAFAGGNLD ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
-3- ELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKA ID NO: 155)-X3-DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEEM MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
1_NTS KTKDENLLEEAERLLEEVKR(SEQ ID NO: 315) 135) ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYE
MEKKISAWSHRQFEKGGGSGGGSGGSAWSHPQFEKG NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE ELARK(SEQ ID NO:101)-X2-NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
PAS16 EHLEELARKGGASPAAPAPASPAGGNLDELHMQMTD ATKAYKNKDRQKLEKVVEELKELLERLLS(SFQ
-3- LVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQK ID NO: 155)-X3-IYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLL MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
l_NTS EEAERLLEEVKR(SEQ ID NO: 316) 135) Xl-ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE ELARK(SEQ ID NO:101)-X2-NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
PAS11 EHLEELARKGGASPAAPAGGNLDELHMQMTDLVYEA ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
-3- LHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVV ID NO: 155)-X3-KELERLGHAEASMQVSDLIYEFMKTKDENLLEEAER MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
1_NTS LLEEVKR(SEQ ID NO: 317) 135) ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYE
MEKKISAWSHROFEKGGGSGGGSGGSAWSHPOFEKG NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE ELARK(SEQ ID NO:101)-X2-PAAYENWWATEMMLELIKSDDEREIREIEEEARRIL NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
EHLEELARKGGASAGGNLDELHMQMTDLVYEALHFA ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
KDEEFQKHVFQLFEKATKAYKNKDROKLEKVVEELK ID NO: 155)-X3-1_PAS AEASMQVSDLIYEFMKTKDENLLEEAERLLEEVKR( MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
7 SEQ ID NO: 318) 135) GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE ELEEOVMHVLDOVSELAHELLHKLTGEELERAAYF
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
EHLEELARKGGSGGSGGNLDELHMQMTDLVYEALHF ELARK(SEQ ID NO:101)-X2-AKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEEL NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK

KELLERLLSGGSGGSGGDKENVLQKIYEIMKELERL ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
GHAEASMQVSDLIYEFMKTKDENLLERAERLLEEVK ID NO: 155)-X3-R(SEQ ID NO: 319) DKENVLOKIYEIMKELERLGHAEASMQVSDLIYEF
MKTKDENLLEEAERLLEEVKR(SEA ID NO:
135) ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
MEKKISAWSHDQFEKGGGSGGGSGGSAWSHDQFEKG NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE ELARK(SEQ ID NO:101)-X2-RAAYENWWATEMMLELIKSDDEREIREIEEEARRIL NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEK
EHLEELARKGGSGGNLDELHMQMTDLVYEALHFAKD ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
EEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKEL ID NO: 155)-X3-LERLLSGGSGGDKENVLQKIYEIMKELERLGHAEAS DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
2-3- MQVSDLIYEFMKTKDENLLEEAERLLEEVKR(SEQ
MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
1_0S5 ID NO: 320) 135) Xl-ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
MEKKISAWSHPQFEKGGGSGGGSGGSAWSEPQFEKG NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE ELARK(SEQ ID NO:101)-X2-RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEK
EHLEELARKGGSGGSGGSGGNLDELHMQMTDLVYEA ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
LHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVV ID NO: 155)-X3-1_GS1 KELERLGHAEASMQVSDLIYEFMKTKDENLLEEAER MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
1 LLEEVKR(SEQ ID NO: 321) 135) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL ELARK(SEQ ID NO:101)-X2-EHLEELARKGGASPAAPAGGELEEQVMHVLDQVSEL ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
AHELLHKLTGEELERAAYFNWWATEMMLELIKSDDE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
REIREIEEEARRILEHLEELARKGGASPAAPAGGEL ELARK(SEQ ID NO:101)-X3-2_2A5 ATEMMLELIKSDDEREIREIEEEARRILEHLEELAR NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
11 K(SEQ ID NO: 322) ELARK(SEQ ID NO:101) Xl-MEKKISAWSHFQFEKGGGSGGGSGGSAWSHDQFEKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL ELARK(SEQ ID NO:101)-X2-EHLEELARKGGSGGSGGSGGELEEQVMHVLDQVSEL ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
AHELLHKLTGEELERAAYFNWWATEMMLELIKSDDE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
REIREIEEEARRILEHLEELARKGGSGGSGGSGGEL ELARK(SEQ ID NO:101)-X3-2_GS1 ATEMMLELIKSDDEREIREIEEEARRILEHLEELAR NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
1 K(SEQ ID NO: 323) ELARK(SEQ ID NO:101) MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL ELARK(SEQ ID NO:101)-X2-EHLEELARKGGSGGSGGELEEQVMHVLDQVSELAHE ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
LLHKLTGEELERAAYFNWWATEMMLELIKSDDEREI NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
REIEEEARRILEHLEELARKGGSGGSGGELEEOVMH ELARK(SEO ID NO:101)-X3-VLDQVSELAHELLHKLIGEELERAAYENWWATEMML ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
2-2- ELIKSDDEREIREIEEEARRILEHLEELARK(SEQ NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
2_GS8 ID NO: 324) ELARK(SEQ ID NO:101) Xl-MEKKISAWSHPOFEKGGGSGGGSGGSAWSHPOFEKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL ELARK(SEQ ID NO:101)-X2-EHLEELARKGGSGGELEEQVMHVLDQVSELAHELLH ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
KLTGEELERAAYFNWWATEMMLELIKSDDEREIREI NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
EEEARRILEHLEELARKGGSGGELEEQVMHVLDQVS ELARK(SEQ ID NO:101)-X3-2-2- DEREIREIEEEARRILEHLEELARK(SEQ ID NO:
NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
2_GS5 325) ELARK(SEQ ID NO:101) ELFEOVMHVLDOVSELAHELLHKLTGEELERAAYF
MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE ELARK(SEQ ID NO:101)-X2-RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEK
EHLEELARKGGSGGGGSGGGGSGGNLDELHMQMTDL ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
VYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKL ID NO: 155)-X3-1_GGG LQKIYEIMKELERLGHAEASMOVSDLIYEFMKTKDE MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
5S15 NLLEEAERLLEEVKR(SEQ ID NO: 326) 135) LEEQVMHVLDQVSELAHELLHKLIGEELERAAYFN
MEKKISAWSHRQFEKGGGSGGGSGGSAWSHPQFEKG WWATEMMLELIKSDDEREIREIEEEARRILEHLEE
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE LARK (SEQ ID No: 101)-X2-RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL NLDELHMQMIDLVYEALHEAKDEEFQKHVEQLFEK
EHLEELARKGGSGGGGSGGGGNLDELHMQMTDLVYE ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
ALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKV ID NO: 155)-X3-1_GGG IMKELERLGHAEASMoVSDLIYEFMKTKDENLLEEA MKTKDENLLEEAERLLEEVKR(SEn ID NO:
G312 ERLLEEVKR(SEQ ID NO: 327) 135) ELEEOVMHVLDOVSELAHELLHKLTGEELERAAYF
MEKKISAWSHPQFEKGGGSGGGSGGSAWSHPQFEKG NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE ELARK(SEQ ID NO:101)-X2-RAAYFNWWATEMMLELIKSDDEREIREIEEEARRIL NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEK
EHLEELARKGGGGSGGGGNLDELHMQMTDLVYEALH ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
FAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEE ID NO: 155)-X3-1_GGG RLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEE MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
GS9 VKR(SEQ ID NO: 328) 135) Xl-ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
MEKKISAWSHROFEKGGGSGGGSGGSAWSHPOFEKG NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE ELARK(SEQ ID NO:101)-X2-RAAYENWWATEMMLELIKSDDEREIREIEEEARRIL NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEK
EHLEELARKGGGSGGGNLDELHMQMTDLVYEALHFA ATKAYKNKDROKLEKVVEELKELLERLLS(SEQ
KDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELK ID NO: 155)-X3-2-3- ELLERLLSGGGSGGGDKENVLOKIYEIMKELERLGH DKENVLOKIYEIMKELERLG(SEQ
ID NO:
i_GGG AEASMQVSDLIYEFMKTKDENLLEEAERLLEEVKR( 135)HAEASMQVSDLIYEFMKTKDENLLEEAERLL
GS7 SEO ID NO: 329) EEVKR

MEKKIGGGDKENVLQKIYEIMKELERLGHAEASMQV DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
SDLIYEFMKTKDENLLEEAERLLEEVKRGGSGGGGS MKTKDENLLEEAERLLEEVKR(SEO ID NO:
GGGGSGGGGSGGGGSGGDKENVLQKIYEIMKELERL 135)-X2-DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
1_000 RGGGSGGGSAWSHPQFEKGGGSGGGSGGSAWSHPQF MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
G525 EK(SEQ ID NO: 330) 135)-X3 MEKKIGGGDKENVLQKIYEIMKELERLGHAEASMQV DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
SDLIYEFMKTKDENLLEEAERLLEEVKRGGSGGGGS MKTKDENLLEEAERLLEEVKR(SEO ID NO:
GGOGSGGGGSGGDKENVLQKIYEIMKELERLGRAEA 135)-X2-DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
1_GGG GGGSAWSHPQFEKGGGSGGGSGGSAWSHPQFEK(SE MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
G120 Q ID NO: 331) 135)-X3 MEKKIGGGDKENVLQKIYEIMKELERLGHAEASMQV DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
SDLIYEFMKTKDENLLEEAERLLEEVKRGGSGGGGS MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
GGGGSGGDKENVLQKIYEIMKELERLGHAEASMQVS 135)-X2-DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
i_GGG WSHPQFEKGGGSGGGSGGSAWSHPQFEK(SEQ ID MKTKDENLLEEAERLLEEVKR(SEQ
ID NO:
G515 NO: 332) 135)-X3 DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
1_GGG GGDKENVLOKIYEIMKELERLGHAEASMQVSDLIYE MKTKDENLLEEAERLLEEVKR(SEO ID NO:

GS10 FMKTKDENLLEEAERLLEEVKRGGGSGGGSAWSHPQ 135)-X2-FEKGGGSGGGSGGSAWSHPAFEK(SEA ID NO:
DKENVLAKIYEIMKELERLGHAEASMQVSDLIYEF
333) MKTKDENLLEEAERLLEEVKR(SEQ
ID NO:
135)-X3 MEKKIGGGELEEQVMHVLDQVSELAHELLHKLTGEE ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
LERAAYENWWATEMMLELIKSDDEREIREIEEEARR NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
ILEHLEELARKGGSGGGGSGGDKENVLQKIYEIMKE ELARK(SEQ ID NO:101)-X2-i_GGG EEVKRGGGSGGGSAWSHPQFEKGGGSGGGSGGSAWS MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
GS10 HPQFEK(SEQ ID NO: 334) 135)-X3 MEKKIGGGNLDELHMQMTDLVYEALHFAKDEEFQKH NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEK
VFOLFFKATKAYKNKDROKT.F.K\RTF.F.T.KFT.T.F.P.T.T.S
ATKAYKNKDROKT,F.KV\TEET.KFT.T.F.RT.T.S(SF.0 GGSGGGGSGGDKENVLQKIYEIMKELERLGHAEASM ID NO: 155)-X2-l_GGG GSAWSHPQFEKGGGSGGGSGGSAWSHPQFEK(SEQ MKTKDENLLEEAERLLEEVKR(SEQ
ID NO:
GS10 ID NO: 335) 135)-X3 MEKKIGGGELEEQVMHVLDQVSELAHELLHKLTGEE ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
LERAAYENWWATEMMLELIKSDDEREIREIEEEARR NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
ILEHLEELARKGGSGGGGSGGNLDELHMQMTDLVYE ELARK(SEQ ID NO:101)-X2-3_GGG VEELKELLERLLSGGGSGGGSAWSHPQFEKGGGSGG ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
GS10 GSGGSAWSHPQFEK(SEQ ID NO: 336) ID NO: 155)-X3 MEKKIGGGNLDELHMQMTDLVYEALHFAKDEEFQKH NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEK
VFQLFEKATKAYKNKDRQKLEKVVEELKELLERLLS ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
GGSGGGGSGGELEEQVMHVLDQVSELAHELLHKLTG ID NO: 155)-X2-GS10 GSGGSAWSHPQFEK(SEQ ID NO: 337) ELARK(SEQ ID NO:101)-X3 Xl-ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
MEKKIGGGELEEQVMHVLDQVSELAHELLHKLTGEE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
LERAAYENWWATEMMLELIKSDDEREIREIEEEARR ELARK(SEQ ID NO:101)-X2-ALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKV ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
VEELKELLERLLSGGSGGGGSGGDKENVLQKIYEIM ID NO: 155)-X3-l_GGG LLEEVKRGGGSGGGSAWSHPQFEKGGGSGGGSGGSA MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
GS10 WSHPOFEK(SEO ID NO: 338) 135)-X4 NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEK
MEKKIGGGNLDELHMQMTDLVYEALHFAKDEEFQKH ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
VFQLFEKATKAYKNKDRQKLEKVVEELKELLERLLS ID NO: 155)-X2-GGSGGGGSGGELEEQVMHVLDQVSELAHELLHKLTG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
EELERAAYFNWWATEMMLELIKSDDEREIREIEEEA NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
RRILEHLEELARKGGSGGGGSGGDKENVLQKIYEIM ELARK(SEQ ID NO:101)-X3-1_GGG LLEEVKRGGGSGGGSAWSHPQFEKGGGSGGGSGGSA MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
GS10 WSHPQFEK(SEQ ID NO: 339) 135)-X4 Xl-ELEEOVMHVLDOVSELAHELLHKLTGEELERAAYF
MEKKIGGGELEEQVMHVLDQVSELAHELLHKLTGEE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
LERAAYENWWATEMMLELIKSDDEREIREIEEEARR ELARK(SEQ ID NO:101)-X2-ILEHLEELARKGGSGGGGSGGGGSGGNLDELHMQMT NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEK
DLVYEALHFAKDEEFQKHVFOLFEKATKAYKNKDRQ ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
KLEKVVEELKELLERLLSGGSGGGGSGGGGSGGDKE ID NO: 155)-X3-l_GGG DENLLEEAERLLEEVKRGGGSGGGSAWSHPQFEKGG MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
0S15 GSGGGSGGSAWSHPOFEK(SEO ID NO: 340) 135)-X4 3-2- MEKKIGGGNLDELHMQMTDLVYEALHFAKDEEFQKH Xl-1_GGG VFOLFEKATKAYKNKDROKLEKVVEELKELLERLLS NLDELHMOMTDLVYEALHFAKDEEFQKHVFQLFEK
GS15 GGSGGGGSGGGGSGGELEEOVMHVLDOVSELAHELL ATKAYKNKDROKLEKVVEELKELLERLLS(SEO
HKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE ID NO: 155)-X2-IEEEARRILEHLEELARKGGSGGGGSGGGGSGGDKE ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
NVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTK NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
DENLLEEAERLLEEVKRGGGSGGGSAWSHPQFEKGG ELARK(SEQ ID NO:101)-X3-GSGGGSGGSAWSHPQFEK(SEQ ID NO: 341) DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
135)-X4 LFEKATKAYKNKDRQKLEKVVEELKELLERLLSGGA EKATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
SPAAPAPGGDKENVLQKIYEIMKELERLGHAEASMQ ID NO: 155)-X2-LCB1 aAWSHPQFEKGGGSGGGSGGSAWSHPQFEK(SEQ
MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
PAS12 ID NO: 342) 135)-X3 MEKKIELEEQVMHVLDQVSELAHELLHKLTGEELER ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
AAYENWWATEMMLELIKSDDEREIREIEEEARRILE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
HLEELARKGGASPAAPAPGGDKENVLQKIYEIMKEL ELARK(SEQ ID NO:101)-X2-LCB1 EVKRGGSGSSGSAWSHPQFEKGGGSGGGSGGSAWSH MKTKDENLLEEAERLLEEVKR(SEQ
ID NO:
PAS12 PQFEK(SEQ ID NO: 343) 135)-X3 Xl-MEKKIELEEQVMHVLDQVSELAHELLHKLTGEELER ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
AAYFNWWATEMMLELIKSDDEREIREIEEEARRILE NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
HLEELARKGGASPAAPAPGGNEDELHMQMTDLVYEA ELARK(SEQ ID NO:101)-X2-LCB3 EELKELLERLLSGGSGSSGSAWSHPQFEKGGGSGGG ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
PAS12 SGGSANSHPQFEK(SEQ ID NO: 344) ID NO: 155)-X3 Xl-MEKKINLDELHMQMTDLVYEALHFAKDEEFQKHVFQ NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
LFEKATKAYKNKURQKLEKVVEELKELLERLLSGGA ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
SPAAPAPGGELEEQVMHVLDQVSELAHELLHKLTGE ID NO: 155)-X2-NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
PAS12 SGGSAWSHPQFEK(SEQ ID NO: 345) ELARK(SEQ ID NO:101)-X3 Xl-ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
MEKKIELEEQVMHVLDQVSELAHELLHKLTGEELER NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
AAYFNWWATEMMLELIKSDDEREIREIEEEARRILE ELARK(SEQ ID NO:101)-X2-HLEELARKGGASPAAPAPGGNLDELHMQMTDLVYEA NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
LHFAKDEEFOKHVFOLFEKATKAYKNKDROKLEKVV ATKAYKNKDROKLEKVVEELKELLERLLS(SEQ
AHB2- EELKELLERLLSGGASPAAPAPGGDKENVLQKIYEI ID NO: 155)-X3-LCB1 RLLEEVKRGGSGSSGSAWSHPQFEKGGGSGGGSGGS MKTKDENLLEEAERLLEEVKR(SEQ
ID NO:
PA512 AWSHPQFEK(SEQ ID NO: 346) 135)-X4 NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
MEKKINLDELHMQMTDLVYEALHFAKDEEFQKHVFQ ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
LFEKATKAYKNKDRQKLEKVVEELKELLERLLSGGA ID NO: 155)-X2-SPAAPAPGGELEEQVMHVLDQVSELAHELLHKLTGE ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
ELERAAYFNWWATEMMLELIKSDDEREIREIEEEAR NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
LCB3- RILEHLEELARKGGASPAAPAPGGDKENVLOKIYEI ELARK(SEQ ID NO:101)-X3-LCB1 RLLEEVKRGGSGSSGSAWSHPQFEKGGGSGGGSGGS MKTKDENLLEEAERLLEEVKR(SEQ
ID NO:
PAS12 AWSHPQFEK(SEQ ID NO: 347) 135)-X4 MEKKINLDELHMQMTDLVYEALHFAKDEEFQKHVFQ Xl-LFEKATKAYKNKDRQKLEKVVEELKELLERLLSGGA NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
SPAAPAPASPAAPAPSAPAGGELEEQVMHVLDQVSE ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ

LAHELLHKLTGEELERAAYFNWWATEMMLELIKSDD ID NO: 155)-X2-EREIREIEEEARRILEHLEELARKGGASPAAPAPAS ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF

PAAPAPSAPAGGDKENVLQKIYEIMKELERLGHAEA NWWATEMMLELIKSDDEREIREIEEEARRILEHLE
PAS24 SMQVSDLIYEFMKTKDENLLEEAERLLEEVKRGGSG ELARK(SEQ ID NO:101)-X3-SSGSAWSHPQFEKGGGSGGGSGGSAWSHPQFEK(SE DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF

O ID NO: 348) MKTKDENLLEEAERLLEEVKR(SEQ
ID NO:
135)-X4 MEKKIELEEQVMHVLDQVSELAHELLHKLTGEELER ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
AAYFNWWATEMMLELIKSDDEREIREIEEEAARILE NWWATEMMLELIKSDDEREIREIEEEAARILEHLE
AHB2v HLEELADTGGASPAADADGGDKENVLQKIYEIMKEL ELART (SEQ ID NO: 164)-X2-DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
LCB1_ EVKRGGSGSSGSAWSHPQFEKGGGSGGGSGGSAWSH MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
PAS12 PQFEK(SEQ ID NO: 349) 135)-X3 MEKKIELEDQVMHVLDQVSELAHELLHKLTGEELER ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
AAYFNWWATEMMLELIKSDDEREIREIEEEAARILE NWWATEMMLELIKSDDEREIREIEEEAARILEHLE
AHB2v HLEELARTGGASPAAPAPGGNLDELHMQMTDLVYEA ELART(SEQ ID NO: 164)-X2-2- TEFAKDEFFOKFFVFOLFEKATKAYKNKDROKT.F.KV\T
NLDELHMOMTDTVYEALHFAKDEEFOKHVFOLFEK
LCB3_ EELKELLERLLSGGSGSSGSAWSHPQFEKGGGSGGG ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
PAS12 SGGSAWSHPQFEK(SEQ ID NO: 350) ID NO: 155)-X3 MEKKINLDELHMQMTDLVYEALHFAKDEEFQKHVFQ NLDELHMQMTDEVYEALHFAKDEEFQKHVFQLFEK
LFEKATKAYKNKDRQKLEKVVEELKELLERLLSGGA ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
LCB3- SPAAPAPGGELEEQVMHVLDQVSELAHELLHKLTGE ID NO: 155)-X2-AHB2v ELERAAYFNWWATEMMLELIKSDDEREIREIEEEAA ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF

2_PAS RILEHLEELARTGGSGSSGSAWSHPQFEKGGGSGGG NWWATEMMLELIKSDDEREIREIEEEAARILEHLE
12 SGGSAWSHPQFEK(SEQ ID NO: 351) ELART (SEQ ID NO: 164)-X3 ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
MEKKIELEECVMHVLDOVSELAHELLHKLTGEELER NWWATEMMLELIKSDDEREIREIEEEAARILEHLE
AAYFNWWATEMMLELIKSDDEREIREIEEEAARILE ELART(SEQ ID NO: 164)-X2-HLEELARTGGASPAAPAPGGNLDELHMQMTDLVYEA NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
AHB2v LHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVV ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
2- EELKELLERLLSGGASPAAPAPGGDKENVLQKIYEI ID NO: 155)-X3-LCB1_ RLLEEVKRGGSGSSGSAMSHPQFEKGGGSGGGSGGS MKTKDENLLEEAERLLEEVKR (SEQ ID NO:
PAS12 AWSHPQFEK(SEQ ID NO: 352) 135)-X4 NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
MEKKINLDELHMQMTDLVYEALHFAKDEEFQKHVFQ ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
LFEKATKAYKNKURQKLEKVVEELKELLERLLSCCA ID NO: 155)-X2-SPAAPAPGGELEEQVMHVLDQVSELAHELLHKLTGE ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF

AHB2v RILEHLEELARTGGASPAAPAPGGDKENVLQKIYEI ELART(SEQ ID NO: 164)-X3-DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
LCB1_ RLLEEVKRGGSGSSGSAWSHPOFEKGGGSGGGSGGS MKTKDENLLEEAERLLEEVKR(SEO ID NO:
PAS12 AWSHPQFEK(SEQ ID NO: 353) 135)-X4 Xl-MEKKISAWSHPQFEKGGGSGGGSGGSAWSEPQFEKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF
GSGSSGELEEQVMHVLDQVSELAHELLHKLTGEELE NWWATEMMLELIKSDDEREIREIEEEAARILEHLE
RAAYFNWWATEMMLELIKSDDEREIREIEEEAARIL ELART(SEQ ID NO: 164)-X2-EHLEELARTCCASPAAPAPASPAAPAPSAPAGGNLD NLDELHMQMTDLVYEALHFAKDEEFQKHVEQLFEK
AHB2v ELHMQMTDLVYEALHEAKDEEFQKHVEQLEEKATKA ATKAYKNKDRQKLEKVVEELKELLERLIA(SEQ
2- YKNKDRQKLEKVVEELKELLERLLSGGASPAAPAPA ID NO: 155)-X3-LCB1_ ASMQVSDLIYEFMKTKDENLLEBAERLLEEVKR(SE MKTKDENLLEEAERLLEEVKR(SEQ ID NO:
PAS24 0 ID NO: 354) 135) MEKKINLDELHMQMTDLVYEALHFAKDEEFQKHVFQ
Xl-LFEKATKAYKNKDRQKLEKVVEELKELLERLLSGGA
NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEK
SPAAPAPASPAAPAPSAPAGGELEEQVMHVLDQVSE
LAHELLHKLTGEELERAAYFNWWATEMMLELIKSDD ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ
LCB3- EREIREIEEEAARILEHLEELARTGGASPAAPAPAS ID NO: 155)-X2-AHB2v PAAPAPSAPAGGDKENVLQKIYEIMKELERLGHAEA ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYF

NWWATEMMLELIKSDDEREIREIEEEAARILEHLE
LCB1 SSGSAWSHPQFEKGGGSGGGSGGSAWSHPQFEK(SE ELART(SEQ ID NO: 164)-X3-PAS24 Q ID NO: 355) DKENVLOKIYEIMKELERLGHAEASMOVSDLIYEF
MKTKDENLLEEAERLLEEVKR(SEQ ID NO:

135) -X4 Table 8A
SEQ ID Name Sequence DKENILQKIYEIMKTLDQLGHAEASMQVSDLI YEFMKQGDERLLEEAERLLEEVERG
1-4C4C45C4C4C4C4C414C4C45C4C4C4C4qC41-4C4C4C4i4C4C414C4C4C4C4C4C4C4SC414C4C4qC4C41-4C4SC4C414C414C4C4 GS GGGG SGGGGS GGGGSDKENI LQKI YE IMKTLDQLGHAEASMQVS DLIYEFMKQGD

DKENILQKIYEIMKTLDQLGHAEASMQVSDLI YEFMKQGDERLLEEAERL LEEVER_A
GSGGSGGSGGSDVDSTDDTDSDSTRDTDSDSDVDSTDDTDSDSTDDTDSDSDVPSTD
PT PSPST PET PS P SAS GDKENI LQKI YE IMKT LDQLGHAEASMQVS DL I YEFMKQGD

NDDELHMQMT DLVYEALH FAKDEE I QKHVFQL FEKATKAYKNKDRQKLEKVVEELKE
LLERLL SGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGS
GGGGSGGGGS GGGGSGGGGS GGGGSNDDELHMQMTDLVYEALHFAKDEEI QKHVFQL

NDDELHMQMT DLVYEALH FAKDEE I QKHVFQL FEKATKAYKNKDRQKLEKVVEELKE
LLERLL SAGSGGSGGSGGSPVP ST PPTP SP ST E'PTP SP S PVP ST PPT P SP ST PPTP S
PS PVPS TPPT PS PSTP PT PS PSASGNDDELHMQMTDLVYEALHFAKDEEI QKHVFQL

DKENILQKIYEIMKTLDQLGHAEASMQVSDLI YEFMKQGDERLLEEAERLLEEVERG
GGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGG
GS GGGG S GGGGS GGGGSNDDELHMQMTDLVYEALHFAKDEEI QKHVFQLFEKATKAY

NDDELHMQMT DLVYEALH FAKDEE QKHVFQL FEKATKAYKNKDRQKLEKVVEELKE
LLERLL S GGGGS GGGGS GGGGS GGGGS GGGGS GGGGSGGGGS GGGGS GGGGS GGGGS
GGGGSGGGGSGGGGSGGGGS GGGGSDKENI LQKI YEIMKTLDQLGHAEASMQVSDL I

DKENILQKIYEIMKTLDQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVERA
GSGGSGGSGGSPVPSTEPTESESTPETPSESEVESTEPTESPSTPPTPSPSPVPSTP
PSPST DDT DS P SAS GNDDELHMQMTDLVYEALHFAKDEEI QKHVEQLFEKATKAY

NDDELHMQMT DLVYEALH FAKDEE I QKHVFQL FEKATKAYKNKDRQKLEKVVEELKE
LLERLL SAGSGGSGGSGGSPVP ST PPTP SP ST E'PTP SP S PVP ST PPT P SP ST PPTP S
PS PVPS TPPT PS PSTP PT PS PSASGDKENT LQKIYEIMKTLDQLGHAEASMQVSDLI

CSL-YEFMKKGDERLLEEAERLLEEVERG

YEFMKKGDERL

CSL-NDDELHMLMTDLVYEALHFAKDEEIKKRVFQLFELADKAYKNNDRQKLEKWEELKE

LLERLLSGGGGSGGGGSGGGGSNDDELHMLMTDLVYEALHFAKDEEIKKRVFQLFEL

CSL-YEFMKKGDERLLEEAERLLEEVERG

GGGSGGGGSGGGGSGGGGSDKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKK

CSL-FELADKAYKNNDRQKLEKVVEELKE

LLERLLSGGGGSGGGGSGGGGSGGGGSNDDELHMLMTDLVYEALHFAKDEEIKKRVF

DKEWILQKIYEIMRLLDELGHAEASMRVSDLI YEFMKKGDERLLEEAERLLEEVERG
CSL-SSGSGS SGSGSSGSGSSGSDKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKK

GDERLLEEAERLLEEVERGSSSGGSSSGGSSSGGSS SGDKEWILQKIYEIMRLLDEL
L,52 0- 458 GHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER

CSL-NDDELHMLMTDLVYEALHFAKDEEIKKPVFQLFELADKAYKNNDRQKLEKVVEELKE

LLERLLSGSSGSGSSGSGSSGSGSSGSNDDELHMLMTDLVYEALHFAKDEEIKKRVF

QLFELADKAYKNNDRQELEKVVEELKELLERLLSGSSSGGSSSGGSSSGGSSSGNDD

ELHMLMTDLVYEALHFAKDEEIKKRVEQLFELADKAYKNNDBQKLEKVVEELKELLE

CSL-DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVERG

SAGGSPAGSPTSTGTSTSGDKEWILQKIYEIMPLLDELGHAEASMRVSDLIYEFMKK

DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVERG
CSL-SAGGSPAGSPTSTGTSGSGDKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKK

GDERLLEEAERLLEEVERGSAGGSPAGSPTSTGTSGSGDKEWILQKIYEIMRLLDEL
461 XTENx3 GHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER
CSL-NDDELHMLMTDLVYEALHEAKDEEIKKRVFQLFELADKAYKNNDRQKLEKVVEELKE

LLERLLSGSAGGSPAGSPTSTGTSGSGNDDELHMLMTDLVYEALHFAKDEEIKKRVF
462 XTENx2 QLFELADKAYKNNDRQKLEKVVEELKELLEPLLS
NDDELHMLMTDLVYEALHFAKDEEIKKPVFQLFELADKAYKNNDRQKLEKVVEELKE
LLERLLSGSAGGSPAGSPTSTGTSGSGNDDELHMLMTDLVYEALHFAKDEEIKKRVF
CSL-QLFELADKAYKNNDRQKLEKVVEELKELLERLLSGSAGGSPAGSPTSTGTSGSGNDD

ELHMLMTDLVYEALHFAKDEEIKKRVFQLFELADKAYKNNDRQKLEKVVEELKELLE
463 XTENx3 RLLS
C-DKEWILQKIYEIMRLLDELGRAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVERG

SSGSGSSGSGSSGSGSSGSDKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKK

GDERLLEEAERLLEEVERGSSSGGSSSGGSSSGGSSSGDKEWILQKIYEIMRLLDEL

C-NDDELHMLMTDLVYEALHFAKDEEIKKRVFnLFELADKAYKNNDRAKLEKVVEELKE

LLERLLSGSSGSGSSGSGSSGSGSSGSNDDELHMLMTDLVYEALHFAKDEEIKKRVF

ELHMLMTDLVYEALHFAKDEEIKKRVFQLFELADKAYKNNDRQKLEKVVEELKELLE

CSL-DKEWILQKIYEIMPLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVERG

GSSAGSPTSTGTSSATPSGSGTGGDKEWILQKIYEIMRLLDELGHAaASMRVSDLIY

464 x3 YEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER
NDDELHMLMTDLVYEALHFAKDEEIKKRVFQLFELADKAYKNNDRQKLEKVVEELKE
CSL-LLERLLSGGSSAGSPTSTGTSSATPSGSGTGGNDDELHMLMTDLVYEALHFAKDEEI

KKRVFOLFELADKAYKNNDROKLEKVVEELKELLERLLSGGSSAGSBTSTGTSSATP

465 x3 VVEELKELLERLLS
LCB1_v DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVERG
1.3_G9 GSSGGG99GGGSSGGGSSGGGSSGDKENILcKIYEIMKTLEQLgHAFP,SMQY9DLIY
466 _2X EFMKQGDERLLEEAERLLEEVER
LCB1_v DKENILQKIYEIMETLEQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVERG
1.3_XT GSSAGSPTSTGTSSATPSGSGTGGDKENILQKIYEIMKTLEQLGRAEASMQVSDLIY
467 EN_2X EFMKQGDERLLEEAERLLEEVER
LCB1_v DKENILQKIYEIMETLEQLGRAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVERG
1.3_EA GSSGEAAAKEAAAKEAAAKGSSGGDKENILcKIYEIMKTLEQLGHAEA9M17VSDLIY
468 AAK_2X EFMKQGDERLLEEAERLLEEVER
LCB1_v DKENILQKIYEIMETLEQLGRAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVERG
1.3_Pr GSSGPSTPETPSRSTEPTESESEGGSSGDKENILQEIYEIMKTLEQLGHAEASMQVS
469 o_2X DLIYEFMKQGDERLLEEAERLLEEVER
0 LCB1 v DKENILQEIYEIMKTLEQLGILAEASMQV3DLIYEEMKQGDERLLEEAERLLEEVERG

1.3_Ub GSSGQIEVKTLTGKTITLEVEESDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGP

LIYEEMKCGDERLLEEAERLLEEVER
DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVERG
LCB1_v GSSAGSPTSTGTSSATPSGSGTGGDKENILQKIYEIMKTLEQLGHAEASMQVSDLIY
1.3_XT EFMKQGDERLLEEAERLLEEVERGGSSAGSPTSTGTSSATPSGSGTGGDKENILQKI
471 EN_3X YEIMMTLEQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVER
DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVERG
LCB1_v GSSGEAAAKEAAAKEAAAKGSSGGDKENILQKIYEIMKTLEQLGHAEASMQVSDLIY
1.3_EA EFMKQGDERLLEEAERLLEEVERGGSSGEAAAKEAAAKEAAAKGSSGGDKENILQKI
472 AAK_3K YEIMKTLEQLGHAFASMQVSDLIYEFMKQGDERLLEEAERLLEEVER
DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEEMKQGDERLLEEAERLLEEVERG
LCB1_v GSSGPSTPPTPSPSTPPTPSPSPGGSSGDKENILQKIYEIMKTLEQLGHAEASMQVS
1.3 Pr DLIYEFMKQGDERLLEEAERLLEEVERGGSSGPSTPPTPSPSTPPTPSPSPGGSSGD
473 o_3X KENILQKIYEIMKTLEQLGHAEASMQVSDLIYEFMKQGDERLLERAERLLEEVER
DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVERG
GSSGQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGR
TLSDYNIQKESTLHLVLRLRGGGGSSGDKENILQKIYEIMKTLEQLGHAEASMQVSD
LCB1_v LIYEEMKOGDERLLEEAERLLEEVERGGSSGQIEVKTLTGKTITLEVEPSDTIENVK
1.3_Ub AKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGGGSSGDKE
474 _3X
NILQKIYEIMKTLEQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVER
DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEVKRG
1GS1_N GSSGGGSSGGGSSGGGSSGGGSSGDKENVLQKIYEIMKELERLGRAaASMQVSDLIY

DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEVKRG
1Pro1_ GSSGPSTPDTDSPSTPDTPSDSPGGSSGDKENVLQKIYEIMKELERLGHAEASMQVS

NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLEEKATKAYKNKDRQKLEKVVEELKE
3GS3_N LLERLLSGGSSGGGSSGGGSSGGGSSGGGSSGNLDELHMQMTDLVYaALHFAKDEEF

NLDELHMQMTDLVYEALHFAKDEREQKHVEQLEEKATKAYKNKDRQKLEKVVEELKE
3Pro3_ LLERLLSGGSSGPSTPPTPSPSTPPTPSPSPGGSSGNLDELHMQMTDLVYEALHFAK

DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEVKRG
1GS1_0 GSSGGGSSGGGSSGGGSSGGGSSGDKENVLQKIYEIMKELERLGHAaASMQVSDLIY

DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEEMKTKDENLLEFAERLLEEVKRG
1Prol_ GSSGPSTPPTPSPSTPPTPSPSPGGSSGDKENVLQKIYEIMKELERLGHAEASMQVS

NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLEEKATKAYKNKDRQKLEKVVEELKE
3GS3_0 LLERLLSGGSSGGGSSGGGSSGGGSSGGGSSGNLDELHMQMTDLVYaALHFAKDEEF

NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE
3Pro3 LLERLLSGGSSGPSTPPTPSPSTPPTPSPSPGGSSGNLDELHMQMTDLVYEALHFAK

DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEVKRG
GSSGGGSSGGGSSGGGSSGGGSSGDKENVLQKIYEIMKELERLGHAaASMQVSDLIY

479 1_NTS YEIMEELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEVKR
DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEVKRG
1Pro1P GSSGPSTPPTPSPSTPPTPSPSPGGSSGDKENVLQKIYEIMKELERLGHAEASMQVS
rol_NT DLIYEFMKTKDENLLEEAERLLEEVKRGGSSGPSTPPTPSPSTPPTPSPSPGGSSGD

KENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLFEAERLLEEVKR
NLDELHMQMTDLVYEALHFAKDEEEQKHVFQLEEKATKAYKNKDRQKLEKVVEELKE
LLERLLSGGSSGGGSSGGGSSGGGSSGGGSSGNLDELHMQMTDLVYaALHFAKDEEF
QKHVEQLEEKATKAYKNKDRQKLEKVVEELKELLERLLSGGSSGGGSSGGGSSGGGS

482 3Pro3P NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE
ro3_NT LLERLLSGGSSGPSTPPTPSPSTPPTPSPSPGGSSGNLDELHMQMTDLVYEALHFAK

DEEFQKHVEQLEEKATKAYKNKDRQKLEKVVEELKELLERLL SGGS S GE'S T PT P S
ST P PT P SP -----------------------PGGS5GNLDELHMCNTDLVYEALHEAKDEEFF)KHVEOLEEKATKAYKN
KDRQKL EKVVEELKELLERL LS
DRPNVLQRIYPIMKELERLGHAEASMQVSDLI YEFMKT KDENLLEEA ERL LEEVKRG
GS SGGGSSGGGS SGGGSSGGGS SGDKENVLQKIYEIMKELERLGHAF.P. SMQVSDLIY

479 1_CTS YEIMKELERLGHAEASMQVS DL YEEMKTKDENLLEEAERLLEEVKR
DKENVLQKIYEIMKELERLGHAEASMQVSDLI YEFMKT KDENLLEEA ERL LEEVKRG
1 r o1 P GS S GP S T P PT PS P ST P PT PS PS
PGGSSGDKENVLQKIYEIMKELERLGHAEASMQVS
rol_CT DL YEFMKT KDENLLEEAERLLEEVKRGGS SGP ST P PT P S RS TP PT P S RS PGGSSGD

KENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEVKR
NLDELHMQMTDLVYEALHFAKDEEFQKHVEQLFEKATKAYKNKDRQKLEKVVEELKE
LLERLL SGGS SGGGSSGGGS SGGGSSGGGS SGNLDELHMQMTDLVYEALHFAKDEEF
QKHVFQLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGGS SGGGS SGGGS SGGGS

481 3_CTS VVEELKELLERLLS
NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE
LLERLL SGGS SGP ST P PT PSPSTP PT PSPS PGGS S GNLDELHMQMT DLVYEALHFAK
3 Pr o3 P DEEFQKHVFQLFEKAT KAYKNKDRQKLEKVVEELKELLERLL SGGS S GP S TP PT P S P
ro3_CT ST P PT P SPS P GGS S GNLDELHMQMTDLVYEALHEAKDEEEQKHVEQLEEKAT KAYKN

DKENVLQKI YEIMKELERLGHAEASMQVSDL I YEFMKT KDENLLEEAERL LEEVKRG
1GS 3_11. GS SGGGSSGGGS SGGGSSGGGS S GNLDELHMQMTDLVYEALH EAKDEEFQ KHVFQL F

DKENVLQKI YEIMKELERLGHAEASMQVSDL I YEFMKT KDENLLEEAERL LEEVKRG
1 r o3_ GO S GP S T PT RS P ST P PT PSPS PGGS SGNLDELHMQMTDLVYEALHE'AKDEEEQKHV

NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE
3GS1_N LLERLL SGGS SGGGSSGGGS SGGGSSGGGS SGDKENVLQKIYEIMKELERLGHAEAS

NLDELHMQMTDLVYEALHFAKDEEFQKHVEQLFEKATKAYKNKDRQKLEKVVEELKE
.3Rrol_ LLERLL SGGS SGPSTP PT PS PSTP PT PS PS PGGSSGDKENVLQKIYEIMKELERLGH

DKENVLQKI YEIMKELERLGHAEASMQVSDL I YEEMKT KDENLLEEAERL LEEVKRG
1GS 3_C OS SGGGSSGGGS SGGGSSGGGS SGNLDELHMQMTDLVYEALHFAKDEEFQKHVFQLF

DKENVLQKI YEIMKELERLGHAEASMQVSDL I YEFMKT KDENLLEEAERL LEEVKRG
1P r o3 OS SGPS T P PT PS P ST P PT PSPS PGGS
SGNLDELHMQMTDLVYEALHFAKDEEFQKHV

NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE
3051_0 LLERLL SGGS SGGGSSGGGS SGGGSSGGGS SGDKENVLQKIYEIMKELERLGHAEAS

NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE
3Pro1_ LLERLL SGGS SGPSTPPTPS PSTPPTPS PS PGGSSGDKENVLOKIYEIMKELERLGH

NLDELHMQMTDLVYEALHFAKDEEFQKHVEQLEEKATKAYKNKDRQKLEKVVEELKE

IMKELERLGHAEASMQVS DL I YEFMKTKD
487 L_NTS ENLLEEAERLLEEVKR

NLDELHMQMTDLVYEALHEAKDEEEQKHVEQLEEKATKAYKNKDRQKLEKVVEELKE

IMKELERLGHAEASMQVS DL I YEFMKTKD
488 l_NTS ENLLEEAERLLEEVKR

NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE

SGDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
489 1_NTS MKTKDENLLEEAERLLEEVKR

NLDELHMQMTDLVYEALHEAKDEEEQKHVEQLEEKATKAYKNKDRQKLEKVVEELKE

YEIMKELERLGHAEASMQVSD
490 1_NTS LI YEFMKTKDENLLEEAERL LEEVKR

DKENVLQKI YEIMKELERLGHAEASMQVSDL I YEFMKT KDENLLEEAERL LEEVKRG
C_4S10-SC41-41-4SSC_4DKENVLC)KIYEIMKELERLC_4HAEASMOVSDLIYEEMKTKDENLLEEAE
491 1_NTS RLLEEVKR

DKENVLQKI YEIMKELERLGHAEASMQVSDL YEFMKT KDENLLEEAERL LEEVKRG

GS SGGGSSGGGS SGDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEEMKTKDENL
492 1_NTS LEEAERLLEEVKR

DKENVLQKI YEIMKELERLGHAEASMQVSDL I YEFMKT KDENLLEEAERL LEEVKRG

GS SGGGSSGGGS SGGGSSGDKENVLQKIYEIMKELERLGHAEASMQVSDL IYEFMKT
493 1_NTS KDENLLEEAERLLEEVKR
ELEEQVMHVLDQVSELAHEL LHKLTGEELERAAYFNWWATEMMLEL I KSDDEREI RE

TEEEARRILEHLEELRKGGSSGGGS SGDKENVLQKIYEIMKELERLGHAEASMQVS
494 1_GS10 DL I YEFMKT KDERLLEEAERLLEEVKR
ELEEQVMHVLDQVSELAHEL LHKLTC EELERAAYFNWWATEMMLEL I KSDDEREI RE

TEARRILEHLERKGGSSGGGSSGGGSSGDKENVLQKIYEINKELERLGHAEA
495 1_GS15 SMQVSDLIYEFMKTKDERLLEEAERLLEEVKR
ELEEQVMHVLDQVSELAHEL LHKLTGEELERAAYFNWVIATEMMLEL I KSDDEREI RE

TEARRILEHLEELARKGGSSGGGSSGGGSSGGGS SGDKENVLQKIYEIMKELERL
496 1_GS2 0 GHAEASMQVS DL I YEFMKTKDERLLEEAERLLEEVKR
ELEEQVMHVLDQVSELAHEL LHKLTGEELERAAYFNWVIATEMMLEL I KSDDEREI RE
I EEEARRI LEHLEELARKGGS GGGS SGELEEQVMHVLDQVSELAHELLHKLTGEEL

ERAAYFNWWATEMMLELI KS DDEREI RE I EEEARRI LEHLEELARKGGSS GGGSSGD
497 1_GS10 KENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDERLLEEAERLLEEVKR
ELQVMHVLDQVSELALLHKLTGLEPYFKWWATEMNLELT KSDDEREI RE
I EEEARRI LEHLEELARKGGS S GGGS SGGGSSGELEEQVMHVLDQVSELAHELLHKL
TGEELERAAYFNWWAT EMML EL I KSDDEREIREI FEEARRI LEHLEELARKGGS S GG

GS SGGGSSGDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEEMKTKDERLLEEAE
498 1_2S15 RLLEEVKR
ELEEQVMHVLDQVSELAKELLHKLTGEELEPAPYFKWWATEMNLELT KSDDEREI RE
I EEEARRI LEHLEELARKGGS S GGGS SGGGSSGGGS SGELEEQVMHVLDQVSELAHE
LLHKLT GEELERAAYFNWWATEMMLELI KS DDERET REI EEEARRI LEHLEELARKG

GS SGGGSSGGGS SGGGSSGDKENVLQKIYEIMKELERLGHAEASMQVSDL IYEFMKT
499 l_GS2 0 KDERLLEEAERLLEEVKR
ELEEQVMHVLDQVSELAHEL LHKLTGEELERAAYFNWWATEMMLEL I KSDDEREI RE

I EEEARRI LEHLEELARKGGS S GGGS SGELEEQVMHVLDQVSELAHELLHKLTGEEL
500 2_GS10 ERAAYFNWWATEMMLELI KS DDEREI RE I EEEARRI
LEHLEELARK
ELEEQVMHVLDQVSELAHEL LHKLTGEELERAAYFNWWATEMMLEL KSDDEREI RE

I EEEARRI LEHLEELARKGGS S GGGS SGGGSSGELEEQVMHVLDQVSELAHELLHKL

LEHLEELARK
ELEEQVMHVLDQVSELAHEL LHKLTGEELERAAYENWINATEMMLEL I KSDDEREI RE

I EEEARRI LEHLEELARKGGS S GGGS SGGGSSGGGS SGELEEQVMHVLDQVSELAHE
502 2_GS2 0 LLHKLT GEELERAAYFNWWATEMMLELI KS DDEREI REI
EEEARRI LEHLEELARK
ELEEQVMHVLDQVSELAKELLHKLTGEELEPAPYFKWWATEMNLELT KSDDEREI RE
I EEEARRI LEHLEELARKGGS S GGGS SGELEEQVMHVLDQVSELAHELLHKLTGEEL
ERAAYFNWWATEMMLELI KS DDEREI RE I EEEARRI LEHLEELARKGGSS GGGS S GE

LEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMLELI KS DDEREI REI
503 2_GS10 EEEARRILEHLEELARK
ELEEQVMHVLDQVSELAKELLHKLTGEELEPAPYFKWWATEMNLELT KSDDEREI RE
I EEEARRI LEHLEELARKGGS S GGGS SGGGSSGELEEQVMHVLDQVS ELAHELLHKL
TGEELERAAYFNWWAT EMML EL I KSDDEREIREI EEEARRI LEHLEELARKGGS SGG

GS SGGGSSGELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELI K
504 2_G515 SDDERE I PEI EEEARRILEHLEELARK
ELEEQVMHVLDQVSELAHEL LHKLTGEELERAAYFNWWATEMMLEL I KSDDEREI RE
I EEEARRI LEHLEELARKGGS S GGGS SGGGSSGGGS SGELEEQVMHVLDQVSELAHE
LLHKLT GEELERAAYFNWWATEMMLELI KS DDEREI REI EEEARRI LEHLEELARKG

GS SGGGSSGGGS SGGGSSGELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWW
505 2_GS2 0 AT EMML EL I KSDDEREIREI EEEARRILEHLEELARK

ELEEQVMHVLDQVSELAHEL LHKLTGEELERAAYFNWVIATEMMLEL I KSDDEREI RE
P

EEEARRI LEHLEELARKGGAS PAAPAPAS PAAPAP SAPAGGELEEQVMHVLDQVSE
LAHELLHKLT GEELERAAYFNWWATEMMLEL I KSDDEREI RE I EEEARRI LEHLEEL

ARK

NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE
LCB1_P LLERLL SGGASPAAPAPASP_AAPAPSAPAGGDKENVLQKI YE IMKELERL GHAEASM

I KS D DERE I RE
LCB1_P IEEEARRILEHLEELARKGGAS PAAPAPAS PAAPAP SAPAGGDKENVLQKIYEIMKE

ELEEQVMHVLDQVS ELAHEL LHKLTGEE LERAAYFNWWATEMMLEL I KS D DERE I RE
T EFEAR RT LEHLEELA PKGC; A S PA APAP AS PA A PA P SA PAGC;ELEEDVMHVLDOVSE
LAHELL HKLT GEELERAAYFNWWATEMMLEL I KS DDERE I RE I EEEARRI LEHLEEL
AHB2_3 ARKGGAS PAAPAPAS PAAPAP SAPAGGE LEEQVMHVLDQVS ELAHELLHKLT GEELE
509 x_PAS RAAYENWWAT EMMLEL I KS D DERE I REI
EEEARRILEHLEELARK
NL DE LHMQMT DLVYEALH FAKD EE FQ KHVFQL FEKATKAYKN RD RQ EL EKVVEE LEE
LLERLL SGGASPAAPAPASPAAPAPSAPAGGELEEQVMHVLDQVSELAHELLHKLTG
EELERAAYFNWWATEMMLEL I KS DDERE I RE I EEEARRI LEHLEELARKG GAS PAAP

YEIMKELERLGHAEASMQVSDLI YE FMKTKDE
510 1_PAS RLLEEAERLLEEVKR
ELEEQVMHVLDQVS ELAHEL LHKLTGEE LERAAYFNWVIATEMMLEL I KS D DERE I RE
I E EEARRI L EHL EELARKGGAS PAAPAPAS PAAPAP SAPAGGNL DE LHMQMT DLVYE
ALHFAKDEE FQKHVFQLFEKAT KAYKNKDRQKLEKVVEELKELLERLL S G GAS PAAP

YEIMKELERLGHAEASMQVSDLI YE EMKTKDE
511 1_PAS RLLEEAERLLEEVKR
DKENVLQKI YEIMKELERLGHAEASMQVS DL I YEFMKTKDENLLEEAERLLEEVKRG

GHAEASMQVS DL I YE
1_PAS 2 EMKTEDENLLEEAERLLEEVKRCCAS PAAPAPAS PAAPAP SAPACC DKENVLQKI YE

ELEEQVMHVLDQVS ELAHEL LHKLTGEE LERAAYENWWATEMMLEL I KS D DERE I RE
I E EEARRI L EHL EELARKGGAS PAAPAPAS PAAPAP SAPAGG EL EEQVMHVL DQVS E

I EEEARRI LEHLEEL
2_PAS2 ARKGGAS PAAPAPAS PAAPAPSAPAGGELEEQVMHVLDQVSELAHELLHKLTGEELE

EEEARRILEHLEELARK
NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE
LLERLL SGGASPAAPAPAS PAAPAPSAPAGGNLDELHMQMTDLVYEALHFAKDEEFQ

GAS PAAPAPAS PAAPAP S
3_PA52 APAGGNLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVV

ELEEQVMHVLDQVS ELAHEL LHKLTGEE LERAAYENWWA TEMMLEL I KS D DERE I RE
I E EEARRI L EHL EELARKGGAS PAAPAPAS PAAPAP SAPAGG EL EEQVMHVL DQVS E

I EEEARRI LEHLEEL
1_PAS2 ARKGGAS PAAPAPAS PAAPAPSAPAGGDKENVLQKI YE IMKELERLGHAEASMQVS D

I KS D DERE I RE
2_PAS 1 I E EEARRI L EHL EELARKGGAS PAAPAPAS PAGGEL EEQVMHVL DQVS ELAH EL LH K

LEHLEELARK

I KS D DERE I RE
2_PAS 1 I EEEARRI LEHLEELARKGGAS PAAPAGGELEEQVMHVLDQVSELAHELLHKLTGEE

EEEARRILEHLEELARK

NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE
l_PAS 1 LLERLL SGGASPAAPAPASPAGGDKENVLQKI YEIMKELERL GHAEASMQVS DL I YE

KDRQKLEKVVEELKE
1_PAS 1 LLERLL SGGASPAAPAGGDKENVLQKIYEIMKELERLGHAEASMQVS DLI YE FMKT

I KS D DERE I RE

TEMMLEL I KS D DERE I RE
1_PAS 1 I E EEARRI L EHL EELARKGGAS PAAPAGGDKENVLQKI YE IMKE LE RL GHAEASMQV

NIDELLMOVTDLIYEALHFAKDEEFQKHAFOLFEKATKAYKNKDKQKLEKVVEELKE
3v2.3- LLERILSGGASPAAPAPASPAAPAPSAPAGGELEEDVMHVLDOVSELAHELLHKLTG

EELERAAYENWWATEMMLELIKSDDEREIREIEEEARRILEHLEELAREGGASPAAP
1_RAS2 APASPAAPARSAPAGGDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEEMKTKDE

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE

IEFEARRILEHLEFLARKGGASPAAPAPASPAAPARSARAGGNIDELLMQVTDLIYE
3v2.3- ALHFAKDEEFQKHAFQLFEKATKAYKNKDKQKLEKVVEELKELLERILSGGASPAAP
1_PAS2 APASPAAPAPSAPAGGDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDE

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE
IEEEAARILEHLEFLARTGGASPAAPAPASPAAPAPSAPAGGELEFQVMHVLDQVSE

LAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIREIEEEAARILEHLEEL
2_P7S2 APTGGASPAARAPASPAAPAPSAPAGGELEFOVMHVLDOVSELAHELLHKLTGEELE
523 4_ompT RAAYFNWWATEMMLELIKSDDEREIREIEEEAARILEHLEELART
DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEVTRG

aASPAAPAPASPAAPAPSAPAGGDKENVLQKIYEIMKELERLGHAEASMQVSDLIYE
1_PAS2 FMKTMDENLLEEAERLLEEVIRGGASDAAPAPASDAADAPSAPAGGDKENVLQKIYE
524 4_ompT IMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEVTR
NIDELLMQVTDLIYEALHFAKDEEFQKHAFQLFEKATKAYKNKDKQKLEKVVEELKE
3v2.3- LLERILSGGASPAAPAPASPAARAPSAPAGGELEEQVMHVLDQVSELAHELLHKLTG

EELERAAYFNWWATEMMLELIKSDDEREIREIEEEAARILEHLEELARTGGASRAAP
1_PAS2 APASPAAPAPSAPAGGDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDE
525 4_ompT RLLEEAERLLEEVKR
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEAARILEHLEELARTGGASPAAPAPASPAAPAPSAPAGGNIDELLMQVTDLIYE
3v2.3- ALHFAKDEEFQKHAFQLFEKATKAYKNKDKQKLEKVVEELKELLERILSGGASPAAP
1_PAS2 APASFAAPAPSAPAGGDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDE
526 4_ompT RLLEEAERLLEEVKR
NIDELLMQVTDLIYEALHFAKDEEFQKHAFQLFEKATKAYKNKDKQKLEKVVEELKE
3v2.3- LLERILSGGASPAAPAPASPAAPAPSAPAGGELEEQVMHVLDQVSELAHELLHKLTG

EELERAAYENWWATEMMLELIKSDDEREIREIEEEARRILEHLEELARKGGASPAAP
1_0A52 APASEAAPAPSAPAGGDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDE

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGASPAAPAPASPAAPAPSAPAGGNIDELLMQVTDLIYE
3v2.3- ALHFAKDEEFQKHAFQLFEKATKAYKNKDKQKLEKVVEELKELLERILSGGASPAAP

NIDELLMQVTDLIYEALHFAKDEEFQKHAFQLFEKATKAYKNKDKQKLEKVVEELKE
3v2.3- LLERILSGGASPAAPAPASPAAPAPSAPAGGELEEQVMHVLDQVSELAHELLHKLTG

EELERAAYFNWWATEMMLELIKSDDEREIREIEEEAARILEHLEELARTGGASPAAP
1_PAS2 APASPAAPAPSAPAGGDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDE
529 4_ompT NLLEEAERLLEEVKR
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEAARILEHLEELARTGGASPAAPAPASPAAPAPSAPAGGNIDELLMQVTDLIYE
3v2.3- ALHFAKDEEFQKHAFQLFEKATKAYKNKDKQKLEKVVEELKELLERILSGGASPAAP
1_PAS2 APASFAAPAPSAPAGGDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDE
530 4_ompT NLLEEAERLLEEVKR

3v2.3- ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE
1_PAS2 IEEEARRILEHLEELARKGGASPAAPAPASPAAPAPSAPAGGNIDELLMQVTDLIYE
4_N-ALHFAKDEEFQKHAFQLFEKATKAYKNKDKQKLEKVVEELKELLERILSGGASPAAP
His-APASPAAPAPSAPAGGDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDE

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE
3v2.3-IEEEAARILEHLEELARTGGASPAAPAPASPAAPAPSAPAGGNIDELLMQVTDLIYE

ALHFAKDEEFQKHAFQLFEKATKAYKNKDKQKLEKVVEELKELLERILSGGASPAAP
4 mPT APASPAAPAPSAPAGGDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDE

NLLEEAERLLEEVKR
His-TEV
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE
IEFEARRILEHLEELARKGGASPAAPAPASPAAPAPSAPAGGNIDELLMQVTDLIYE

ALHFAKDEEFQKHAFQLFEKATKAYKNKDKQKLEKVVEELKELLERILSGGASPAAP
1_PAS2 APASPAAPAPSAPAGGDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDE
531 4_NTSF NLLEEAERLLEEVKR
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGASPAAPAPASPAAPAPSAPAGGNIDELLMQVTDLIYE
1_PA32 ALHFAKDEEFQKHAFQLFEKATKAYKNKDKQKLEKVVEELKELLERILSGGASPAAP
4_NT33 APASFAARAPSAPAGGDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDE

ELEEQVMHVLDQVSELAHELLHKLIGEELERAAYFNWWATEMMLELIKSDDEREIRE
IEFEARRILEHLEELARKGGASPAAPAPASPAAPAPSAPAGGNIDELLMQVTDLIYE

ALHFAKDEEFQKHAFQLFEKATKAYKNKDKQKLEKVVEELKELLERILSGGASPAAP
1_PAS2 APASPAAPAPSAPAGGDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDE
531 4_NTSM NLLERAERLLEEVKR

IEEEARRILEHLEELARKGGASPAAPAPASPAAPAPSAPAGGNIDELLMQVTDLIYE

1_NTS3 APASPAGGDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEEMKTKDENLLEEAER

ELEEQVMHVLDQVSELAHELLHKLIGEELERAAYFNWWATEMMLELIKSDDEREIRE
aAS16- IEEEARRILEHLEELARKGGASPAAPAPASPAGGNIDELLMQVTDLIYEALHFAKDE
1_NTS3 EFQKHAFQLFEKATKAYKNKDKQKLEKVVEELKELLERILSGGASPAAPAPASPAGG

DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEVKR

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE

1_NTS3 AFQLFEKATKAYKNKDKQKLEKVVEELKELLERILSGGASPAAPAPASPAGGDKENV

LQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEVKR

IEEEARRILEHLEELARKGGASPAAPAPASPAAPAPSAPAGGNIDELLMQVTDLIYE

1_NTS3 AGGDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEV

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE

1_NTS3 EFQKHAFQLFEKATKAYKNKDKQKLEKVVEELKELLERILSGGASPAAPAGGDKENV

LQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEVKR

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLEEIKSDDEREIRE

1_NTS3 AFQLFEKATKAYKNKDKQKLEKVVEELKELLERILSGGASPAAPAGGDKENVLQKIY

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE
IEEEARRILEHLEELARKGGGGELEEQVMHVLDQVSELAHELLHKETGEELERAAYF
538 2-2_G4 NWWATEMMLELIKSDDEREIREIEEEARRILEHLEELARK
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE
IEEEARRILEHLEELARKGGELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
539 2-2_G2 WATEMMLELIKSDDEREIREIEEEARRILEHLEELARK

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE
3_PAS2 IEEEARRILEHLEELARKGGASPAAPAPASPAAPAPSAPAGGNIDELLMQVTDLIYE

LS

I KS D DERE I RE
3_PAS 1 I EEEARRI LEHLEELARKGGAS PAAPAPAS PAGGNI DELLMQVT DL YEALHFAKDE

I KS D DERE I RE
3_PAS1 IEEEARRILEHLEELRKGGAS PAAPAGGNIDELLMQVTDLI YEALHFAKDEEFQKH

DKENVLQKI YEIMKELERLGHAEASMQVS DL I YEFMKTKDENLLEEAERLLEEVKRG
ES P6 PAPA S P AA PA PSAP AGGELEECVMHVLDOVSELAHELLHKLT C;E. ERAA Y

EEEARRILEHLEELARKGGASPAAPAPASPAAP
1_PAS2 AP SAPAGGDKENVLQKI YEIMKEL ERLGHAEASMQVSDL I YE FMKTKDENLLEEAER

PAS 24 - IEEEARRILEHLEELARKGGASPAAPAPASPAAPAPSAPAGGNLDELMNQ1vITDLVYE
3- ALHFAKDEE FQKHVFQLFEK_AT KAYKNKDRQKLEKVVEELKELLERLL S G GAS PAAP

544 1_NTS NLLEEAERLLEEVKR

PAS 24 - IEEEARRILEHLEELARKGGASPAAPAPASPAAPAPSAPAGGNLDELMMQ1vITDLVYE

545 1_NTS LLEEVKR

PAS 24 - AP SAPA GGDKENVLQKI YEIMKEL ERLGH_AEASMQVSDL I YE FMKTKDENLLEFAER
546 1_NTS LLEEVKR

LHMQMT DLVYEALH FAKD E

547 1_NTS DKENVLQKI YEIMKELERLGHAEASMQVS DL I
YEFMKTKDENLLEEAERLLEEVKR

PAAPAGGNLDELHMQMTDLVYEALHFAKDEEFQKH
PAS 16- VFQL FE KAT K_AYKNKD RQ KL EKVVEE LK EL LE RLL S GGAS FAAPAPAS FAGG
DKENV
548 1_NTS LQKI YE IMKELERLGHAEASMQVS DL I
YEFMKTKDENLLEEAERLLEEVKR

SAPAGGNL DE LHMQMT DLVYE

549 l_NTS KR

LHMQMT DLVYEALH FAKD E

550 1_NTS LQKI YE IMKELERLGHAEASMQVS DL I
YEFMKTKDENLLEEAERLLEEVKR

PAAPAGGNLDELHMQMTDLVYEALHFAKDEEFQKH
PAS ii- VFQL FE KAT K.AYKNKDRQKL EKVVEELKEL LERLL S GGAS FA_APAGGDKENVLQKI Y
551 1_NTS EIMKEL ERL GHAEASMQVS D LI YE FMKT
KDENLLEEAERLLEEVKR
EL EEQVMHVL DQVS ELAHEL LHKLTGEE LERAAYFNIZATATEMML EL I KS D DERE I RE
I EEEARRI L EHL EELARKGGASAGGN LD ELHMQMTDLVYEALHFAKDEEFQKHVFQL

YE IMKELER
552 l_PAS 7 LGHAEASMQVSDLI YE FMKT KDENLLEEAERLLEEVKR
EL EEQVMHVL DQVS ELAHEL LHKLTGEE LERAAYFNWWATEMML EL I KS D DERE I RE
I EEEARRI L EHL EELARKGG S GGS GGNLDELHMQMTDLVYEALHFAKDEE FQKHVFQ

GGDKENVLQKI YE IMKEL
553 1_G S7 ERLGHA.EASMQVSDLI YE FMKT KDENLL EEAERLLEEVKR

ELEEQVMHVLDQVSELAHEL LHKLTGEELERAAYFHWWATEMMLEL I KSDDEREI RE
EEEARRI L EHL EELARKGG GGNLDEL HMCVTDLVYEALHEAKDEEFOKHVEC)L FE

YEIMKELERLGHA
554 1_GS5 EASMQVS DL I YE EMKT KDEN LLEEAERL LEEVKR
FLFQVMHVLDQVSELALLHKLTGEELEPAPYFMWWATEMNLELI KSDDEREI RE
I EEEARRI LEHLEELARKGGS GGS GGS G GNLDELHMQMT DLVYEALHFAKDEEFQKH

GGSGGSGGSGGDKENVLQKI Y
555 1_GS11 EIMKELERLGHAEASMQVSDLI YEFMKT KDENLLEEAERLLEEVKR
ELEEQVMHVLDQVSELAHEL LHKLTGEELERAAYFNWWATEMMLEL I KSDDEREI RE
EEEARRI LEHLEELARKGGAS PAAPAGGELEEQVMHVLDQVSELAHELLHKLTGEE

EEEARRILEHLEELARKGGASPAAPAG
2_PAS 1 GELPEQVMHVLDQVSELAHELLHKLT GP ELERAAYFNWWATEMMLELI KS DDPREI

ELEEQVMHVLDQVSELAHEL LHKLTGEELERAAYFHWWATEMMLEL I KSDDEREI RE
I EEEARRI LEHLEELARKGGS GGS GGS G GELEEQVMHVLDQVSELAHELLHKLTGEE
LERAAYFNWWAT EMMLEL I KSDDEREI REI EEEARRILEHLEELARKGGS GGSGGSG

KS DDEREI R
557 2_GS11 EI EEEARRI LEHLEELARK
ELEEQVMHVLDQVSELAHEL LHKLTGEELERAAYFHWWATEMMLEL I KSDDEREI RE
EEEARRI LEHLEELARKGGS GCS GGEL EEQVMHVLDQVSELAHELLHKL TGEELER
AAYFNWWATEMPILELI KS DDEREI REIEEEARRILEHLEELARKGGSGGS GGELEEQ

DDEREI REIEEEA
558 2_G58 RRILEHLEELARK
ELEEQVMHVLDQVSELAHEL LHKLTGEELERAAYFNWWATEMMLEL I KSDDEREI RE
I EEEARRI LEHLEELARKGGS GGELEEQVMHVLDQVSELAHELLHKLT GEELERAAY
FNWWAT EMMLEL I KSDDEREI REI EEEARRILEHLEELARKGGSGGELEEQVMHVLD

REI EEEARRI LEH
559 2__GS5 LEELARK
ELEEQVMHVLDQVSELAHEL LHKLTGEELERAAYFHWWATEMMLEL I KSDDEREI RE

GGSGGNLDELHMQMTDLVYEALHFAKDEE
1_GGGG FQKHVFQLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGGSGGGGSGGGGSGGDK

YEFMKTKDENLLEEAERLLEEVKR
ELEEnVMHVLDC)VSELAHEL LHKLTC_4EELERAAYFHWWATEMMLEL KSDDEREI RE

GGNLDELHMQMTDLVYEALHFAKDEEFQK
1_GGGG HVFQLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGGSGGGGSGGGGDKENVLQK

YEFMKTKDENLLEEAERLLEEVKR
ELEEQVMHVLDQVSELAHEL LHKLTGEELERAAYFHWWATEMMLEL I KSDDEREI RE

GGGGNLDELHMQMTDLVYEALHFAKDEEFQKHVF
l_GGGG QL FEKATKAYKNKDRQKLEKVVEELKEL LERLLS GGGGS GGGGDKENVLQ KI YEIMK

ELEEQVMHVLDQVSELAREL LHKLTGEELERAAYFNWWATEMMLEL I KSDDEREI RE

GGGNLDELHMQMTDLVYEALHFAKDEEFQKHVFQL

YEFMKTKDENLLEEAERLLEEVKRG
1_GGGG GS GGGG S GGGGS GGGGS GGG GS GGDKENVLQKI YEIMKELERLGHAEASMQVSDLI Y

YEFMKTKDENLLEEAERLLEEVKRG
1_GGGG GS GGGG S GGGGS GGGGS GGDKENVLQKI YEIMKELERLGHAEASMQVSDL IYEFMKT

YEFMKTKDENLLEEAERLLEEVKRG
1_6GG6 GS GGGG S GGGGS GGDKENVLQKI YEIMKELERLGHAEASMQVSDLI YEFMKTKDENL

YEFMKTKDENLLEEAERLLEEVKRG
1_GGGG GS GGGG S GGDKENVLnKI YEIMKELERLGHAEASMoVSDLIYEFMKTKDENLLEEAE

KSDDERF I RE
1_GGGG I EEEARRI LEHLEELARKGGS GGGGS GGDKENVLQKIYEIMKELERLGHAEASMQVS

FEKATKAYKNKDRQKLEKVVEELKE
1_GC_4C_4G LLERLL ------------------- 14C4C4C4C4C4DKENVLC)KI YE IMKELERLC_4HA
EASMMTS DL YEFMKTKD

TEMMLEL I KS D DERE I RE
3_GGGC-', I EEEARRI LEHLEELARKGG S GGGGS GGNLDELHMQMTDLVYEALHFAKDEEFQKHV

FEKATKAYKNKDRQKLEKVVEELKE
.2_GGGG LLERLL S GC S GGGGSGGELEEQVMHVLDQVSELAHELLHKLTGEELEPAAYENWWAT

ELEEQVMHVLDQVS ELAHEL LHKLTGEE LERAAYFNWWATEMMLEL I KS D DERE I RE

GGNLDELHMQMTDLVYEALHFAKDEEFQKHV
l_GGGG FQLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGGS GGGG S GGDKENVLQKI YE I
.572 STO MKELERLGHAEASMQVSDLI YE FMKT KD ENLLEEAERLLEEVKR
NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE

GEELERAAYENWWAT
1_GGGG EMMLEL I KS DDEREI REI EEEARRI LEHLEELARKGGS GGGG S GGDKENVLQKI YE I

ELEEQVMHVLDQVS ELAHEL LHKLTGEE LERAAYFNWWATEMMLEL I KS D DERE I RE

IEARRIL5HLEARKGGSGGGGSGGGGSGGNLDELH1vIQMTDLVYEALHFAKD5E
1_GGGG FQKHVFQLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGGSGGGGS GGGGSGGDK

YEFMKTKDENLLEEAERLLEEVKR
NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE

ELAHELLHKLT GEE LERAAYF
1_GGGG NWWATEMMLELI KS DDEREI RE I EEEARRI LEHLEELARKGGSGGGGS GGGGSGGDK

KDENLLEEAERLLE EVKP

FEKATKAYKNKDRQKLEKVVEELKE
LCB1_P LLERLL SGGASPAAPAPGGDKENVLQKI YE IMKELERLGHAEASMQVS DL IYEFMKT

I KS D DERE I RE
LCBT_P IEEEARRILEHLEELARKGGAS PAAPAP GGDKENVLQKI YEIMKELERLGHAEASMQ

LERAAYFNWWATEMMLEL I KS D DERE I RE
LCB3_P I EEEARRI LEHLEELARKGGAS PAAPAP GGNLDELHMQMTDLVYEALHEAKDEEFQK

NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE
AHB2_P LLERLL S GGASRAARARGGE LEEQVMHVLDQVS ELAHELLHKLT GEELERAAYFNWW

I KS D DERE I RE
LC:B3- I EEEARRI LEHLEELARKGGAS PAAPAP
GGNLDELHMQMTDLVYEALHFAKDEEFQK
LCBT_P HVFQLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGGASPAAPAPGGDKENVLQK
579 AS12 IYEINK5LERLCFASMQVSDLIYNKTKDFNLLEEAERLLFEVKF.

NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE

SGGASPAAPAPGGELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWW
LCBT_P AT EMML EL I KSDDERE REI EEEARRILEHLEELARKGGASPAAPAPGGDKENVLQK

ERLLEEVKR
NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE

SGGASPAAPAPASP_AAPAPSAPAGGELEEQVMHVLDQVSELAHELLHKLTG

LEHLEELARKG GAS PAAP
LCB 1_P APAS PAARAP SAPAGGDKENVLQKI YEIMKELERLGHAEASMQVSDLI YE FMKTKDE

AHB2v2 ELEEQVMHVLDQVS ELAHEL LHKLTGEE LERAAYENWWATEMMLEL I KS D DERE I RE
LCB1_P I EEEAARI LEHLEELART GGAS PAAPAP GGDKENVLQKI YEIMKELERLGHAEASMQ

AHB2v2 ELEEQVMHVLDQVS ELAHEL LHKLTGEE LERAAYFNWWATEMMLEL I KS D DERE I RE

FEKATKAYKNKDRQKLEKVVEELKE
AHB2v2 LLERLL SGC_4ASPAAPAPC_4C_4ELEEC)VMHVLDC)VSELAHELLHKLTC_4EELERAAYFNWW
584 _PAS12 AT EMML EL I KSDDERE I REI EEEAARILEHLEELART
AHB2v2 ELEEQVMHVLDQVSELAHEL LHKLTGEE LERAAYFMTWATEMMLEL KSD =ET RE

LCB1_P HVFQLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGGASPAAPAPGGDKENVLQK
585 AS12 IINKLERLGFiAEASMQVSDLIYEMKTKDNLLEEAERLLEVKR

AHB2v2 NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE
LLERLL SGGASPAAPAPGGELEEQVMHVLDQVSELAHELLFIKLTGEELERAAYFNWW
LCBl_P AT EMML EL I KSDDERE I REI EEEAARILEHLEELARTGGASPAAPAPGGDKENVLQK
586 AS12 IYrINKrLERLGFASMQVSDLIYNKTKDFNLLEEAERLLEEVKF, ELQVMHVLDQVSELALLHKLTGLERYFJWWATEMNLELI KSD DEREI RE
AHB2v2 I EEEAARI LEHLEELART GGAS PA/PAPAS PAAPAP SAPAGGNLDELHMQMTDLVYE

LCBl_P APAS PAAPAP SAPAGGDKENVLQKI YEIMKELERLGHAEASMQVSDLI YE FMKTKDE
587 _AS24 NLLEEAERLLEEVKR

YKNKDRQKLEKVVEELKE
AHB2v2 LLERLL SGGASPAAPAPASPAAPAPSAPAGGELEEQVMHVLDQVSELAHELLHKLTG
EELERAAYFNWWATEMMLEL I KS DDERE I RE I EEEAARI LEHLEELA RTG GAS PAAP
LCB1_F' APAS PAAPAP SAPAGGDKENVLQKI YEIMKELERLGHAEASMQVSDLI YE FMKTKDE

In some embodiments, the polypeptides comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a genus selected from those recited in the middle column of Table 8. In these embodiments, Xl, X2, X3 (when recited in the genus), and X4 (when recited in the genus) may be present or absent, and when present may be any sequence of 1 or more amino acids. By way of example, the genus in the middle column, first row of sequences in Table 8 is X1-(SEQ ID NO:4)-X2-(SEQ ID
NO:4). In this embodiment, X2 may be present or absent and, when present, may (for example) comprise an amino acid linker of any suitable length and amino acid composition as deemed appropriate.
X1 may be present or absent, and when present may comprise any amino acid residue or residues as deemed appropriate, including but not limited to a leader sequence, a detectable tag, a purification tag, etc.
In another example, the genus in the middle column, last row of sequences in Table 8 is X1-(SEQ ID NO: 155)-X2-(SEQ ID NO: 164)-X3-(SEQ ID NO: 135)-X4. In this embodiment, X2 and X3 may be present or absent and, when present, may (for example) comprise an amino acid linker of any suitable length and amino acid composition as deemed appropriate. X1 and X4 may be present or absent, and when present may comprise any amino acid residue or residues as deemed appropriate, including but not limited to a leader sequence, a detectable tag, a purification tag, secretion signal etc.

In some embodiments, the optional domain that is present between monomer domains is present and may comprise an amino acid linker. Under this embodiment, (a) in the first example above X2 would be present and comprise an amino acid linker of any appropriate length and amino acid composition, and X1 may be present or absent; and (b) in the second example above one or both of X2 and X3 would be present and comprise an amino acid linker of any appropriate length and amino acid composition, and X1 and X4 may independently be present or absent.
In any embodiment or combination of embodiments of the polypeptides disclosed herein, the polypeptide may further comprise one or more additional functional peptide domain. Any such additional functional peptide domain may be used as appropriate for an intended purpose. In various non-limiting embodiments, the additional functional peptide domain may comprise, for example, a targeting domain, a detectable domain, a scaffold domain, a secretion signal, an Fc domain, or a further therapeutic peptide domain In one embodiment, the additional functional domain comprises an Fc domain, including but not limited to an Fc domain comprising an amino acid sequence comprising the amino acid sequence of SEQ ID NO:64.
Fc domain:
EPKSSDKTFITCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSKEDPEVKFNWYVDCVEVHNAKTKPRE
EQYNS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI
AVEW
ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:
64) In another embodiment, the added functional domain may comprise an oligomerization domain. Any oligomerization domain may be used as suitable to generate an oligomer as suitable for an intended purpose. In one non-limiting embodiment, the oligomerization domain may comprise a homotrimerization domain. Exemplary oligomerization domains may comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:179-189 and 589-594.
1rfo GYIPEAPRDGQAYVRKDGEWVLLSTFL (SEQ ID NO: 179) Ina int EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNAEAWYNLGNAYYKQGDYDEAIEYY
2-R3 QKALELDPNNAEAKQNLGNAKQKQG(SEQ ID NO: 180) 111d0 EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNAEAWYNLGNAYYKQGDYDEAIEYYQKALEL
int DPNNAEAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAKQNLGNAKQKQG(SEQ ID NO:
2 181) 6msr GSEYEIRKALEELKASTAELKRATASLRASTEELKKNPSEDALVENNRLIVEHNA

IVENNRI IAAVLELIVRAIK ( SEQ ID NO: 182) RMKQIEDKIEEILSKIYHIENEIARIKKLIGER (SEQ ID NO:
1gcm 183) pP0-ncHi GSEYEIRKALEELKASTAELKRSTASLRASTEELKKNPSEDALVENNRLIVENNA
IIVENNRIIAAVLELIVRAIK(SEQ ID NO: 184) 1na0 NLAEKMYKAGNAMYRKGQYTIAIIAYTLALLKDPNNAEAWYNLGNAAYKKGEYDEAIEAYQKALELDP
3 NNAEAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAKQNLGNAKQKQG(SEQ ID NO:
185) GEIAKSLKEIAKSLKEIAWSLKEIAKSLKG(SEQ ID NO:
4pn9 186) VLRIIAKVLK(SEQ ID NO: 187) 5.1 IIAK(SEQ ID NO: 188) S317 SEKALRELKKSTDELERSTEELEKNGSPEALVENNRLIVENNKIIVEVLR( 5.2 SEQ ID NO: 189) 031 IRKVKEESKRIVEEAEEEIRRAKEESRKIADESR (SEQ ID NO: 589) EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNAEAWYNLGNAYYKQG

9.2 NNAEAWYNLGNAYYKQGDYDEAIEYYQKALEL(SEQ ID NO: 590) 1na0 int v2 DYDEAIYYQKALELDPNNAEAKQNLGNAKQKQ(SEQ ID NO: 591) Ina int v3 DYDEIEYYQKALELDPNNAEAKQNLGNAKQKQ(SEQ ID NO: 592) 1na0 EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNAEAWYNLGNAYYKQG
int DYDEAIYYQKALELDPNNAEAWYNLGNAYYKQGDYDEAIEYYQKALELDPN
2 v2 NAEAKQNLGNKQKQ(SEQ ID NO: 593) 6m sr EYEIRKALEELKASTAELKRATASLRASTEELKKNPSEDALVENNRLIVEH
v2 NAIIVENRIIAAVLELIVRAIK(SEQ ID NO: 594) In one embodiment, the polypeptide comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of 5 SEQ ID NOS 356-453 and 595-692 and a genus selected from those recited in the right hand column of Table 9 wherein genus positions Xl, X2, X3, and X4 may be present or absent, and when present may be any sequence of 1 or more amino acids. In all embodiments, any N-terminal methionine residues may be present or absent in the polypeptide. In one embodiment, any N-terminal methionine residues are absent in the polypeptide.
Table 9. Homotrimer Desi2ns Annotated: Xl, X2, X3, and X4 may bc present or absent, and when present may be any Name Protein sequence of 1 or more amino acids MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDOVSELAHELLHKLTGEELERLAYENW
SGSGSGYIPEAPRDOQAYVRKDGEWVL WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
LSTFLGGSGSSGSAWSHPQFEKGGGSG K(SEQ ID NO:101)-X2-AHB2- GGSGGSAWSHPQFEK(SEQ ID NC: GYIPEAPRDGQAYVRKDGEWVLLSTFL
SEQ ID
6GS-1rfo 356) NO: 179)-X3 MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
SGSGSGSGSGSGSGSGSGSGSGSGSGS
WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
ELEEQVMHVLDQVSELAHELLHKLTGE K(SEQ ID NO:101)-X2-ELERAAYFNWWATEMMLELIKSDDERE ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW

28G5- GYIPEAPRDGQAYVRKDGEWVLLSTFL K(SEQ ID NO:101)-X3-GYIPEAPRDGQAYVRKDGEWVLLSTFL(SEQ ID
6GS-irto SAWSHPQFEK(SEQ ID NO: 35/) NO: 1/9)-X4 MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
SGSGGYIPEAPRDGQAYVRKDGEWVLL WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
STFLGGSGSSGSAWSHPQFEKGGGSGG K(SEQ ID NO:101)-X2-AHB2- GSGGSAWSHPQFEK(SEQ ID NO:
GYIPEAPRDGQAYVRKDGEWVLLSTFL(SEQ ID
50S-1rfo 358) NO: 179)-X3 MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERLAYFNW
SGSGYIPEAPRDGQAYVRKDGEWVLLS WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
TFLGGSGSSGSAWSHPQFEKGGGSGGG K(SEQ ID NO:101)-X2-AHB2- SGGSAWSHPQFEK(SEQ ID NO: GYIPEAPRDGQAYVRKDGEWVLLSTFL(SEQ
ID
45S-lrfo 359) NO: 179)-X3 MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
SGGYIPEAPRDGQAYVRKDGEWVLLST WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
FLGGSGSSGSAWSHPQFEEGGGSGGGS K(SEQ ID NO:101)-X2-AHB2- GGSAWSHPQFEK(SEQ ID NO: GYIPEAPRDGQAYVRKDGEWVLLSTFL(SEQ
ID
305-1rfo 360) NO: 179)-X3 MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
SGSGSGSGSGSGSGSGSGSGSGSGSGS
WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
ELEEQVMHVLDQVSELAHELLHKLTGE K(SEQ ID NO:101)-X2-EIRRAAYFNUWATEMMLEIJKSDDFRE ELEEOVMHVLDOVSELAHELLHKLTC;EFLERAAYENW

280S- PEAPRDGQAYVRKDGEWVLLSTFLGGS K(SEQ ID NO:101)-X3-AHB2- GSSGSAWSHPQFEKGGGSGGGSGGSAW GYIPEAPRDGQAYVRKDGEWVLLSTFL(SEQ
ID
305-irto SHPQFEK(SEQ ID NO: 361) NO: 1/9)-X4 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYENWWATEMMLELIKS

SGSSEELRAVADLQRLNIELARKLLEA ELEEQVMHVLDQVSELAHELLHKLTGEELERLAYFNW
VARLQELNIDLVRKTSELTDEKTIREE WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
IRKVKEESKRIVEEAEEEIRRAKEESR K(SEQ ID NO:101)-X2-4G5- SGGGSGGSAWSHPQFEK(SEQ ID
KTSELTDEKTIREEIRKVKEESKRIVEEAEEEIRRAK
5L6HC3_1 NO: 362) EESRKIADESR (SEQ ID NO: 589) MEKKIELEEOVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS

SGSGSEELRAVADLQRLNIELARKLLE ELEEQVMNVLDQVSELAHELLHKLTGEELERLAYENW
AVARLQELNIDLVRKTSELTDEKTIRE WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
EIRKVKEESKRIVEELEEEIRRAKEES K(SEQ ID NO:101)-X2-5GS- GSGGGSGGSAWSHPQFEK(SEQ ID
KTSELTDEKTIREEIRKVKEESKRIVEEAEEEIRRAK
5L6H03_1 NO: 363) EESRKIADESR (SEQ ID NO: 589) MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS
DDEREIREIEEEARRILEHLEELARKG
SGSGSGSGSGSGSGSGSGSGSGSGSGS
ELEEQVMHVLDQVSELAHELLHKLTGE
ELERAAYFNWWATEMMLELIKSDDERE
IREIEEEARRILEHLEELARKGSGSSE XI-ELRAVADLQRLNIELARKLLEAVARLQ ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW

WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
280S- EESKRIVEEAEEEIRRAKEESRKIADE K(SEQ ID NO:101)-X2-4G5- GGSAWSHPQFEK(SEQ ID NO:
WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
5L6H03_1 364) K(SEQ ID NO:101)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS
DDEREIREIEEEARRILEHLEELARKG
SGSGSGSGSGSGSGSGSGSGSGSGSGS
ELEEQVMHVLDQVSELAHELLHKLTGE
ELERAAYFNWWATEMMLELIKSDDERE

EELRAVADLQRLNIELARKLLEAVARL ELEEQVMHVLDQVSELAHELLHKLTGEELERLAYENW

WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
286S- KEESKRIVEEAEEEIRRAKEESRKIAD K(SEQ ID NO:101)-X2-5GS- SGGSAWSHPQFEK(SEQ ID NO:
WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
5L6H03_1 365) K(SEQ ID NO:101)-Z3 MEKKINLDELHMQMTDLVYEALHEAKD Xl-EEFQKHVFQLFEKATKAYKNKDRQKLE NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKAT
KVVEELKELLERLLSGSGSGSGYIPEA KAYKNKDROKLEKVVEELKELLERLLS(SE0 ID
PRDGQAYVRKDGEWVLLSTFLGGSGSS NO: 155)-X2-GYIPEAPRDGQAYVRKDGEWVLLSTFL(SEO ID
6GS-irfo QFEK(SEQ ID NO: 366) NO: 179)-X3 MEKKINLDELHMQMTDLVYEALHFAKD Xl-EEFOKHVFOLFEKATKAYKNKDROKLE NLDELHMQMTDLVYEALHFAKDEEFOKHVFOLFEKAT
KVVEELKELLERLLSGSGSGGYIPEAP KAYKNKDRQKLEKVVEELKELLERLLS(SEQ
ID
RDGOAYVRKDGEWVLLSTFLGGSGSSG NO: I55)-X2-GYIPEAPRDGQAYVRKDGEWVLLSTFL(SEQ ID
5GS-lrfo FEK(SEQ ID NO: 367) NO: I79)-X3 MEKKINLDELHMQMTDLVYEALHFAKD XI-EEFOKHVFQLFEKATKAYKNKDRQKLE NLDELHMQMTDLVYEALHFAKDEEFOKHVFQLFEKAT
KVVEELKELLERLLSGSGSGYIPEAPR KAYKNKDROKLEKVVEELKELLERLLS(SE0 ID
DGQAYVRKDGEWVLLSTFLGGSGSSGS NO: 155)-X2-LCB3- AWSHFOFEKGGGSGGGSGGSAWSHPQF GYIPEAPRDGQAYVRKDGEWVLLSTFL(SEO
ID
4GS-irto EK(SEQ ID NO: 368) NO: 119)-X3 MEKKINLDELHMQMTDLVYEALHFAKD

KVVEELKELLERLLSGSGSGSEELRAV NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKAT
ADLQRLNIELARKLLEAVARLQELNID KAYKNKDRQKLEKVVEELKELLERLLS(SEQ ID
LVRKTSELTDEKTIREEIRKVKEESKR NO: 155)-X2-SOS- GSSGSAWSHPQFEKGGGSGGGSGGSAW
KTSELTDEKTIREEIRKVKEESKRIVEEAEEEIRRAK
5L6H03_1 SHPQFEK(SEQ ID NO: 369) EESRKIADESR (SEQ ID NO: 589) KAYKNKDRQKLEKVVEELKELLERLLS(SE0 ID

4GS- GSGSGSGSGSGSGSGSNLDELHMQMTD NO: 155)-X2-5L6H03_1 LVYEALHFAKDEEFOKHVFOLFEKATK NLDELHMOMTDLVYEALHFAKDEEFOKHVFOLFEKAT
AYKNKDRQKLEKVVEELKELLERLLSG KAYKNKDRQKLEKVVEELKELLERLLS(SEQ ID
SGSSEELRAVADLQRLNIELARKLLEA NO: 155)-X3 VARLQELNIDLVRKTSELTDEKTIREE
IRKVKEESKRIVEEAEEEIRRAKEESR
KIADESRGGSGSSGSAWSHPQFEKGGG
SGGGSGGSAWSHPQFEK(SEQ ID
NO: 370) MEKKINLDELHMQMTDLVYEALHFAKD
EEFQKHVFQLFEKATKAYKNKDRQKLE
KVVEELKELLERLLSGSGSGSGSGSGS
GSGSGSGSGSGSGSGSNLDELHMQMTD
LVYEALHFAKDEEFQKHVFQLFEKATK

SGSGSEELRAVADLQRLNIELARKLLE NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKAT
LCB3- AVARLQELNIDLVRKTSELTDEKTIRE KAYKNKDRQKLEKVVEELKELLERLLS(SEQ
ID
28GS- EIRKVKEESKRIVEEAEEEIRRAKEES NO: 155)-X2-LCB3- RKIADESRGGSGSSGSANSHPQFEKGG NLDELHMoMTDLVYEALHFAKDEEFOKHVFoLFEKAT
5GS- GSGGGSGGSAWSHPQFEK(SEQ ID
KAYKNKDRQKLEKVVEELKELLERLLS(SEQ ID
5L6H03_1 NO: 371) NO: 155)-X3 MEKKIEEAELAYLLGELAYKLGEYRIA

QGDYDEAIEYYQKALELDPNNAEAWYN DKENVLQKIYEIMKELERLGEAEASMQVSDLIYEFMK
LGNAYYKQGDYDEAIEYYQKALELDPN TKDENLLEEAERLLEEVKR(SEQ ID NO:
NAEAWYNLGNAYYKQGDYDEAIEYYQK 135)-X2-ALELGSGSGSDKENVLQKIYEIMKELE EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNA
HLGHAEASMQVSDLIYEFMKTKDENLL EAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAW
36729.2_ EEAERLLEEVKRGGSGSSGSAWSHPQF YNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAWYNL
LCB-1v2.2 EKGGGSGGGSGGSAWSHPQFEK(SEQ GNAYYKQGDYDEAIEYYQKALEL (SEQ
ID NO:
6G3 ID NO: 372) 590) MEKKIEEAELAYLLGELAYKLGEYPIA

QGDYDEAIEYYQKALELDPNNAEAWYN DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMK
LGNAYYKQGDYDEAIEYYQKALELDPN TKDENLLEEAERLLEEVKR(SEQ ID NO:
NAEAWYNLGNAYYKQGDYDEATEYYQK 135)-X2-ALELGSGSDKENVLQKIYEIMKELERL EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNA
GHAEASMQVSDLIYEFMKTKDENLLEE EAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAW
36729.2_ AERLLEEVKRGGSGSSGSAWSHPQFEK YNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAWYNL
LCB1v2.2 GGGSGGGSGGSAWSHPQFEK(SEQ ID GNAYYKQGDYDEAIEYYOKALEL (SEQ
ID NO:
4GS NO: 373) 590) MEKKIEEAELAYLLGELAYKLGEYRIA
IRAYRIALKRDPNNAEAWYNLGNAYYK Xi-QGDYDEAIEYYQKALELDPNNAEAWYN DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMK
LGNAYYKQGDYDRAIEYYQKALELDPN TKDENLLEEAERLLEEVKR(SEQ ID NO:
NAEAWYNLGNAYYKQGDYDEAIEYYQK 135)-.X2-ALELGSDKENVLQKIYEIMKELERLGH EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNA
AEASMQVSDLIYEFMKTKDENLLEEAE EAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAW
36729.2_ RLLEEVKRGGSGSSGSAWSHPQFEKGG YNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAWYNL
LCB1v2.2 GSGGGSGGSAWSHPQFEK(SEQ ID GNAYYKQGDYDEAIEYYQKALEL (SEQ
ID NO:
265 NO: 374) 590) MEKKINLDELHMQMTDLVYEALHFAKD
EEFQKHVFQLFEKATKAYKNKDRQKLE
KVVEELKELLERLLSGGASPAAPAPAS
RAAPAPSAPAGGNLDELHMQMTDLVYE
ALHFAKDEEFQKHVFQLFEKATKAYKN
KDRQKLEKVVEELKELLERLLSGSGSS -ATKAYKNKDRQKLEKVVEELKELLERLLS(SEQ ID
9AS24- KEESKRIVEEAEEEIRRAKEESRKIAD NO: 155)-X2-4GS- SGGSAWSHPQFEK(SEQ ID NO: KAYKNKDRQKLEKVVEELKELLERLLS(SEQ
ID
5L6H03 1 375) NO: 155)-X3

81 KAYKNKDROKLEKVVEELKELLERLLS(SEF) ID
5GS- PAAPAPSAPAGGNLDELHMQMTDLVYE NO: 155)-X2-5L6HC3_1 ALHFAKDEEFQKHVFQLEEKATKAYKN NLDELNMQMTDLVYEALHEAKDEEEQKHVEQLEEKAT
KDRQKLEKVVEELKELLERLLSGSGSG KAYKNKDRQKLEKVVEELKELLERLLS(SEQ ID
SFELRAVADLQRLNIFLARKLLEAVAR NO: 155)-X3 LQELNIDLVRKTSELTDEKTIREEIRK
VKEESKRIVEEAEEEIRRAKEESRKIA
DESRGGSGSSGSAWSHPQFEKGGGSGG
GSGGSAWSHPQFEK(SEQ ID NO:
376) EASMQVSDLIYEFMKTKDENLLEEAER DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMK
LLEEVKRGGGSGGGSGGELEEQVMHVL TKDENLLEEAERLLEEVKR(SEQ ID NO:
DQVSELAHELLHKLTGEELERAAYFNW 135)-X2-WATEMMLELIKSDDEREIREIEEEARR ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW

WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
LOGS- YVRKDGEWVLLSTFLGGSGSSGSAWSH K(SEQ ID NO:101)-X3-A11D2- PQFEKGGGSGGGSGGSAWSHPQFEK(S
GYIPEAPRDGQAYVRKDGEWVLLSTFL(SEQ ID
4G5-lrfo EQ ID NO: 377) NO: 179)-X4 MEKKIDKENVLQKIYEIMKELERLGHA

LLEEVKRGSGSGSGSGSGSGSGSGSGS
DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMK
GSGSGSGSELEEQVMHVLDQVSELAHE TKDENLLEEAERLLEEVKR(SEQ ID NO:
LLHKLTGEELERAAYFNWWATEMMLEL 135)-X2-IKSDDEREIREIEEEARRILEHLEELA ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
LCBI- RKGSGSGYIREARRDGQAYVRKDGEWV
WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
20GS- LLSTFLGGSGSSGSAWSHPQFEKGGGS K(SEQ ID NO:101)-X3-AHB2- GGGSGGSAWSHPQFEK(SEQ ID NO:
GYIPEAPRDGQAYVRKDGEWVLLSTFL(SEQ ID
4GS-Irfo 378) NO: 179)-X4 EEFQKHVFQLFEKATKAYKNKDRQKLE NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEKAT
KVVEELKELLERLLSGGGSGGGSGGEL KAYKNKDRQKLEKVVEELKELLERLLS(SEQ ID
EEQVMHVLDQVSELAHELLHKLTGEEL NO: 155)-X2-ERAAYFNWWATEMMLELIKSDDEREIR ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW

LOGS- EAPRDGQAYVRKDGEWVLLSTFLGGSG K(SEQ ID NO:101)-X3-GYIPEAPRDGQAYVRKDGEWVLLSTFL(SEQ ID
4GS-Irfo HPQFEK(SEQ ID NO: 379) NO: 179)-X4 MEKKINLDELHMMTDLVYEALHFAKD
EEFQKHVFQLFEKATKAYKNKDRQKLE Xl-KVVEELKELLERLLSGSGSGSGSGSGS NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEKAT
GSGSELEEQVMHVLDQVSELAHELLHK KAYKNKDRQKLEKVVEELKELLERLLS(SEQ ID
LTGEELERAAYFNWWATEMMLELIKSD NO: 155)-X2-DEREIREIEEEARRILEHLEELARKGS ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW

16GS- FLGGSGSSGSAWSHPQFEKGGGSGGGS K(SEQ ID NO:101)-X3-AHB2- GGSAWSHPOFEK(SEQ ID NO: GYIPEAPRDGQAYVRKDGEWVLLSTFL(SE0 ID
4G5-irto 380) NO: 119)-X4 MEKKISAWSHPQFEKGGGSGGGSGGSA
WSHPQFEKGGSGSSGMEEAELAYLLGE
LAYKLGEYRIAIRAYRIALKRDPNNAE
AWYNLGNAYYKQGDYDEAIEYYQKALE
LDPNNAEAWYNLGNAYYKQGDYDEAIE
YYOKALELDPNNAEAWYNLGNAYYKQG

QKIYEIMKELERLGHAEASMQVSDLIY DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMK
36729.2 EFMKTKDENLLEEAERLLEEVKRGSGS TKDENLLEEAERLLEEVKR(SEQ ID
NO:
6GS_LCB1 GSGSGSGSGSGSGSGSGSGSGSGSNLD 135)-X2-v2.2- ELHMQMTDLVYEALHFAKDEEFQKHVF NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEKAT
28GS- QLFEKATKAYKNKDRQKLEKVVEELKE KAYKNKDRQKLEKVVEELKELLERLLS(SEQ
ID
LCB3 LLERLLS(SEQ ID NO: 381) NO: 155) 36729.2 MEKKISAWSHPQFEKGGGSGGGSGGSA X1-6GS_L0B1 WSHPCFEKGGSGSSGMEEAELAYLLGE DKENVLOKIYEIMKELERLGHAEASMOVSDLIYEFMK

82 v2.2- LAYKLGEYRIAIRAYRIALKRDPNNAE TKDENLLEEAERLLEEVKR(SEQ ID NO:
9GS-LCB3 AWYNLGNAYYKnGDYDFAIEYYOKALF 135)-X2-LDPNNAEAWYNLGNAYYKQGDYDEAIE NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEKAT
YYQKALELDPNNAEAWYNLGNAYYKQG KAYKNKDRQKLEKVVEELKELLERLLS(SEQ ID
DYDEAIEYYQKALELGSGSGSDKENVL NO: 155) QKIYEIMKELERLGHAEASMQVSDLIY
EFMKTKDENLLEEAERLLEEVKRGSGS
GSGSGMLDELHMQMTDEVYEALHFAKD
EEFQKHVFQLFEKATKAYKNKDRQKLE
KVVEELKELLERLLS(SEQ ID NO:
362) MEKKISAWSHPQFEKGGGSGGGSGGSA
WSHPQFEKGGSGSSGMEEAELAYLLGE
LAYKLGEYRIAIRAYRIALKRDPNNAE
AWYNLGNAYYKQGDYDEAIEYYQKALE
LDPNNARAWYNLGNAYYKQGDYDEAIE
YYQKALELDPNNAEAWYNLGNAYYKQG
DYDEAIEYYQKALELGSGSGSDKENVL
oKIYEIMKELERLGHAEASMnVSDLIY XI-EFMKTKDENLLEEAERLLEEVKRGSGS DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMK
36729.2_ GSGSGSGSGSGSGSGSGSGSGSGSELE TKDENLLEEAERLLEEVKR(SEO ID NO:
6GS_LCB1 EQVMHVLDQVSELAHELLHKLTGEELE 135)-X2-v2.2- RAAYFNWWATEMMLELIKSDDEREIRE ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
28GS- IEEEARRILEHLEELARK(SEQ ID
WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
Ai-1B2 NO: 383) K(SEQ ID NO: 101) MEKKISAWSHPQFEKGGGSGGGSGGSA
WSHPQFEKGGSGSSGMEEAELAYLLGE
LAYKLGEYRIAIRAYRIALKRDPNNAE
AWYNLGNAYYKQGDYDEAIEYYQKALE
LDPNNAEAWYNLGNAYYKQGDYDEAIE
YYQKALELDPNNAEAWYNLGNAYYKQG

QKIYEIMKELERLGHAEASMQVSDLIY DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMK
EFMKTKDENLLEEAERLLEEVKRGSGS TKDENLLERAERLLEEVKR(SEQ ID NO:
36729.2_ GSGSGELEEQVMHVLDQVSELAHELLH 135)-X2-6GS_LCB1 KLTGEELERAAYFNWWATEMMLELIKS ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
v2.2- DDEREIREIEEEARRILEHLEELARK( WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
9GS-AFB2 SEQ ID NO: 384) K(SEQ ID NO:101) EASMQVSDLIYEFMKTKDENLLEEAER DKENVLOKIYEIMKELERLGHAEASMQVSDLIYEFMK
LLEEVKRGGGSGGGSGGNLDELHMQMT TKUENLLEEAERLLEEVKR(SEQ ID NO:
DLVYEALHFAKDEEFQKHVFQLFEKAT 135)-X2-KAYKNKDRQKLEKVVEELKELLERLLS NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEKAT
LCB1- GSGSGYIPEAPRDGQAYVRKDGEWVLL KAYKNKDRQKLEKVVEELKELLERLLS(SEQ
ID
10GS- STFLGGSGSSGSAWSHPQFEKGGGSGG NO: 155)-X3-LCB3- GSGGSAWSHPQFEK(SEQ ID NO:
GYIPEAPRDGQAYVRKDGEWVLLSTFL(SEQ ID
4GS-1rfo 385) NO: 179)-X4 aASMQVSDLIYEFMKTKDENLLEEAER DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMK
LLEEVKRGSGSGSGSGSGSGSGSGSGS IKDENLLEEAERLLEEVKR(SEQ ID NO:
GSGSGSGSNLDELHMQMTDLVYEALHE 135)-X2-AKDEEFQKHVFQLFEKATKAYKNKDRQ NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEKAT

KAYKNKDRQKLEKVVEELKELLERLLS(SEQ ID
28G5- APRDGQAYVRKDGEWVLLSTFLGGSGS NO: 155)-X3 GYIREARRDGQAYVRKDGEWVLLSTFL(SEQ ID
4GS-1rfo PQFEK(SEQ ID NO: 386) NO: 179)-X4 KLIGEELERAAYENWWATEMMLELIKS ELEEQVMHVLDQVSELAHELLHKLIGEELERAAYENW
DDEREIREIEEEARRILEHLEELARKG WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR

GGSGGGSGGNLDELHMOMTDLVYEALH K(SEQ ID NO:101)-X2-FAKDEEFQKHVFQLFEKATKAYKNKDR NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEKAT

QKLEKVVEELKELLERLLSGSGSGYIP KAYKNKDRQKLEKVVEELKELLERLLS(SEQ
ID
EAPRDGQAYVRKDGEWVLLSTFLGGSG NO: 155) -X3-4GS-lrfo SSGSAWSHPQFEKGGGSGGGSGGSAWS GYIPEAPRDGQAYVRKDGEWVLLSTEL(SEQ
ID

83 HPQFEK(SEQ ID NO: 387) NO: 179)-X4 MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
SGSGSGSGSGSGSGSNLDELHMQMTDL WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
VYEALHFAKDEEFQKHVFQLFEKATKA K(SEQ ID NO:101)-X2-YKNKDRQKLEKVVEELKELLERLLSGS NLDELHMQMTDLVYEALHEAKDEEFQKHVEOLFEKAT
AHB2- GSGYIPEAPRDGQAYVRKDGEWVLLST KAYKNKDRQKLEKVVEELKELLERLLS(SEQ
ID
16GS- FLGGSGSSGSAWSHPQFEKGGGSGGGS NO: 155)-X3-LCB3- GGSAWSHPQFEK(SEQ ID NO: GYIPEAPRDGQAYVRKDGEWVLLSTFL(SEQ
ID
4G5-1rfo 388) NO: 179)-X4 MEKKIDKENVLQKIYEIMKELERLGHA
EASMQVSDLIYEFMKTKDENLLEEAER
LLEEVKRGSGSGSGSGNLDELHMQMTD
LVYEALHFAKDEEFQKHVFQLFEKATK

SGSGSEELRAVADLQRLNIELARKLLE DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMK
LCB1- AVARLQELNIDLVRKTSELTDEKTIRE TKDENLLEEAERLLEEVKR(SEQ ID NO:
90S- EIRKVKEESKRIVEEAEEEIRRAKEES 135)-X2-5GS- GSGGGSGGSAWSHPQFEK(SEQ ID
KAYKNKDRQKLEKVVEELKELLERLLS(SEQ ID
5L6HC3_1 NO: 389) NO: 155)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERLAYFNNWATEMMLELIKS
DDEREIREIEEEARRILEHLEELARKG
SGSGSGSGNLDELHMQMTDLVYEALHF

KLEKVVEELKELLERLLSGSGSGSEEL ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW

9GS- NIDLVRKTSELTDEKTIREEIRKVKEE K(SEQ ID NO:101)-X2-NLDELHMQMTDLVYEALHFAKDEEFQKHVFOLEEKAT

KAYKNKDRQKLEKVVEELKELLERLLS(SEQ ID
5L6H03_1 aAWSHPQFEK(SEQ ID NO: 390) NO: 155)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNNWATEMMLELIKS

SGSEEAELAYLLGELAYKLGEYRIAIR ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
AYRIALKRDPNNAEAWYNLGNAYYKQG WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AHB2- DYDEAIYYQKALELDPNNAEAKQNLGN K(SEQ ID NO:101)-X2-EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNA
1na0_1nt GGGSGGSAWSHPQFEK(SEQ ID NO:
EAWYNLONAYYKQGDYDEAIYYQKALELDPIINAEAKQ
2-R3 391) NLGNAKQKQ (SEQ ID NO: 591) MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS

SGSGSEEAELAYLLGELAYKLGEYRIA ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
IRAYRIALKRDPNNAEAWYNLGNAYYK WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AHB2- QGDYDEIEYYQKALELDPNNAEAKQNL K(SEQ ID NO:101)-X2-EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNA
1na0_int GSGGGSGGSAWSHPQFEK(SEQ ID
EAWYNLGNAYYKQGDYDEIEYYQKALELDPNNAEAKQ
2-R3 NO: 392) NLGNAKQKQ (SEQ ID NO: _592) MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS
DDEREIREIEEEARRILEHLEELARKG Xl-SGSEEAELAYLLGELAYKLGEYRIAIR ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
AYRIALKRDPNNAEAWYNLGNAYYKQG WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
DYDEAIYYQKALELDPNNAEAWYNLGN K(SEQ ID NO:101)-X2-EAWYNLGNAYYKQGDYDEAIYYQKALELDPNNAEAWY
Ma() int EKGGGSGGGSGGSAWSHPQFEK(SEQ
NLGNAYYKQGDYDEAIEYYQKALELDPNNAEAKQNLG
2 ID NO: 393) NKQKQ (SEQ ID NO: 593) ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENW

84 ma Dint DDEREIREIEEEARRILEHLEELARKG WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
2 SGSGSEEAELAYLLGELAYKLGEYRIA K(SEQ ID NO:101)-X2-IRAYRIALKRDPNNAEAWYNLGNAYYK EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNA
QGDYDFAIYYQKALELDRNNAEAWYNL EAWYNLGNAYYKQGDYDEATYYQKALELDPNNAEAWY
GNAYYKQGDYDEAIEYYQKALELDPNN NLGNAYYKQGDYDEAIEYYQKALELDPNNAEAKQNLG
AEAKQNLGNKQKQGGGSGSSGSAWSHP NKQKQ (SEQ ID NO: 593) QFEKGGGSGGGSGGSAWSEPQFEK(SE
Q ID NO: 394) MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENW
SGSGSEYEIRKALEELKASTAELKRAT WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
ASLRASTEELKKNPSEDALVENNRLIV K(SEQ ID NO:101)-X2-EHNAIIVENRIIAAVLELIVRAIKGGS EYEIRKALEELKASTAELKRATASLRASTEELKKNPS

4GS-6msr SHPQFEK(SEQ ID NO: 395) (SEQ ID NO: 594) MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNMWATEMMLELIKS Xl-DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
SGSGSGSEYEIRKALEELKASTAELKR WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
ATASLRASTEELKKNPSEDALVENNRL K(SEQ ID NO:101)-X2-IVEHNAIIVENRIIAAVLELIVRAIKG EYEIRKALEELKASTAELKRATASLRASTEELKKNPS

6G5-6msr AWSHPQFEK(SEQ ID NO: 396) (SEQ ID NO: 594) MEKKISAWSHPQFEKGGGSGGGSGGSA
WSHPQFEKGGSGSSGEEAELAYLLGEL

WYNLGNAYYKQGDYDEAIEYYQKALEL EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNA
DPNNAEAWYNLGNAYYKQGDYDEAIEY EAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAW
YQKALELDPNNAEAWYNLGNAYYKQGD YNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAWYNL
YDEAIEYYQKALELGSGSGSDKENVLQ GNAYYKQGDYDEAIEYYQKALEL (SEQ ID NO:
36729.2_ KIYEIMKELERLGHAEASMQVSDLIYE 590)-X2-LCB1v2.2 FMKTKDENLLEEAERLLEEVKR(SEQ DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMK
6GS ID NO: 397) TKDENLLEEAERLLEEVKR(SEQ ID NO:
135) MEKKISAWSHPQFEKGGGSGGGSGGSA
WSHPQFEKGGSGSSGEEAELAYLLGEL

WYNLGNAYYKQGDYDEAIEYYQKALEL EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNA
DPNNAEAWYNLGNAYYKQGDYDEAIEY EAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAW
YQKALELDPNNAEAWYNLGNAYYKQGD YNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAWYNL
YDEAIEYYQKALELGSGSDKENVLQKI GNAYYKQGDYDEAIEYYQKALEL (SEQ ID
NO:
36729.2_ YEIMKELERLGHAEASMQVSDLIYEFM 590)-X2-LCB1v2.2 KTKDENLLEEAERLLEEVKR(SEQ ID DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMK
4GS NO: 398) TKDENLLEEAERLLEEVKR(SEQ ID NO:
135) MEKKISAWSHPQFEKGGGSGGGSGGSA
WSHPQFEKGGSGSSGEEAELAYLLGEL

WYNLGNAYYKQGDYDEAIEYYQKALEL EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNA
DPNNAEAWYNLGNAYYKQGDYDEAIEY EAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAW

YDEAIEYYQKALELOSDKENVLQKIYE GNAYVKQGDYDEATEXYQKALFL (SEC) TD
NO:
36729.2_ IMKELERLGHAEASMQVSDLIYEFMKT 590)-X2-LCB1v2.2 KDENLLEEAERLLEEVKR (SEQ ID
DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEEMK
2G3 NO: 399) TKDENLLEEAERLLEEVKR(SEQ ID NO:
135) MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYENWWATEMMLELIKS

SGSGSGSEEAELAYLLGELAYKLGEYR ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
IAIRAYRIALKRDPNNAEAWYNLGNAY WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AHB2- YKQGDYDEAIEYYQKALELDPNNAEAK K(SEQ ID NO:101)-X2-EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNA
ina0_int KGGGSGGGSGGSAWSHPQFEK(SEQ EAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAK
2-R3 ID NO: 400) QNLGNAKQKQG (SEQ ID NO: 180)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS

SGSGSGSERAELAYLLGELAYKLGEYR ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
IAIRAYRIALKRDPNNAEAWYNLGNAY WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
YKQGDYDEAIEYYQKALELDPNNAEAW K(SEQ ID NO:101)-X2-EAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAW
1na0_int WSHPQFEKGGGSGGGSGGSAWSHPQFE YNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAKQNL
2 K(SEQ ID NO: 401) GNAKQKQG(SEQ ID NO: 181)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYENWWATEMMLELIKS

SGSGSGSGSEYEIRKALEELKASTAEL ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
KRATASLRASTEELKKNPSEDALVENN WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
RLIVEHNAIIVENNRIIAAVLELIVRA K(SEQ ID NO:101)-X2-IKGGSGSSGSAWSHPQFEKGGGSGGGS
GSEYEIRKALEELKASTAELKRATASLRASTEELKKN
AHB2- GGSAWSHPOFEK(SEQ ID NO:
PSEDALVENNRLIVEHNAIIVENNRIIAAVLELIVRA
805-6msr 402) IK(SEQ ID NO: 182)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYENWWATEMMLELIKS
DDEREIREIEEEARRILEHLEELARKG Xl-SGSGSGSGSGSEYEIRKALEELKASTA ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
ELKRATASLRASTEELKKNPSEDALVE WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
NNRLIVEHNAIIVENNRIIAAVLELIV K(SEQ ID NO: 101)-X2-Ai-1B2- RAIKGGSGSSGSAWSHPQFEKGGGSGG GSEYEIRKALEELKASTAELKRATASLRASTEELKKN
10GS- GSGGSAWSHPQFEK(SEQ ID NO:
PSEDALVENNRLIVEHNAIIVENNRIIAAVLELIVRA
6msr 403) IK(SEQ ID NO: 182)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS
DDEREIREIEEEARRILEHLEELARKG Xl-SGSGSGSGSEEAELAYLLGELAYKLGE ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENW
YRIAIRAYRIALKRDPNNAEAWYNLGN WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AHB2- AYYKQGDYDEAIEYYQKALELDPNNAE K(SEQ ID NO:101)-X2-1na0 int FEKGGGSGGGSGGSAWSHPQFEK(SEQ EAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAK
2-03 ID NO: 404) QNLGNAKQKQG(SEQ ID NO: 180)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS
DDEREIREIEEEARRILEHLEELARKG Xl-SGSGSGSGSEEAELAYLLGELAYKLGE ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENW
YRIAIRAYRIALKRDPNNAEAWYNLGN WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AYYKQGDYDEAIEYYQKALELDPNNAE K(SEQ ID NO:101)-X2-ina0_int SAWSHPQFEKGGGSGGGSGGSAWSHPQ YNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAKQNL
2 FEK(SEO ID NO: 405) GNAKQKQG(SEO ID NO: 181)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYENWWATEMMLELIKS Xl-DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDOVSELAHELLHKLTGEELERAAYENW
SGSRMKQIEDKIEEILSKIYHIENEIA WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
RIKKLIGERGGSGSSGSAWSHPOFEKG K(SEQ ID NO:101)-X2-AHB2- GGSGGGSGGSAWSHPQFEK(SEQ ID
RMKQIEDKIEEILSKIYHIENEIARIKKLIGER
4G5-igcm NO: 406) (SEQ ID NO: 183)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYENWWATEMMLELIKS Xl-DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDOVSELAHELLHKLTGEELERAAYENW
SGSGSGSRMKQIEDKIEEILSKIYHIE WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
NEIARIKKLIGERGGSGSSGSAWSHPO K(SEQ ID NO:101)-X2-AHB2- FEKGGGSGGGSGGSAWSHPQFEK(SEQ RMKQIEDKIEEILSKIYHIENEIARIKKLIGER(SEQ
8G5-1gcm ID NO: 407) ID NO: 183)-X3 4GS-pRO- DDEREIREIEEEARRILEHLEELARKG WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR

2-noHis SGSGSEYEIRKALEELKASTAELKRST K(SEQ ID NO:101)-X2-ASLRASTEELKKNPSEDALVENNRLIV GSEYEIRKALEELKASTAELKRSTASLRASTEELKKN
ENNAIIVENNRIIAAVLELIVRAIKGG PSEDALVENNRLIVENNAIIVENNRIIAAVLELIVRA
SGSSGSAWSHPQFEKGGGSGGGSGGSA IK(SEQ ID NO: 184)-X3 WSHPQFEK(SEQ ID NO: 408) MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS
DDEREIREIEEEARRILEHLEELARKG

KRSTASLRASTEELKKNPSEDALVENN NWWATEMMLELIKSDDEREIREIEEEARRILEHLEEL
RLIVENNAIIVENNRIIAAVLELIVRA ARK(SEQ ID NO:101)-X2-SOS-pRO- GGSAWSHPQFEK(SEQ ID NO:
PSEDALVENNRLIVENNAIIVENNRIIAAVLEEIVRA
2-noHis 409) IK(SEQ ID NO: 184)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS

SGSGSNLAEKMYKAGNAMYRKGQYTIA ELEEQVMHVLDQVSELAHELLHKETGEELERAAYENW
IIAITLALLKDPNNAEAWYNEGNAAYK WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
KGEYDEAIEAYQKALELDPNNAEAWYN K(SEQ ID NO:101)-X2-LGNAYYKQGDYDRAIEYYQKALELDPN NLAEKMYKAGNAMYRKGQYTIAIIAYTLALLKDPNNA

6GS- HPQFEKGGGSGGGSGGSAWSHPQFEK( YNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAKQNL
1na0_3 SEQ ID NO: 410) GNAKQKQG(SEQ ID NO: 105)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS
DDEREIREIEEEARRIEEHLEELARKG Xl-SGSGSGSGSNLAEKMYKAGNAMYRKGQ ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
YTIAIIAYTLALLKDPNNAEAWYNLGN WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AAYKKGEYDEAIRAYQKALELDPNNAE K(SEQ ID NO:101)-X2-AWYNLGNAYYKQGDYDEAIEYYQKALE NLAEKMYKAGNAMYRKGQYTIAIIAYTLALLKDPNNA

10GS- aAWSHRQFEKGGGSGGGSGGSAWSHPQ YNLGNAYYKQGDYDEAIEYYQKALELDRNNAEAKQNL
1na0_3 FEK(SEQ ID NO: 411) GNAKQKQG(SEQ ID NO: 105)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS Xl-DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENW
SGSGSGEIAKSLKEIAKSLKEIAWSLK WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
EIAKSLKGGGSGSSGSAWSHPQFEKGG K(SEQ ID NO:101)-X2-AHB2- GSGGGSGGSAWSHPQFEK(SEQ ID
GEIAKSLKEIAKSLKEIAWSLKEIAKSLKG(SEQ ID
6GS-4pn9 NO: 412) NO: 186)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS Xl-DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKETGEELERLAYFNW
SGSGSGSGSGEIAKSLKEIAKSLKEIA WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AHB2- WSLKEIAKSLKGGGSGSSGSAWSHFQF K(SEQ ID NO:101)-X2-10GS- EKGGGSGGGSGGSAWSHPQFEK(SEQ
GEIAKSLKEIAKSLKEIAWSLKEIAKSLKG(SEQ ID
4pn9 ID NO: 413) NO: 186)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS

GSGGEEAELAYLLGELAYKLGEYRIAI ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
RAYRIALKRDPNNAEAWYNLGNAYYKQ WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AHB2- GDYDEAIEYYQKALELDPNNAEAKQNL K(SEQ ID NO:101)-X2-1na0_int GSGGGSGGSAWSHPQFEK(SEQ ID
EAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAK
2-R3 NO: 414) QNLGNAKQKQG(SEQ ID NO: 100)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS Xl-DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
GGGGSI-GGSGGGEEAELAYLLGELAYKLGEYRI WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AIRAYRIALKRDPNNAEAWYNLGNAYY K(SEQ ID NO:101)-X2-Ina int KQGDYDEAIEYYQKALELDPNNAEAKQ EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNA

NEGNAKQKOGGGSGSSGSAWSHPQFEK EAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAK

GGGSGGGSGGSAWSHPQFEK(SEQ ID ONLGNAKQKQG(SEQ ID NO: 180)-X3 NO: 415) MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS

GGGSGGGGEEAELAYLLGELAYKLGEY ELEEQVMHVLDQVSELAHELLHKETGEELERAAYENW
RIAIRAYRIALKRDPNNAEAWYNLGNA WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AHB2- YYKQGDYDEATEYYQKALELDPNNAEA K(SEQ ID NO:101)-X2-lna0_int EKGGGSGGGSGGSAWSHPQFEK(SEQ EAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAK
2-R3 ID NO: 416) QNLGNAKQKQG(SEQ ID NO: 180)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS
DDERETRETEFEARRTLEHLEELARKG Xl-GSGGEEAELAYLLGELAYKLGEYRIAI ELEEQVMHVLDQVSELAHELLHKETGEELERAAYENW
RAYRIALKRDPNNAEAWYNEGNAYYKQ WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
GDYDEAIEYYQKALELDPNNAEAWYNL K(SEQ ID NO:101)-X2-ina0_int PQFEKGGGSGGGSGGSAWSHPQFEK(S YNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAKQNL
2 EQ ID NO: 417) GNAKQKQG(SEQ ID NO: 181)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS

AIRAYRIALKRDPNNAEAWYNLGNAYY WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
KQGDYDEAIEYYQKALELDPNNAEAWY K(SEQ ID NO:101)-X2-lna0_int SHPQFEKGGGSGGGSGGSAWSHPOFEK YNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAKQNL
2 (SEQ ID NO: 418) GNAKQKQG(SEQ ID NO: 181)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS
DDEREIREIEEEARRILEHLEELARKG Xl-GGGSGGGGEEAELAYLLGELAYKLGEY ELEEQVMHVLDQVSELAHELLHKETGEELERAAYENW
RIAIRAYRIALKRDENNAEAWYNLGNA WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
YYKQGDYDEAIEYYQKALELDENNAEA K(SEQ ID NO:101)-X2-1na0_int AWSHPQFEKGGGSGGGSGGSAWSHPQF YNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAKQNL
2 EK(SEQ ID NO: 419) GNAKQKQG(SEQ ID NO: 101)-X3 MEKKIELEEOVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS Xl-DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKETGEELERLAYFNW
GSGGGSEYEIRKALEELKASTAELKRA WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
TASLRASTEELKKNPSEDALVENNRLI K(SEQ ID NO:101)-X2-6msr AWSHPQFEK(SEQ ID NO: 420) IK(SEQ ID NO: 182)-X3 MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
GGSGGGGSEYEIRKALEELKASTAELK WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
RATASLRASTEELKKNPSEDALVENNR K(SEQ ID NO:101)-X2-6msr GSAWSHPQFEK(SEQ ID NO: 421) IK(SEQ ID NO: 182)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYENWWATEMMLELIKS Xl-DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW

GGGSGGGGGSEYEIRKALEELKASTAE WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR

LKRATASLRASTEELKKNPSEDALVEN K(SEQ ID NO:101)-X2-NRLIVEHNAIIVENNRIIAAVLELIVR GSEYEIRKALEELKASTAELKRATASLRASTEELKKN
6msr AIKGGSGSSGSAWSHPQFEKGGGSGGG PSEDALVENNRLIVEHNAIIVENNRIIAAVLELIVRA

SGGSAWSHPOFEK(SEQ ID NO: IK(SEQ ID NO: 182)-X3 422) MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
GSGGRMKQIEDKIEEILSKIYHIENEI
WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AHB2- ARIKKLIGERGGSGSSGSAWSHPQFEK K(SEQ ID NO:101)-X2-GGGGS5- GGGSGGGSGGSAWSHPQFEK (SEQ
RMKQIEDKIEEILSKIYHIENEIARIKKLIGER(SEQ
1gcm ID NO: 423) ID NO: 183)-X3 MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
GGSGGGRMKQIEDKIEEILSKIYHIEN WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AHR2- ETARTKKLIGERGGSGSSGSAWSHPOE K(SE0 Tn NO:101)-X2-GGGGS7- EKGGGSGGGSGGSAWSHPQFEK(SEQ
RMKQIEDKIEEILSKIYHIENEIARIKKLIGER(SEQ
1gcm ID NO: 424) ID NO: 183)-X3 MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
GGGSGGGGRMKQIEDKIEEILSKIYHI
WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AHB2- ENEIARIKKLIGERGGSGSSGSAWSHP K(SEQ ID NO:101)-X2-GGGGS9- QFEKGGGSGGGSGGSAWSHPQFEK(SE RMKQIEDKIEEILSKIYHIENEIARIKKLIGER(SEQ
1gcm Q ID NO: 425) ID NO: 183)-X3 MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
GSGGGSEYEIRKALEELKASTAELKRS WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AHB2- TASLRASTEELKKNPSEDALVENNRLI K(SEQ ID NO:101)-X2-pRO-2- GSGSSGSAWSHPQFEKGGGSGGGSGGS PSEDALVENNRLIVENMAIIVENNRIIAAVLELIVRA
noHis AWSHPQFEK(SEQ ID NO: 426) IK(SEQ ID NO: 184)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERkAYENWWATEMMLELIKS Xl-DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
GGSGGGGSEYEIRKALEELKASTAELK WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AHB2- RSTASLRASTEELKKNPSEDALVENNR K(SEQ ID NO:101)-X2-pRO-2- KGGSGSSGSAWSHPQEEKGGGSGGGSG PSEDALVENNRLIVENNAIIVENNRIIAAVLELIVRA
noHis GSANSHPQFEK(SEQ ID NO: 427) IK(SEQ ID NO: 184)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERLAYENWWATEMMLELIKS
DDEREIREIEEEARRILEHLEELARKG Xl-GGGSGGGGGSEYEIRKALEELKASTAE ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
LKRSTASLRASTEELKKNPSEDALVEN WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AHB2- NRLIVENNAIIVENNRIIAAVLELIVR K(SEQ ID NO:101)-X2-pRO-2- SGGSAWSHPQFEK(SEQ ID NO:
PSEDALVENNRLIVENNAIIVENNRIIAAVLELIVRA
noHis 428) IK(SEQ ID NO: 184)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS
DDEREIREIEEEARRILEHLEELARKG Xl-GSGGNLAEKMYKAGNAMYRKGQYTIAI ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
LAYTLALLKDPNNAEAWYNLGNAAYKK WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
GEYDEAIEAYQKALELDPNNAEAWYNL K(SEQ ID NO:101)-X2-GNAYYKQGDYDEAIEYYQKALELDPNN NLAEKMYKAGNAMYRKGQYTIAIIAYTLALLKDPNNA

GGGGS5- PQFEKGGGSGGGSGGSAWSHPQFEK(S YNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAKQNL
1na0_3 EQ ID NO: 429) GNAKOKQG(SEQ ID NO: 185)-X3 KLTGEELERAAYENWWATEMMLELIKS ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW

DDEREIREIEEEARRILEHLEELARKG WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
Ina 3 GGSGGGNLAEKMYKAGNAMYRKGQYTI K(SEQ ID NO:101)-X2-AIIAYTLALLKDPNNAEAWYNLGNAAY NLAEKMYKAGNAMYRKGQYTIAIIAYTLALLKDPNNA

KKGEYDEAIEAYQKALELDPNNAEAWY EAWYNLGNAAYKKGEYDEAIEAYQKALELDPNNAEAW
NLGNAYYKOGDYDEAIEYYnKALELDP YNLGNAYYKOGDYDRAIEYYnKALELDPNNAEAKnNL
NNAEAKQNLGNAKQKQGGGSGSSGSAW GNAKQKQG(SEQ ID NO: 185)-X3 SHPQFEKGGGSGGGSGGSAWSHPQFEK
(SEQ ID NO: 430) MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS

GGGSGGGGNLAEKMYKAGNAMYRKGQY ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
TIAIIAYTLALLKDPNNARAWYNLGNA WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AYKKGEYDEAIEAYQKALELDPNNAEA K(SEQ ID NO:101)-X2-WYNLGNAYYKQGDYDEAIEYYQKALEL NLAEKMYKAGNAMYPKGQYTIAIIAYTLALLKDPNNA

lna0_3 EK(SEQ ID NO: 431) GNAKQKQG(SEQ ID NO: 185)-X3 MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
GSGGGEIARSLKEIAKSLKEIAWSLKE WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AHB2- LAKSLKGGGSGSSGSAWSEPQFEKGGG K(SEQ ID NO:101)-X2-GGGGS5- SGGGSGGSAWSHPQFEK(SEQ ID
GETAKSLKEIAKSLKEIAWSLKEIAKSLKG(SEQ ID
4pn9 NO: 432) NO: 186)-X3 MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
GGSGGGGEIAKSLKEIAKSLKEIAWSL WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AHB2- KEIAKSLKGGGSGSSGSAWSHPQFEKG K(SEQ ID NO:101)-X2-GGGGS7- GGSGGGSGGSAWSHPQFEK(SEQ ID
GEIAKSLKEIAKSLKEIAWSLKEIAKSLKG (SEQ
4pn9 NO: 433) ID NO: 186)-X3 MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
GGGSGGGGGEIAKSLKEIAKSLKEIAW WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AI-152- SLKEIAKSLKGGGSGSSGSAWSHPQFE K(SEQ NO:101)-X2-GGGGS9- KGGGSGGGSGGSAWSHPQFEK(SEQ
GEIAKSLKEIAKSLKEIAWSLKEIAKSLKG(SEQ ID
4pn9 ID NO: 434) NO: 186)-X3 MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
GSEALEELEKALRELKKSTDELERSTE WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
ELEKNPSEDALVENNRLIVENNKIIVE K(SEQ ID NO:101)-X2-2GS- GGGSGGGSGGSAWSHPQFEK(SEQ ID VENNRLIVENNKIIVEVLRIIAKVLK (SEQ
ID
SB115 NO: 435) NO:181)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS Xl-DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
GGSSEALEELEKALRELKKSTDELERS WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
TEELEKNPSEDALVENNRLIVENNKII K(SEQ ID NO:101)-X2-4G5- EKGGGSGGGSGGSAWSHPQFEK(SEQ
VENNRLIVENNKIIVEVLRIIAKVLK(SEQ ID
5B175 ID NO: 436) NO:187)-X3 MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERkAYENW
GGGSGSEALEELEKALRELKKSIDELE WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
RSTEELEKNPSEDALVENNRLIVENNK K(SEQ ID NO:101)-X2-60S- QFEKGGGSGGGSGGSAWSHPQFEK(SE VENNRLIVENNKIIVEVLRITAKVLK(SEQ
ID
5B175 Q ID NO: 437) NO:187)-X3 ELEEQVMHVLDQVSELAHELLHKLTGEELERLAYFNW

3B175.1 DDEREIREIEEEARRILEHLEELARKG WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
GSPELEKALRELKKSTDELERSTEELE K(SEQ ID NO:101)-X2-KNGSPEALVENNRLIVENNKIIVEVLR SPELEKALRELKKSTDELERSTEELEKNGSPEALVEN
IIAKGGSGSSGSAWSHPQFEKGGGSGG NRLIVENNKIIVEVLRIIAK(SEQ ID NO:
100)-GSGGSAWSHPQFEK(SEQ ID NO: X3 438) MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
GGSSPELEKALRELKKSTDELERSTEE WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
LEKNGSPEALVENNRLIVENNKIIVEV K(SEQ ID NO:101)-X2-40S- GGGSGGSAWSHPQFEK(SEQ ID NO: NRLIVENNKIIVEVLRIIAK(SEQ ID
NO: 108)-SB175.1 439) X3 MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
GGGSGSPELEKALRELKKSIDELERST WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
EELEKNGSPEALVENNRLIVENNKIIV K(SEQ ID NO:101)-X2-6GS- GSGGGSGGSAWSHDQEEK(SEQ ID NRLIVENNKIIVEVLRIIAK(SEQ ID
NO: 108)-SB175.1 NO: 440) X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS Xl-DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
GSEKALRELKKSTDELERSTEELEKNG WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
AHB2- SPEALVENNRLIVENNKIIVEVLRGGS K(SEQ ID NO:101)-X2-SEKALRELKKSTDELERSTEELEKNGSPEALVENNRL
3B175.2 SHPQFEK(SEQ ID NO: 441) IVENNKIIVEVLR(SEQ ID NO: 189)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS Xl-DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
GGSSEKALRELKKSTDELERSTEELEK WATEMMLELIKSDDEREIREIEEEARRILERLEELAR
AHB2- NGSPEALVENNRLIVENNKIIVEVLRG K(SEQ ID NO:101)-X2-SEKALRELKKSTDELERSTEELEKNGSPEALVENNRL
5B175.2 AWSHPQFEK(SEQ ID NO: 442) IVENNKIIVEVLR(SEQ ID NO: 189)-MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYFNWWATEMMLELIKS Xl-DDEREIREIEEEARRILEHLEELARKG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
GGGSGSEKALRELKKSTDELERSTEEL WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR

SEKALRELKKSTDELERSTEELEKNGSPEALVENNRL
SB175.2 GSAWSHPQFEK(SEQ ID NO: 443) IVENNKIIVEVLR(SEQ ID NO:
189)-X3 MEKKISAWSHPQFEKGGGSGGGSGGSA

ELKKSTDELERSTEELEKNPSEDALVE
SEALEELEKALRELKKSTDELERSTEELEKNPSEDAL
NNRLIVENNKIIVEVLRIIAKVLKGGG VENNRLIVENNKIIVEVLRITAKVLK(SEQ ID
5B175- GSGDKENVLQKIYEIMKELERLGHAEA NO: 187)-X2-DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMK
LCB1v2.2 EEVKR(SEQ ID NO: 444) TKDENLLERAERLLEEVKR(SEQ ID NO:
135) MEKKISAWSHPQFEKGGGSGGGSGGSA
WSHPQFEKGGSGSSGSEALEELEKALR Xl-ELKKSTDELERSTEELEKNPSEDALVE
SEALEELEKALRELKKSTDELERSTEELEKNPSEDAL
NNRLIVENNKIIVEVLRIIAKVLKGGG VENNRLIVENNKIIVEVLRITAKVLK(SEQ ID
5B175- GSGGGGSDKENVLQKIYEIMKELERLG NO:187)-X2-LCB1v2.2 ERLLEEVKR(SEQ ID NO; 445) TIMENLLEEAERLLEEVKR(SEQ ID NO:
135) .
WSHPQFEKGGSGSSGSPELEKALRELK
SPELEKALRELKKSTDELERSTEELEKNGSPEALVEN
LCB1v2 2 KSTDELERSTEELEKNGSPEALVENNR NRLIVENNKIIVEVLRIIAK(SEQ ID NO: 158)-.

NVLOKIYEIMKELERLGHAEASMQVSD DKENVLOKIYEIMKELERLGHAEASMQVSDLIYEEMK
LIYEFMKTKDENLLEEAERLLEEVKR( TKDENLLEEAERLLEEVKR(SEQ ID NO:
135) SEQ ID NO: 446) MEKKISAWSHPQFEKGGGSGGGSGGSA

KSTDELERSTEELEKNGSPEALVENNR SPELEKALRELKKSTDELERSTEELEKNGSPEALVEN
LIVENNKIIVEVLRITAKGGGGSGGGG NRLIVENNKIIVEVLRIIAK(SEQ ID NO:
138)-SB175.1- SDKENVLQKIYEIMKELERLGHAEASM X2 LCB1v2.2 VKR(SEQ ID NO: 447) TKDENLLEEAERLLEEVKR(SEQ ID NO:
135) MEKKINLDELHMQMTDLVYEALHFAKD

KVVEELKELLERLLSGGGGSGGGSEAL NLDELHMOMTDLVYEALHFAKDEEFOKHVFQLFEKAT
EFLEKALRELKKSTDELERSTEELFKN KAYKNKDROKLEKVVEFTKELLERLLS(SED
TO
PSEDALVENNRLIVENNKIIVEVLRII NO: 155)-X2-8GS- GGSGGGSGGSAWSHPQFEK(SEQ ID
VENNRLIVENNKIIVEVLRIIAKVLK(SEQ ID
SB1/5 NO: 448) NO:18/)-X3 MEKKINLDELHMQMTDLVYEALHFAKD
EEFQKHVFQLFEKATKAYKNKDRQKLE Xl-KVVEELKELLERLLSGGGGSGSEALEE NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEKAT
LEKALRELKKSTDELERSTEELEKNPS KAYKNKDRQKLEKVVEELKELLERLLS(SEQ
ID
EDALVENNRLIVENNKIIVEVLRIIAK NO: 155)-X2-6GS- SGGGSGGSAWSHPQFEK(SEQ ID VENNRLIVENNKIIVEVLRIIAKVLK(SEQ
ID
5B175 NO: 449) NO:187)-X3 MEKKINLDELHMQMTDLVYEALHFAKD
EEFQKHVFQLFEKATKAYKNKDRQKLE Xl-KVVEELKELLERLLSGGGSSEALEELE NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEKAT
KALRELKKSTDELERSTEELEKNPSED KAYKNKDRQKLEKVVEELKELLERLLS(SEQ
ID
ALVENNRLIVENNKIIVEVLRIIAKVL NO: 155)-X2-4GS- GGSGGSAWSHPQFEK(SEQ ID NC:
VENNRLIVENNKIIVEVLRITAKVLK(SEQ ID
SB175 450) NO:187)-X3 MEKKINLDELHMQMTDLVYEALHFAKD

KVVEELKELLERLLSGGSEALEELEKA NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKAT
LRELKKSTDELERSTEELEKNPSEDAL KAYKNKDRQKLEKVVEELKELLERLLS(SEQ
ID
VENNRLIVENNKIIVEVLRIIAKVLKG NO: 155)-X2-2G5- SGGSAWSHPQFEK(SEQ ID NO: VENNRLIVENNKIIVEVLRIIAKVLK(SEQ
ID
3B175 451) NO:187)-X3 MEKKIELEEQVMHVLDQVSELAHELLH
KLTGEELERAAYENWWATEMMLELIKS Xl-DDEREIREIEEEARRILEFLEELARKG ELEEQVMNVLDQVSELAHELLHKLTGEELERAAYENW
GSEALEELEKALRELKKSTDELERSTE WATEMMLELIKSDDEREIREIEEEARRILEHLEELAR
ELEKNPSEDALVENNRLIVENNKIIVE K(SEQ ID NO:101)-X2-AHB2v1- VLRIIAKVLKGGSGSSGSAWSHRQFEK SEALEELEKALRELKKSTUELERSTEELEKNPSEDAL
2GS- GGGSGGGSGGSAWSHPQFEK(SEQ ID VENNRLIVENNKIIVEVLRIIAKVLK(SEQ
ID
SB175 NO: 452) NO:187)-X3 MEKKIELEEQVMHVLDQVSELAHELLH

DDEREIREIEEEAARILEHLEELARTG ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNW
GSEALEELEKALRELKKSTDELERSTE WATEMMLELIKSDDEREIREIEEEAARILEHLEELAR
ELEKNPSEDALVENNRLIVENNKIIVE T(SEQ ID NO: 164)-X2-AHB2v2- VLRIIAKVLKGGSGSSGSAWSHPOFEK SEALEELEKALRELKKSTDELERSTEELEKNPSEDAL
2GS- GGGSGGGSGGSAWSHPQEEK(SEQ ID VENNRLIVENNKIIVEVLRIIAKVLK(SEQ
ID
5B175 NO: 453) NO:187) -X3 Table 9A
Name Sequence SEQ

ID

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE
595 1rfo IEEFARRILEHLEELARKGSGSGSGYIPEAPRDGQAYVRKDGEWVLLSTFL
ELEDDVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGSGSGSGSGSGSGSGSGSGSGSGSGSGSELEEQVMHVLD

OVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIREIFEEARRILEH
596 1rfo LEELARKGSGSGSGYIPEAPRDGQAYVRKDGEWVLLSTFL

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE
597 lrfr TFEFARRTTFHTEETARKGSGSGGYTPFAPRDGOAYVRKDGFWVLLSTFT.

ELEDDVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE
598 1rfo IEEEARRILEHLEELARKGSGSGYIPEAPRDGQAYVRKDGEWVLLSTFL

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE
599 1rfo IEEFARRILEHLEELARKGSGGYIPEAPRDGOAYVRKDGEWVLLSTFL
ELEDDVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGSGSGSGSGSGSGSGSGSGSGSGSGSGSELEEQVMHVLD

QVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIREIFEEARRILEH
600 1rfo LEELARKGSGGYIPEAPRDGQAYVRKDGEWVLLSTFL
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE

TEEEARRILEHLEELARKGSGSSEELRAVADLQRLNIELARKLLEAVARLQELNIDL
601 5L6HC3_1 VRKTSELTDEKTIREEIRKVKEESKRIVEEAEEEIRRAKEESRKIADESR
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE

TEEEARRILEHLEELARKGSGSGSEELRAVADLQRLNIELARKLLEAVARLQELNID
602 5L6HC3_1 LVRKTSELTDEKTIREEIRKVKEESKRIVEEAEEEIRRAKEESRKIADESR
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE
TEEEARRILEHLEELARKGSGSGSGSGSGSGSGSGSGSGSGSGSGSELEEQVMHVLD

QVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIREIEEEARRILEH

LEELARKGSGSSEELRAVADLQRLNIELARKLLEAVARLQELNIDLVRKTSELTDEK
603 5L6HC3_1 TIREEIRKVKEESKRIVEEAEEEIRRAKEESRKIADESR
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE
IFEEARRILEHLEELARKGSGSGSGSGSGSGSGSGSGSGSGSGSGSELEEQVMHVLD

QVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIREIEEEARRILEH

LEELARKGSGSGSEELRAVADLQRLNIELARKLLEAVARLQELNIDLVRKTSELTDE
604 5L6HC3_1 KTIREEIRKVKEESKRIVEEAEEEIRRAKEESRKIADESR

NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE
605 1rfo LLERLLSGSGSGSGYIPEAPRDGQAYVRKDGEWVLLSTFL

NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE
606 1rfo LLERLLSGSGSGGYIPEAPRDGQAYVRKDGEWVLLSTFL

NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE
607 1rfo LLERLLSGSGSGYIREAPRDGQAYVRKDGEWVLLSTFL
NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE

LLERLLSGSGSGSEELRAVADLQRLNIELARKLLEAVARLQELNIDLVPKTSELTDE
608 5L6HC3_1 KTIREEIRKVKEESKRIVEFAEEEIRRAKEESRKIADESR
NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE
LLERLLSGSGSGSGSGSGSGSGSGSGSGSGSGSGSNLDELHMQMTDLVYEALHFAKD
1(753-2 S- FFFOKH1TFOLFFKATKAYKNKDROKLEKVVEFLKELLERLLSGSgSSFET.RAV917T.0 RLNIELARKLLEAVARLQELNIDLVRKTSELTDEKTIREEIRKVKEESKRIVEEAEE
609 5L6HC3_1 EIRRAKEESRKIADESR
NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE
LLERLLSGSGSGSGSGSGSGSGSGSGSGSGSGSGSNLDELHMQMTDLVYEALHFAKD

EEFQKHVTQLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGSGSGSEELRAVADL

QRLNIELARKLLEAVARLQELNIDLVRKTSELTDEKTIREEIRKVKEESKRIVEEAE
610 5L6HC3_1 EEIRRAKEESRKIADESR
EFAELAYLLGELAYKLGEYRIATRAYRIALKRDPNNAEAWYNLGNAYYKQGDYDEAT
EYYQKALELDPNNAEAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAWYNLGNA
36729.2_LCB YYKQGDYDFAIEYYQKALELGSGSGSDKENVLQKIYEIMKELERLGHAEASMQVSDL
611 1v2 .260S IYEFMKTKDENLLEEAERLLEEVKR

36729.2_LCB EFAELAYLLGELAYKLGEYRIATRAYRIALKRDPNNAEAWYNLGNAYYKQGDYDEAT

1v2.2_4GS
EYYOKALELDPNNAEAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAWYNLGNA
YYKCGDYDEATEYYCKALELGSGSDKENVLCKIYEIMKELERLGHAEASMOVSDLTY
EFMKTKDENLLEEAERLLEEVKR
EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNAEAWYNLGNAYYKQGDYDFAI
EYYQKALELDPNNAFAWYNLGNAYYKQGDYDEATEYYQKALELDRNNAEAWYNLGNA
36729.2_LCB YYKQGDYDEAIEYYQKALELGSDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
613 1v2.2_2GS MKTKDENLLEEAERLLEEVKR
NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE
LLERLLSGGASPAAPAPASPAAPAPSAPAGGNLDELHMQMTDLVYEALHFAKDEEFQ

ELARKLLEAVARLQELNIDLVRKTSELTDEKTIREEIRKVKEESKRIVEEAEEEIRR
614 5L6H63_1 AKEESRKIADESR
NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE
LLERLLSGGASPAAPAPASPAAPAPSAPAGGNLDELHMQMTDLVYEALHFAKDEEFQ

IELARKLLEAVARLQELNIDLVRKTSELTDEKTIREEIRKVKEESKRIVEEAEEEIR
615 5L6H03_1 RAKEESRKIADESR
DKENVLOKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEVKRG

GGSGGGSGGELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIK

SDDEREIRETEEEARRILEHLEELARKGSGSGYIPEAPRDGQAYVRKDGEWVLLSTF
616 1rfo DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEVKRG

SGSGSGSGSGSGSGSGSGSGSGSGSGSELEEQVMHVLDQVSELAHELLHKLIGEELE

RAAYFNWWATEMMLELIKSDDEREIREIEEEARRILEHLEELARKGSGSGYIBEARR
611 irfo DGQAYVRKDGEWVLLSTFL
NLDELHMQMTDLVYEALHEAKDEEFQKHVEQLFEKATKAYKNKDRQKLEKVVEELKE

LLERLLSGGGSGGGSGGELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWAT

EMMLELIKSDDEREIREIEEEARRILEHLEELARKGSGSGYIPEAPRDGQAYVRKDG
618 1rfo EWVLLSTFL
NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE

LLERLLSGSGSGSGSGSGSGSGSELEEQVMHVLDQVSELAHELLHKLTGEELERAAY

FNWWATEMMLELIKSDDEREIREIEEEARRILEHLEELARKGSGSGYIPEAPRDGQA
619 lrfn YVRKDGFWVLLSTFL
EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNAEAWYNLGNAYYKQGDYDEAI
EYYQKALELDPNNAEAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAWYNLGNA
YYKQGDYDEAIEYYQKALELGSGSGSDKENVLQKIYEIMKELERLGHAEASMQVSDL
36729.2_6GS IYEFMKTKDENLLEEAERLLEEVKRGSGSGSGSGSGSGSGSGSGSGSGSGSGSNLDE
LCB1v2.2- LHMQMTDLVYEALHFAKDEEFQKHVEQLEEKATKAYKNKDRQKLEKVVEELKELLER

EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNAEAWYNLGNAYYKQGDYDEAI
EYYQKALELDPNNAEAWYNLGNAYYKQGDYDEAIEYYQKALELDRNNAEAWYNLGNA
36129.2_6GS YYKQGDYDEAIEYYQKALELGSGSGSDKENVLQKIYEIMKELERLGHAEASMQVSDL
LCB1v2.2- IYEFMKTKDENLLEEAERLLEEVKRGSGSGSGSGNLDELHMQMTDLVYEALHFAKDE

EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNAEAWYNLGNAYYKQGDYDEAI
EYYQKALELDPNNAEAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAWYNLGNA
YYKQGDYDEAIEYYQKALELGSGSGSDKENVLQKIYEIMKELERLGHAEASMQVSDL
36729.2 6GS IYEFMKTKDENLLEEAERLLEEVKRGSGSGSGSGSGSGSGSGSGSGSGSGSGSELEE
_LCB1v2.2-QVMHVLDQVSELAHELLNKLTGEELERAAYENWWATEMMLELIKSDDEREIREIEEE

EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNAEAWYNLGNAYYKQGDYDEAI
EYYQKALELDPNNAEAWYNLGNAYYKQGDYDEAIEYYQKALELDENNAEAWYNLGNA
36729.2_6GS YYKQGDYDEAIEYYQKALELGSGSGSDKENVLQKIYEIMKELERLGHAEASMQVSDL
_LCB1v2.2-IYEFMKTKDENLLEEAERLLEEVKRGSGSGSGSGELEEQVMHVLDQVSELAHELLHK

LTGEELERAAYENWWATEMMLELIKSDEEREIREIEEEARRILEHLEELARK

DKENVLQKIYELMKELERLGHABASMQVSDLIYEbMKTKDENLLEEAERLLEEVKKG

GGSGGGSGGNLDELHMQMTDLVYEALNFAKDEEFQKHVFQLFEKATKAYKNKDRQKL
624 1rf0 EKVVEELKELLERLLSGSGSGYIPEAPRDGQAYVRKDGEWVLLSTFL

SGSGSGSGSGSGSGSGSGSGSGSGSGSNLDELHMQMTDLVYEALHFAKDEEFQKHVF

1rfo QLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGSGSGYIPEAPRDGQAYVRKDGE
WVLLSTFL
FLEDDVMHVLDQ.VSFLAHELLHELTGFELFRAAYFNWWATEMMLFLIKSDDERFTRE

TEEFARRILEHLEELARKGGGSGGGSGGNLDELHMQMTDLVYEALHFAKDEEFQKHV

FQLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGSGSGYIPEAPRDGQAYVRKDG
626 1rfo EWVLLSTFL
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGSGSGSGSGSGSGSGSNLDELHMQMTDLVYEALHFAKDE

EFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGSGSGYIPEAPRDGQA
627 1rfo YVRKDGEWVLLSTFL
DKENVLQKIYEIMKELERLGHAEASMQVSDLIYEEMKTKDENLLERAERLLEEVKRG

SGSGSGSGNLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLE

KVVEELKELLERLLSGSGSGSEELRAVADLQRLNIELARKLLEAVARLQELNIDLVR
628 5L6HC3_1 KTSELTDEKTIREEIRKVKEESKRIVEEAEEEIRRAKEESRKIADESR
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE
IEEEARRILEHLEELARKGSGSGSGSGNLDELHMQMTDLVYEALHEAKDEEFQKHVE

QLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGSGSGSEELRAVADLQRLNIELA

RKLLEAVARLQELNIDLVRKTSELTDEKTIREEIRKVKEESKRIVEEAEEEIRRAKE
629 5L6HC3_1 ESRKIADESR

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE
1na0_int2-IEEFARRILEHLEELARKGSGSEEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPN

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE
1na0_int2-IEEFARRILEHLEELARKGSGSGSEEAELAYLLGELAYKLGEYRIAIRAYRIALKRD

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE
IEEEARRILEHLEELARKGSGSEEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPN

NAEAWYNLGNAYYKQGDYDEAIYYQKALELDPNNAEAWYNLGNAYYKQGDYDEAIEY
632 1na0_int2 YQKALELDPNNAEAKQNLGNKQKQ
ELEEQVMHVLDQVSELAHELLHKLTGEFLERAAYENWWATEMMLELIKSDDEREIRE
IEEEARRILEHLEELARKGSGSGSEEAELAYLLGELAYKLGEYRIAIRAYRIALKRD

PNNAEAWYNLGNAYYKQGDYDEAIYYQKALELDPNNAEAWYNLGNAYYKQGDYDEAI
633 1na0_int2 EYYQKALELDPNNAEAKQNLGNKQKQ
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGSGSGSEYEIRKALEELKASTAELKRATASLRASTEELK
634 6msr KNPSEDALVENNRLIVEHNAIIVENRIIAAVLELIVRAIK
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGSGSGSGSEYEIRKALEELKASTAELKRATASLRASTEE
635 6msr LKKNPSEDALVENNRLIVEHNAIIVENRIIAAVLELIVRAIK
EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNAEAWYNLGNAYYKQGDYDEAI
EYYQKALELDPNNAEAWYNLGNAYYKQGDYDEATEYYQKALELDPNNAEAWYNLGNA
36729.2_LCB YYKQGDYDEAIEYYQKALELGSGSGSDKENVLQKIYEIMKELERLGHAEASMQVSDL
636 1v2 .266S IYEFMKTKDENLLEEAERLLEEVKR
EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNAEAWYNLGNAYYKQGDYDEAI
EYYQKALELDPNNAEAWYNLGNAYYKQGDYDEATEYYQKALELDPNNAEAWYNLGNA
36729.2_LCB YYKQGDYDEAIEYYQKALELGSGSDKENVLQKIYEIMKELERLGHAEASMQVSDLIY
637 1v2 .24G5 EFMKTKDENLLEEAERLLEEVKR
EEAELAYLLGELAYKLGEYRIAIRAYRIALKRDPNNAEAWYNLGNAYYKQGDYDEAI
EYYQKALELDPNNAEAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAWYNLGNA
36729.2_LCB YYKQGDYDEAIEYYQKALELGSDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
638 1v2.2_2GS MKTKDENLLEEAERLLEEVKR

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE
1na0_int2-IEEEARRILEHLEELARKGSGSGSGSEEAELAYLLGELAYKLGEYRIAIRAYRIALK

RDPNNAEAWYNLGNAYYKQGDYDEATEYYQKALELDRNNAEAKQNLGNAKQKQG
ELEEQVMHVLDQVSELAHELLHKLTGEFLERAAYENWWATEMMLELIKSDDEREIRE
IEEEARRILEHLEELARKGSGSGSGSEEAELAYLLGELAYKLGEYRIAIRAYRIALK

RDPNNAEAWYNLGNAYYKQGDYDEATEYYQKALELDRNNAEAWYNLGNAYYKQGDYD
640 1na0_int2 EAIEYYQKALELDPNNAEAKQNLGNAKQKQG

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE
AHB2-8(S-IFEEARRILEHLEELARKGSGSGSGSGSEYEIRKALEELKASTAELKRATASLRAST
641 6msr EELKKNPSEDALVENNRLIVEHNAIIVENNRIIAAVLELIVRAIK
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IFEEARRILEHLEELARKGSGSGSGSGSGSEYEIRKALEELKASTAELKRATASLRA
642 6msr STEELKKNPSEDALVENNRLIVEHNAIIVENNRIIAAVLELIVRAIK

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE
1na0_int2-IEEEARRILEHLEELARKGSGSGSGSGSERAELAYLLGELAYKLGEYRIAIRAYRIA

LKRDPNNAEAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAKQNLGNAKQKQG
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE
IFEEAERILEHLEELARKGSGSGSGSGSEEAELAYLLGELAYKLGEYRIAIRAYRIA

LKRDPNNAEAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAWYNLGNAYYKQGD
644 ina0_int2 YDEAIEYYQKALELDPNNAEAKQNLGNAKQKQG

ELEEQVMHVLDQVSELAHELLHELTGEELERAAYENWWATEMMLELIKSDDEREIRE
645 1gcm IEEEARRILEHLEELARKGSGSRMKQIEDKIEEILSKIYHIENEIARIKKLIGER
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGSGSGSGSRMKQIEDKIEEILSKIYHIENEIARIKKLIG
646 igcm ER
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEFARRILEHLEELARKGSGSGSEYEIEKALEEPKASTAELKESTASLEASTEELK
647 pRO-2-noHis KNPSEDALVENNRLIVENNAIIVENNRIIAAVLELIVRAIK
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGSGSGSGSGSEYEIRKALEELKASTAELKRSTASLRAST
648 pRO-2-noHis EELKKNPSEDALVENNRLIVENNAIIVENNRIIAAVLELIVRAIK
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE
IEEEARRILEHLEELARKGSGSGSNLAEKMYKAGNAMYRKGQYTIAIIAYTLALLKD

DNNAEAWYNLGNAAYKKGEYDRAIEAYQKALELDPNNAEAWYNLGNAYYKQGDYDEA
649 ma 03 IEYYQKALELDPNNAEAKQNLGNAKQKQG
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE
IEEEARRILEHLEELARKGSGSGSGSGSNLAEKMYKAGNAMYRKGQYTIAIIAYTLA

LLKDPNNAEAWYNLGNAAYKKGEYDEAIKAYQKALELDPNNAEAWYNLGNAYYKQGD
650 ma 03 YDEAIEYYQKALELDPNNAEAKQNLONAKQKQC

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE
651 4pn9 IFEEARRILEHLEELARKGSGSGSGEIAKSLKEIAKSLKEIAWSLKEIAKSLKG
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGSGSGSGSGSGEIAKSLKEIAKSLKEIAWSLKEIAKSLK
652 4pn9 ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE
1na0_int2-IFEEARRILEHLEELARKGGSGGEEAELAYLLGELAYKLGEYRIAIRAYRIALKRDP

ELEEQVMHVLDQVSELAHELLHELTGEELERAAYENWWATEMMLELIKSDDEREIRE
1na0_int2-IEEEARRILEHLEELARKGGGSGGGEEAELAYLLGELAYKLGEYRIAIRAYRIALKR

DPNNAKAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNARAKQNLGNAKQKQG

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE
1na0_int2-IEEEARRILEHLEELARKGGGGSGGGGEEAELAYLLGELAYKLGEYRIAIRAYRIAL

KRDRNNARAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAKONLGNAKOKQG
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGSGGEEAELAYLLGELAYKLGEYRIAIRAYRIALKRDP

NNAEAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAWYNLGNAYYKQGDYDEAI
656 1na0_int2 EYYQKALELDPNNAEAKQNLGNAKQKQG
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGGSGGGEEAELAYLLGELAYKLGEYRIAIRAYRIALKR

DPNNAEAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAWYNLGNAYYKQGDYDE
657 1na0_int2 AIEYYQKALELDPNNAEAKQNLGNAKQKQG

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGGGSGGGGEEAELAYLLGELAYKLGEYRIAIRAYRIAL

KRDPNNAEAWYNLGNAYYKQGDYDEAIEYYQKALELDPNNAEAWYNLGNAYYKQGDY
658 1na0_int2 DEATEYYQKALELDPNNAEAKQNLGNAKQKQG
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGSGGGSEYEIRKALEELKASTAELKRATASLRASTEEL
659 GGGGS5-6msr KKNPSEDALVENNPLIVEHNAIIVENNRIIAAVLELIVRAIK
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGGSGGGGSEYEIRKALEELKASTAELKRATASLRASTE
660 GGGGS7-6msr ELKKNFSEDALVENNRLIVEHNAIIVENNRIIAAVLELIVRAIK
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGGGSGGGGGSEYEIRKALEELKASTAELKRATASLRAS
661 6GG659-6msr TEELKKNPSEDALVENNRLIVEHNAIIVENNRIIAAVLELIVRAIK

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE
662 GGGGS5-1gcm IEEEARRILEHLEELARKGGSGGRMKQIEDKIEEILSKIYHIENEIARIKKLIGER
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGGSGGGRMKQIEDKIEEILSKIYHIENEIARIKKLIGE
663 GGGGS/-igcm R
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGGGSGGGGRMKQIEDKIEEILSKIYHIENEIARIKKLI
664 GGGGS9-1gcm GDR

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE
GGGGS5-pRO- IEEEARRILEHLEELARKGGSGGGSEYEIRKALEELKASTAELKRSTASLRASTEEL
665 2-noHis KKNPSEDALVENNRLIVENNAIIVENNRIIAAVLELIVRAIK

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE
GOGGS7-pRO- IEEEARRILEHLEELARKGGGSGGGGSEYEIRKALEELKASTAELKRSTASLRASTE
666 2-noHis ELKKNFSEDALVENNRLIVENNAIIVENNRIIAAVLELIVRAIK

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE
GOGGS9-pRO- IEEEARRILEHLEELARKGGGGSGGGGGSEYEIRKALEELKASTAELKRSTASLRAS
667 2-noHis TEELKKNPSEDALVENNRLIVENNAIIVENNRIIAAVLELIVRAIK
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGSGGNLAEKMYKAGNAMYRKGQYTIATIAYTLALLKDP

NNAEAWYNLGNAAYKKGEYDEAIEAYQKALELDPNNAEAWYNLGNAYYKQGDYDEAI
668 ma 03 EYYQKALELDPNNAEAKQNLGNAKQKQG
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGGSGGGNLAEKMYKAGNAMYRKGQYTIAIIAYTLALLK

DPNNAEAWYNLGNAAYKKGEYDEAIEAYQKALELDPNNAEAWYNLGNAYYKQGDYDE
669 ma 03 AIEYYQKALELDPNNAEAKQNLGNAKQKQG
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGGGSGGGGNLAEKMYKAGNAMYRKGQYTIATIAYTLAL

LKDPNNAEAWYNLGNAAYKKGEYDEAIEAYQKALELDPNNAEAWYNLGNAYYKQGDY
670 ma 03 DEAIEYYQKALELDPNNAEAKQNLGNAKQKQG

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE
671 GGGGS5-4pn9 IEEEARRILEHLEELARKGGSGGGEIAKSLKEIAKSLKEIAWSLKEIAKSLKG

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE
672 00G057-4pn9 IEEEARRILEHLEELARKGGGSGGGGEIAKSLKEIAKSLKEIAWSLKEIAKSLKG

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE
673 GGGGS9-4pn9 IEEEARRILEHLEELARKGGGGSGGGGGEIAKSLKEIAKSLKEIAWSLKEIAKSLKG
ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGSEALEELEKALRELKKSTDELERSTEELEKNFSEDAL

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGGSSEALEELEKALRELKKSTDELERSTEELEKNPSED

ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGGGSGSEALEELEKALRELKKSTDELERSTEELEKNPS

ELEEQVMHVLDQVSELAHELLHKLIGEELERAAYFNWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGSPELEKALRELKKSIDELERSTEELEKNGSPEALVEN
677 SB175.1 NRLIVENNKIIVEVLRIIAK
ELEEQVMHVLDQVSELAHELLHKLIGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGGSSPELEKALRELKKSTDELERSTEELEKNGSPEALV
678 SB175.1 ENNRLIVENNKIIVEVLRIIAK
ELEEQVMHVLDQVSELAHELLHKLIGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGGGSGSPELEKALRELKKSTDELERSTEELEKNGSPEA
679 SB175.1 LVENNRLIVENNKIIVEVLRIIAK
ELEEQVMHVLDQVSELAHELLHKLIGEELERAAYENWWATEMMLELIKSDDEREIRE

TEEEARRILEHLEELARKGGSEKALRELKKSTDELERSTEELEKNGSPEALVENNRL
41 SB175.2 IVENNKIIVEVLR
ELEEQVMHVLDQVSELAHELLHKLICEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGGSSEKALRELKKSTDELERSTEELEKNGSPEALVENN
681 SB175.2 RLIVENNKIIVEVLR
ELEEQVMHVLDQVSELAHELLHKLIGEELERAAYENWWATEMMLELIKSDDEREIRE

IEEEARRILEHLEELARKGGGGSGSEKALRELKKSTDELERSTEELEKNGSFEALVE
682 SB115.2 NNRLIVENNKIIVEVLR
SEALEELEKALRELKKSIDELERSTEELEKNPSEDALVENNRLIVENNKIIVEVLRI

IAKVLKGGGGSGDKENVLUKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLE
683 LCB1v2.2 EAERLLEEVKR
SEALEELEKALRELKKSTDELERSTEELEKNPSEDALVENNRLIVENNKIIVEVLRI

684 LCB1v2.2 NLLEEAERLLEEVKR
SB115.1-SPELEKALRELKKSTDELERSTEELEKNGSPEALVENNRLIVENNKIIVEVLRIIAK

GGGGSGDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENTLLEEAERLL
685 LCB1v2.2 EEVKR
SB175. 1-SPELEKALRELKKSTDELERSTEELEKNGSPEALVENNRLIVENNKIIVEVLRIIAK
lOGS-GGGGSGGGGSDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEA
686 LCB1v2.2 ERLLEEVKR
NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE

LLERLLSGGGGSGGGSEALEELEKALRELKKSTDELERSTEELEKNPSEDALVENNR

NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE

LLERLLSGGGGSGSEALEELEKALRELKKSTDELERSTEELEKNPSEDALVENNRLI

NLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE

LLERLLSGGGSSEALEELEKALRELKKSIDELERSTEELEKNPSEDALVENNRLIVE

NLDELHMQMTDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKDRQKLEKVVEELKE

LLERLLSGGSEALEELEKALRELKKSIDELERSTEELEKNPSEDALVENNRLIVENN

ELEEQVMHVLDQVSELAHELLHKLIGEELERAAYENWWATEMMLELIKSDDEREIRE
AHB2v1-2GS- IEEEARRILEHLEELARKGGSEALEELEKALPELKKSTDELERSTEELEKNPSEDAL

ELEEQVMHVLDQVSELAHELLHKLIGEELERAAYENWWATEMMLELIKSDDEREIRE
AHB2v2-2GS- TEEFAARILEHLEELARTGGSEALEELEKALRELKKSTDELERSTEELEKNFSEDAL

In some embodiments, the polypeptides comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of a genus selected from those recited in the middle column of Table 9. In these embodiments, Xl, X2, X3 (when recited in the genus), and X4 (when recited in the genus) may be present or absent, and when present may be any sequence of 1 or more amino acids, as described above for embodiments listed in Table 8. In some embodiments, the optional domain that is present between monomer domains is present and may comprise an amino acid linker, as described above for embodiments listed in Table 8.
In another embodiment, the polypeptides comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to an amino acid sequence comprising the amino acid sequence selected from the group consisting of SEQ ID NOS:693 to 701, wherein any N-terminal methionine residue may be absent or present, and wherein residues in parentheses may be present or absent (preferably absent) and are not considered in determining percent identity.
In one embodiment, the N-terminal methionine residue is absent and the optional residues are absent.
Table 9B
Name Sequence MELEEQVMHVLDQVSELAHELLHKLIGEELERAAYFNWWATEMMLELIKSDDEREIREIEEEARR
C389 AHB2v1 ILEHLEELARKGGSEALEELEKALRELKKSIDELERSTEELEKNPSEDALVENNRLIVENNKIIV
2GS-SB175 EVLRIIAKVLK (SEQ ID NO: 693) MELEEQVMHVLDQVSELAHELLHKLIGEELERAAYFNWWATEMMLELIKSDDEREIREIEEEAAR
AHB2v2_12PAS ILEHLEELARTGGASPAAPAPGGNLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEKATKAYKN

LCB3v2.2 12 KDRQKLEKVVEELKELLERLLSGGASPAAPAPGGDKENVLQKIYEIMKELERLGHAEASMQVSDL
PAS LCB1v2.2 IYEFMKTKDENLLEEAERLLEEVKR (SEQ ID NO: 6941 MELEEQVMHVLDQVSELAHELLHKLIGEELERAAYFNWWATEMMLELIKSDDEREIREIEEEAAR
AHB2v2_24PAS ILEHLEELARTGGASPAAPAPASPAAPAPSAPAGGNLDELHMQMTDLVYEALHFAKDEEFQKHVF

LCB3v2.2_24 QLFEKATKAYKNKDRQKLEKVVEELKELLERLLSGGASPAAPAPASPAAPAPSAPAGGDKENVLQ
PAS_LCB1v2.2 KIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEVKR(SEQ ID NO: 695) MELEEQVMHVLDQVSELAHELLHKLIGEELERAAYFNWWATEMMLELIKSDDEREIREIEEEARR

GS_LCB1v2.2 IVEVLRIIAKVLK(SEQ ID NO: 696) MELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMMLELIKSDDEREIREIEEEARR
AHB2v1_100S
ILEHLEELARKGGGSGGGSGGNLDELHMQMIDLVYEALHFAKDEEFQKHVFQLFEKATKAYKNKD
LCB3v2.2_10G RQKLEKVVEELKELLERLLSGGGSGGGSGGDKENVLQKIYEIMKELERLGHAEASMQVSDLIYEF
S LCB1v2.2 MKTKDENLLEEAERLLEEVKR(SEQ ID NO: 697) MELEEQVMHVLDQVSELAHELLHKLIGEELERAAYFNWWATEMMLELIKSDDEREIREIEEEARR
C390-AHB2v1- ILEHLEELARKGGGSSEALEELEKALRELKKSIDELERSTEELEKNPSEDALVENNRLIVENNKI
4GS-SB175 IVEVLRIIAKVLK(SEQ ID NO: 696) C326-AHB2v1- MELEEQVMHVLDQVSELAHELLHKLIGEELERAAYFNWWATEMMLELIKSDDEREIREIEEEARR
4GS-1rfo ILEHLEELARKGSGSGYIPEAPRDGQAYVRKDGEWVLLSTFL(SEQ ID NO:
698) AHB2v1-10GS-LCB3_v2.3-(MSHHHHHHHHSENLYFOSGG)ELEEQVMHVLDQVSELAHELLHKLTGEELERAAYENWWATEMM
LCBI_v2.2 LELIKSDDEREIREIEEBARRILEHLEELARKGGGSGGGSGGNIDELLMQVTDLIYEALHFAKDE
with His Tev EFOKHAFOLFEKATKAYKNKDKOKLEKVVEELKELLERILSGGGSGGGSGGDKENVLOKIYEIMK
tag ELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEVKR(SEQ ID NO:
699) LCB1v3 with (MSHHHHHHHESENLYFQSGGG)DKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEFMKQGDER
His Tev tag LLEEAERLLEEVER(SEQ ID NO: 700) LCB1-Fc9 DKENILOKIYEIMKTLDOLGHAEASMOVSDLIYEFMKOGDERLLEEAERLLEEVERGGSGSGGSGSGSG
With signal GSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV
sequence EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL
leader PPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG
removed NVESCSVMHEALHNHYTOKSLSLSPGK(SEQ ID NO: 701) The polypeptide of any embodiment or combination of embodiments described here may further be linked to a stabilization domain to promote increased residency time upon administration to a subject. Any suitable stabilization domain may be used for an intended purpose. Exemplary stabilization domains include, but are not limited to, polyethylene glycol (PEG), albumin, hydroxyethyl starch (HES), conformationally disordered polypeptide sequence composed of the amino acids Pro, Ala, and/or Ser ('PASylation'), and/or a mucin diffusivity polypeptide composed of amino acids Lys and Ala, with or without Glu.
Non-limiting embodiments of such mucin diffusivity polypeptides include, but are not limited to:
Mucin domain: AKAKAKAKAKAKAKAKAKAKGG (SEQ ID NO: 61); GGAKAKAKAKAKAKAKAKAKAK
(SEQ ID
NO: 62) Exemplary polypeptides of these embodiments may, for example, comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 65-96, wherein in embodiments where a secretion signal is present (MARAWIFFLLCLAGRALA; SEQ ID NO:63) it can be replaced with any other secretion signal.
Mucin_LCBl_vl.l_Cys_ AKAKAKAKAKAKAKAKAKAKGGDKENILQKIYEIMKTLDQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVERC

(SEQ ID NO:65) >Mucin_LCB1_v1.3 AKAKAKAKAKAKAKAKAKAKGGDKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVER
(SEQ
ID NO:66) >LCB1_v1.3_Mucin DKENILOKIYEIMKTLEOLGHAEASMOVSDLIYEFMKOGDERLLEEAERLLEEVERGGAKAKAKAKAKAKAKAKAKAK
SEQ
ID NO:67) KC Fusions (Bold = Secretion Signal, underline = LCB, Yellow is the GS Linker, Green is Sc) >LCB1-Fcl (BM4D-LCB1-GS4-Fc-Opt-WT) (The LCB1 sequences = LCB1-1 of first provisional) MARAWIFFLLCLAGRALADKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVERGSGSE
PKSS
DKTHTCPPCPAPELLGGPSVFLFRPKRKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVV
SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQ
BENNYKTTPFVLDSDGSFELYSKLTVDKSRWQQGNVESCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 68) > LCB1-Fc2 (BM40-LCB1-GS15-Fc-Opt-WT) (The LCB1 sequence = LCB1-1 of first provisional) MARAWIFFLLCLAGRALADKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEaAERLLEEVERGGSGS
GGSG
SGSGGSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPRDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK
TKPR
EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPS
DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ
ID
NO: 69) >LCB1-Fc3 (BM4D-Fc-Opt- GS15-2-LCB1-WT) (The LCB1 sequence - LCB1-1 of first provisional) MARAWIFFLLCLAGRALAEPKSSDKTHTCPPCPAPELLGGPSVFLEPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN
WYVD
GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT
KNQV
SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVESCSVMHEALHNHYTQKSLS
LSPG
KSGGSGSGSGGSGSGS DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER
(SEQ ID
NO: 70) >LCB1-Fc4 (BM4D-LCB1-0515-Fc-Opt-GS15-2-LCB1-WT) (The LCB1 sequences - LCB1-1 of first provisional) MARAWIFFLLCLAGRALADKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEaAERLLEEVERGGSGS
GGSG
SGSGGSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK
TKPR
EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPS
DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVESCSVMHEALHNHYTQKSLSLSPGKSGGSGSG
SGGS
GSGSDKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER (SEQ ID NO: 71) >LCB1-Fc5 (BM4D-LCB1-GS4-Fc-Opt-Q38) (The LCB1 sequence = LCB1-3 of first provisional) MARAWIFFLLCLAGRALADKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKQGDERLLEEAERLLEEVERGSGSE
PKSS
DKTHTCPPCPADELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVV
SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
SNGQ
PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 72) >LCB1-Fc6 (BM4D-LCB1-GS15-Fc-Opt-Q38) (The LCB1 sequence = LCB1-3 of first provisional) MARAWIFFLLCLAGRALADKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKQGDERLLEEAERLLEEVERGGSGS
GGSG
SGSGGSEPKSSDKTHTCPBCPAPELLGGPSVELFPFKPKDTLMISRTPEVTCVVVDVSHEDFEVKFNWYVDGVEVHNAK
TKPR
EEQYNSTYRVVSVLTVLHODWLNGKEYKCKVSNKALPAPIEKTISKAKGOPREPOVYTLPPSRDELTKNOVSLTCLVKG
FYPS
DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ
ID
NO:73) >LCB1-Fc7 (BM40-Fc-Opt-G515-2-LCB1-Q3B) (The LCB1 sequence = LCB1-3 of first provisional) MARAWIFFLLCLAGRALAEPKSSDKTHTCPPCPAPELLGGPSVFLEPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN
WYVD
GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT
KNOV
SLTCLVKGFYESDIAVEWESNGQPENNYKTTETVLDSDGSFFLYSKLTVDKSRWQQGNVESCSVMHEALHNHYTQKSLS
LSBG
KSGGSGSGSGGSGSGSDKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKQGDERLLERAERLLEEVER (SEQ
ID
MO: 74) >LCB1-Fc8 (BM4D-LCB1-Q38-G515-Fc-Oot-5515-2-LCB1-Q38) (The LCB1 sequences =

of first provisional) MARAWIFFLLCLAGRALADKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKQGDERLLEEAERLLEEVERGGSGS
GGSG
SGSGGSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDREVKFNWYVDGVEVHNAK
TKPR

EEQYNSTYRVVSVLTVLHODWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPOVYTLPPSRDELTKNQVSLTCLVKG
FYPS
DIAVEWESNGQPENNYKTTRPVLDSDGSFFLYSKLTVDKSRWQQONVFSCSVMHEALHNHYTQKSLSLSPCKSGGSGSG
SGGS
GSGSDKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKQGDERLLEEAERLLEEVER (SEQ ID NO: 75) > LCB1-6M-Fc9 (BM40-LCB1-6M -4N,14K,15T,18Q,27Q,38Q -6S15-Fc-Opt) (The LCB1 sequence = LCB1 v1.1 of this provisional) MARAWIFFLLCLAGRALADKENILQKIYEIMKTLDQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVERGGSGS
GGSG
SGSGGSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK
TKPR
EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPS
DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ
ID
NO: 76) > LCB1-6M-Ngly-Fc10 (BM4D-LCB1-6M-Ngly -4N,14K,15T,18Q,27N,33Q -6S15-Fc-Opt) (The LCB1 sequence = LCB1-5 of the original provisional = LOB1_v1.1 = LCB1-4 with N-link Glycosylation) MARAWIFFLLCLAGRALADKENILQKIYEIMKTLDQLGHAEASMNVSDLIYEFMKQGDERLLEEAERLLEEVERGGSGS
GGSG
SGSGGSERKSSDKTHTCPPCPAPELLGGPSVFLFRPKRKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK
TKPR
EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPS
DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ
ID
NO: 77) > LCB3-6M-Fc11 (BM40-LCB3-6M -8Q,260,281-1,35K,37T,43K -GS15-Fc-Opt) (LCD sequence is the same as LCB3-3 of First Provisional) MARAWIFFLLCLAGRALANDDELHMQMTDLVYEALHFAKDEEI
QKHVFQLFEKATKAYKNKDRQKLEKVVEELKELLERLL SG
GSGSGGSGSGSGGSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD
GVEV
HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNOKEYKCKVSNKALPAPIEKTISKAKOQPREPQVYTLPPSRDELTKNQV
SLTC
LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSUSVMHEALHNHYTQKSLSLSPG
K
(SEQ ID NO:78) > LCB3-6M-NGly-Fc12 (BM4 -LCB3-6M-Ngly -8Q,26Q,28H,35N,37T,43K -GS15-Fc-Opt) (LCB
sequence is the same as LCB3-4 of First Provisional which is LCB3-3 with N-link Glycosylation) MARAWIFFLLCLAGRALANDDELHMQMTDLVYEALHFAKDEEI
QKHVFQLFENATKAYKNKDRQKLEKVVEELKELLERLL SG
GSGSGGSGSGSGGSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD
GVEV
HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPBSRDELTKNQV
SLTC
LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
K
(SEQ ID NO:79) > LCB1-6M-GPGcP-Fc13 (BM40-LCB1-6M -4N,14K,15T,180,27Q,38Q -GPGcP-Fc-Opt) (LCB
sequence is the same as LCB3-3 of First Provisional) MARAWIFFLLCLAGRALADKENILQKIYEIMKTLDQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVERAGSGG
SGGS
GGSPVPSTPPTPSPSTPPTPSPSGGSGNSSGSGGSPVPSTPPTPSPSTPPTPSPSASEPKSSDKTHTCPPCPAPELLGG
PSVF
LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK
CKVS
NKALPABIEKTISKAKGQPREBQVYTLBPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQBENNYKTTPBVLDSDGS
FFLY
SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:80) >
LCB3-6M-GPGcP-Fc14 (BM40-LCB3-6M -8Q,26Q,28H,35K,37T,43K -GPGcP-Fc-Opt) (LCB
sequence is the same as LCB3-3 of First Provisional) MARAWIFFLLCLAGRALANDDELHMQMTDLVYEALHFAKDEEI
QKHVFQLFEKATKAYKNKDRQKLEKVVEELKELLERLL SA
GSGGSGGSGGSPVPSTPPTPSPSTPPTPSPSGGSGNSSGSGGSPVPSTPPTPSPSTPPTPSPSASEPKSSDKTHTCPPC
PAPE
LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYHSTYRVVSVLTVLHOD
WLNG
KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPBRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP
PVLD
SUGSFELYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 51) = LCB1-6M-0630-Fc15 (BM40-LCB1-6M -4N,14K,15T,18Q,27Q,38Q -0530-Fc-Opt)LCB1-MARAWIFFLLCLAGRALADKENILQKIYEIMKTLDQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVERGGGSG
GGGS
GGGGSGGGGSGGGGSGGGGSGEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV
KFNW
YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
ELTK
NQVSLTCLVKGEYPSDIAVEWESNGQPENNYKTTBPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK
SLSL
SPGK (SEQ ID NO:82) > LCB3-6M-G530-Fc16 (BM40-LCB3-6M -8Q,26Q,28H,35K,37T,43K -GS30-Fc-Opt) (LCB
sequence is the same as LCB3-3 of First Provisional) MARAWIFFLLCLAGRALANDDELHMOITDLVYEALHFAKDEEI
QKHVFQLFEKATKAYKNKDRQKLEKVVEELKELLERLL SG
GGSGGGGSGGGGSGGGGSGGGGSGGGGSGEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
VSHE
DPEVKFNWYVDGVEVENAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV
YTLP
PSRDELTKNOVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWOOGNVFSCSVNHEA
LHNH
YTQKSLSLSPGK (SEQ ID NO:83) > LCB1-v1.3-Fc17 (BM40-LCB1-v1.3 -4N,14K,15T,17E,18Q,27Q,38Q -G515-Fc-Opt) MARKWIFFLLCLAGRALADKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVERGGSGS
GGSG
SGSGGSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK
TKPR
EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPS
DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ
ID
MO: 64) > LCB1-v1.3-Ngly-6c18 (8M40-LCB1-v1.3 Ngly -4N,14K,15T,17E,18Q,27N,38Q -GS15-Fc-Opt) (>LCB1_v1.5 (= LCB1_v1.3 with N-link Glycosylation) MARAWIFFLLCLAGRALADKENILQKIYEIMKTLEQLGHAEASMNVSDLIYEFMKQGDERLLEEAERLLEEVERGGSGS
GGSG
SGSGGSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK
TKPR
EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPS
DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ
ID
NO:85) > LCB1-v1.3-GPGcP-Fc19 (BM40-LCB1-v1.3-Fc19 -4N,14K,15T,17E,18Q,27Q,380¨GPGcP-Fc-Opt) MARAWIFFLLCLAGRALADKENILQKIYEIMKTLEQLGHAEASMQVSDLIYEFMKQGDERLLEEAERLLEEVERAGSGG
SGGS
GGSPVPSTPPTPSFSTPPTPSPSGGSGNSSGSGGSPVPSTPPTPSPSTPPTPSPSASEPKSSDKIHTCPPCPAPELLGG
PSVF
LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK
CKVS
NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS
FFLY
SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 86) > LCB1-v1.3-GS30-5c20 (8M40-LCB1-v1.3 -4N,14K,15T,17E,180,270,380 -GS30-Fe-Opt) GGCS
GGGGSGGGGSGGGGSGGGGSGEPKSSDKTHTCPPCPAPELLGGPSVFLEPPKPKDTLMISRTPEVTCVVVDVSHEDPEV
KFNW
YVDGVEVHNAKTKPREEOYNSTYRVVSVLTVLHODWLNGKEYKCKVSNKALPAPIEKTISKAKGOPREPOVYTLPPSRD
ELTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK
SLSL
SPGK (SEQ ID NO:87) MARAWIFFLLCLAGRALADKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENL
LEEAERLLEEVKRGGSGSGGSGSGSGGSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPK

Fc21-DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL
v EQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYILPPSRDELTKNQVSLTCLVK
FcIgG1. WT
GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
LHNHYTQKSLSLSPGK (SEQ ID NO: 88) MARAWIFFLLCLAGRALADKENVLQKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENL
Fc22- LEEAERLLEEVKRGGSGSGGSGSGSGGSEPKSSDKTHTCPRCPAPELLGGPSVFLFPPKPK
LCB1v2.2-DTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVL
FcIgG3 WT
HQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVK
GFYPSDIAVEWESSGQPENNYNTTDPMLDSDGSFFLYSKLTVDKSRWQQGNIFSCSVMHEA

LHNRFTQKSLSLSPGK (SEQ ID NO: 89) MARAWI FFLLCLAGRALAN I DELLMQVTDL I YEALH FAKDEE FQ KHAFQL FEKAT KAYKNK
DKQKLEKVVEELKELLERIL SGGGSGGGSGGDKENVLQKI YEIMKELERLGHAEASMQVSD
2 Fc3-10GS-23 LCB3¨v LIYEFMKTKDENLLEEAERLLEEVKRGGSGSGGSGSGSGGSEPKSSDKTHTCPPCPAPELL
LCB1 F .
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY
v2.2 ¨ I gG1WT
NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE
c LTKNQVSLTOLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ
QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 90) MARAWIFFLLCLAGRALAELEEQVMHVLDQVSELAHELLHKLTGEELERAAYFNWWATEMM
Fc24 AHB2-LELIKSDDEREIREIEEEARRILEHLEELARKGGGSGGGSGGNIDELLMQVTDLIYEALHF

AKDEEFQKHAFQLFEKATKAYKNKDKQKLEKVVEELKELLERILSGGGSGGGSGGDKENVL
LCB3_v2 3-QKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEVKRGGSGSGGSGSG

.
SGGSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTOVVVDVSHEDPE
VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE
LOB 1 v2 .2¨F KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
cIgG1 WT
PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID
NO: 91) MARAWIFFLLCLAGRALANIDELLMQVIDLIYEALHFAKDEEFQKHAFQLFEKATKAYKNK
DKQKLEKVVEELKELLERILSGGGSGGGSGGELEEQVMHVLDQVSELAHELLHKLIGEELE
RAAYFNWWATEMMLELIKSDDEREIREIEFEARRILEHLEELARKGGGSGGGSGGDKENVL
QKIYEIMKELERLGHAEASMQVSDLIYEFMKTKDENLLEEAERLLEEVKRGGSGSGGSGSG
Fc25_LCB3 v SGGSEPKSSDKTHTCPPCPAPELLGGPSVELFPPKPKDTLMISRTPEVTCVVVDVSHEDPE
2.3-10GS-VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE

KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
LCB1_v2.2 F PPVLDSDGSFFLYSKLTVDKSRWQQGNVESCSVMHEALHNHYTQKSLSLSPGK(SEQ ID
cIgG1 WT NO: 92) MARAWI FFLLCLAGRALAN I DELLMQVTDL I YEALH FAKDFE FQ KHAFQL FFKAT KAYKNK
DKQKLEKVVEELKELLERIL SGGGSGGGSGGDKENVLQKI YEIMKELERLGHAEASMQVSD
LIYEFMKTKDENLLEEAERLLEEVKRGGSGSGGSGSGSGGSEPKSSDKTHTCPPCPAPELL
Fc26_LCB3 v AGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY
2.3-10GS-NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE
LCB1_v2.2 F LTKNQVSLTOLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ
cIgG1 GA QGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO: 93) MARAWI FFLLCLAGRALAN I DELLMQVTDL I YEALH FAKDEE FQ KHAFQL FFKAT KAYKNK
DKQKLEKVVEELKELLERIL SGGGSGGGSGGDKENVLQKI YEIMKELERLGHAEASMQVSD
LIYEFMKTKDENLLEEAERLLEEVKRGGSGSGGSGSGSGGSEPKSSDKTHTCPPCPAPELL
Fc27_LCB3 v RGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY
2.3-10GS-NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKARPAPIEKTISKAKGQPREPQVYTLPPSRDE
LCB1_v2.2 F LTKNQVSLTOLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ
cIgG1 GRLR QGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO: 94) MARAWI FFLLCLAGRALAN I DEL LMQVT DL I YEALHFAKDEEFQKHAFQLFEKATKAYKNK
DKQKLEKVVEELKELLERIL SGGGSGGGSGGDKENVLQKI YEIMKELERLGHAEASMQVSD
Fc28_LCB3 v LIYEFMKTKDENLLEEAERLLEEVKRGGSGSGGSGSGSGGSEPKSSDKTHTCPPCPAPELL
2.3-10GS-AGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY
LCB1_v2.2 F NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPLPEEKTISKAKGQPREPQVYTLPPSRDE
cIgG1 GAALI LTKNQVSLTOLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ
QGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO: 95) MARAWI FFLLCLAGRALAN I DELLMQVTDL I YEALH FAKDEE FQ KHAFQL FEKAT KAYKNK
DKQKLEKVVEELKELLERIL SGGGSGGGSGGDKENVLQKI YEIMKELERLGHAEASMQVSD
Fc29_LCB3 v LIYEFMKTKDENLLEEAERLLEEVKRGGSGSGGSGSGSGGSEPKSSDKTHTCPPCPAPELL
2.3-10GS-AGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY
LCB1_v2.2 F NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPLPEEKTISKAKGQPREPQVYTLPPSRDE
cIgG1 GAALI LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ
ELS QGNVFSCSVLHEALHSHYTQKSLSLSPGK(SEQ ID NO: 96) The disclosure further provides oligomers of the polypeptide of any embodiment or combination of embodiments herein. In one embodiment, the oligomers are oligomers of polypeptides disclosed herein that comprise oligomerization domains. In one embodiment, the oligomer comprises a trimer, including but not limited to a homotrimer.
In another embodiment, the disclosure provides compositions, comprising 2, 3, 4, or more copies of the polypeptide of any embodiment or combination of embodiments herein attached to a support, including but not limited to a polypeptide particle support, such as a nanoparticle or virus like particle.
As disclosed herein, the polypeptides bind to the SARS-CoV-2 Spike glycoprotein, and thus are useful (for example), as therapeutics to treat SARS-CoV-2 infection. In one embodiment, the polypeptides bind to the SARS-CoV-2 Spike glycoprotein with an affinity of at least 10 nM, measured as described in the attached examples.
In another aspect, the disclosure provides nucleic acids encoding a polypeptide of the disclosure. The nucleic acid sequence may comprise RNA (such as mRNA) or DNA.
Such nucleic acid sequences may comprise additional sequences useful for promoting expression and/or purification of the encoded protein, including but not limited to polyA
sequences, modified Kozak sequences, and sequences encoding epitope tags, export signals, and secretory signals, nuclear localization signals, and plasma membrane localization signals. It will be apparent to those of skill in the art, based on the teachings herein, what nucleic acid sequences will encode the proteins of the invention.
In another aspect, the disclosure provides expression vectors comprising the nucleic acid of any embodiment or combination of embodiments of the disclosure operatively linked to a suitable control sequence. "Expression vector" includes vectors that operatively link a nucleic acid coding region or gene to any control sequences capable of effecting expression of the gene product. "Control sequences" operably linked to the nucleic acid sequences of the disclosure are nucleic acid sequences capable of effecting the expression of the nucleic acid molecules. The control sequences need not be contiguous with the nucleic acid sequences, so long as they function to direct the expression thereof. Thus, for example, intervening untranslated yet transcribed sequences can be present between a promoter sequence and the nucleic acid sequences and the promoter sequence can still be considered "operably linked" to the coding sequence. Other such control sequences include, but are not limited to, polyadenylation signals, termination signals, and ribosome binding sites. Such expression vectors can be of any type known in the art, including but not limited to plasmid and viral-based expression vectors. The control sequence used to drive expression of the disclosed nucleic acid sequences in a mammalian system may be constitutive (driven by any of a variety of promoters, including but not limited to, CMV, SV40, RSV, actin, EF) or inducible (driven by any of a number of inducible promoters including, but not limited to, tetracycline, ecdysone, steroid-responsive).
In one aspect, the present disclosure provides cells comprising the polypeptide, the composition, the nucleic acid, and/or the expression vector of any embodiment or combination of embodiments of the disclosure, wherein the cells can be either prokaryotic or eukaryotic, such as mammalian cells. In one embodiment the cells may be transiently or stably transfected with the nucleic acids or expression vectors of the disclosure. Such transfection of expression vectors into prokaryotic and eukaryotic cells can be accomplished via any technique known in the art. A method of producing a polypeptide according to the invention is an additional part of the invention. The method comprises the steps of (a) culturing a host according to this aspect of the invention under conditions conducive to the expression of the polypeptide, and (b) optionally, recovering the expressed polypeptide. In other embodiments, the polypeptides may be produced via any other suitable technique, including but not limited to using cell-free protein synthesis (or in vitro transcription and translation).
In another aspect, the disclosure provides pharmaceutical compositions/vaccines comprising (a) the polypeptide, the nucleic acid, the expression vector, and/or the host cell of any embodiment or combination of embodiments herein; and (b) a pharmaceutically acceptable carrier.
The compositions may further comprise (a) a lyoprotectant; (b) a surfactant;
(c) a bulking agent; (d) a tonicity adjusting agent; (e) a stabilizer; (f) a preservative and/or (g) a buffer. In some embodiments, the buffer in the pharmaceutical composition is a Tris buffer, a histidine buffer, a phosphate buffer, a citrate buffer or an acetate buffer.
The composition may also include a lyoprotectant, e.g. sucrose, sorbitol or trehalose. In certain embodiments, the composition includes a preservative e.g. benzalkonium chloride, benzethonium, chl orohexi dine, phenol, m-cresol, benzyl alcohol, methyl paraben, propylparaben, chlorobutanol, o-cresol, p-cresol, chlorocresol, phenylmercuric nitrate, thimerosal, benzoic acid, and various mixtures thereof. In other embodiments, the composition includes a bulking agent, like glycine. In yet other embodiments, the composition includes a surfactant e.g., polysorbate-20, polysorbate-40, polysorbate- 60, polysorbate-65, polysorbate-80 polysorbate-

85, poloxamer-188, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan trilaurate, sorbitan tristearate, sorbitan trioleaste, or a combination thereof. The composition may also include a tonicity adjusting agent, e.g., a compound that renders the formulation substantially isotonic or isoosmotic with human blood. Exemplary tonicity adjusting agents include sucrose, sorbitol, glycine, methionine, mannitol, dextrose, inositol, sodium chloride, arginine and arginine hydrochloride. In other embodiments, the composition additionally includes a stabilizer, e.g., a molecule which substantially prevents or reduces chemical and/or physical instability of the nanostructure, in lyophilized or liquid form. Exemplary stabilizers include sucrose, sorbitol, glycine, inositol, sodium chloride, methionine, arginine, and arginine hydrochloride.
The polypeptide, the nucleic acid, the expression vector, and/or the host cell may be the sole active agent in the composition, or the composition may further comprise one or more other agents suitable for an intended use.
In a further aspect, the disclosure provides methods for treating a severe acute respiratory syndrome (SARS) coronavirus infection (including SARS-Co-V and SARS-CoV-2), comprising administering to a subject in need thereof an amount of the polypeptide, the nucleic acid, the expression vector, the host cell, the oligomer, the composition, and/or the pharmaceutical composition of any of the preceding claims, effective to treat the infection. In one embodiment, the SARS coronavirus comprises SARS-CoV-2.
In another aspect, the disclosure provides methods for limiting development of a severe acute respiratory syndrome (SARS) coronavirus infection (including SARS-Co-V and SARS-CoV-2), comprising administering to a subject in need thereof an amount of the polypeptide, the nucleic acid, the expression vector, the host cell, the oligomer, the composition, and/or the pharmaceutical composition of any of the preceding claims, effective to treat the infection. In one embodiment, the SARS coronavirus comprises SARS-CoV-2.
The polypeptide, the nucleic acid, the expression vector, the host cell, and/or the pharmaceutical composition may be administered via any suitable administrative route as deemed appropriate by attending medical personnel. In one embodiment, the polypeptide, the nucleic acid, the expression vector, the host cell, the oligomer, the composition, and/or the pharmaceutical composition is administered intra-nasally, In another embodiment, the polypeptide, the nucleic acid, the expression vector, the host cell, the oligomer, the composition, and/or the pharmaceutical composition is administered systemically.
When the method comprises treating a SARS coronavirus infection, the one or more polypeptides, nucleic acids, expression vectors, host cells, and/or pharmaceutical compositions are administered to a subject that has already been diagnosed as having a SARS

coronavirus infection. As used herein, "treat" or "treating" means accomplishing one or more of the following: (a) reducing severity of symptoms of the infection in the subject; (b) limiting increase in symptoms in the subject; (c) increasing survival; (d) decreasing the duration of symptoms; (e) limiting or preventing development of symptoms; and (f) decreasing the need for hospitalization and/or the length of hospitalization for treating the infection.
When the method comprises limiting development of SARS coronavirus infection, the one or more polypeptides, nucleic acids, expression vectors, host cells, and/or pharmaceutical compositions are administered prophylactically to a subject that is not known to have a SARS
coronavirus infection, but may be at risk of such an infection. As used herein, "limiting"
means to limit development of a SARS coronavirus infection in subjects at risk of such infection, which may be any subject.
The subject may be any subject, such as a human subject Exemplary symptoms of SARS-CoV-2 infection include, but are not limited to, fever, fatigue, cough, shortness of breath, chest pressure and/or pain, loss or diminution of the sense of smell, loss or diminution of the sense of taste, and respiratory issues including but not limited to pneumonia, bronchitis, severe acute respiratory syndrome (SARS), and upper and lower respiratory tract infections.
As used herein, an "effective amount" refers to an amount of the composition that is effective for treating and/or limiting SARS-CoV-2 infection. The polypeptide, composition, nucleic acid, or composition of any embodiment herein are typically formulated as a pharmaceutical composition, such as those disclosed above, and can be administered via any suitable route, including orally, parentally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. The term parenteral as used herein includes, subcutaneous, intravenous, intra-arterial, intramuscular, intrasternal, intratendinous, intraspinal, intracranial, intrathoracic, infusion techniques or intraperitoneally. Polypeptide compositions may also be administered via microspheres, liposomes, immune-stimulating complexes (ISCOMs), or other microparticul ate delivery systems or sustained release formulations introduced into suitable tissues (such as blood). Dosage regimens can be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic response). A suitable dosage range may, for instance, be 0.1 [tg/kg-100 mg/kg body weight of the polypeptide or nanoparticle thereof The composition can be delivered in a single bolus, or may be administered more than once (e.g., 2, 3, 4, 5, or more times) as determined by attending medical personnel.

The disclosure also provides methods for designing polypeptides that bind to the receptor binding site (RBD) of SARS-Cov-2, wherein the methods comprise steps as described in the examples that follow. Such methods may comprise the steps of polypeptide design (as described in any embodiment or combination of embodiments in the examples), cell-free synthesis, and evaluation for SARS-Cov-2 RBD binding using any suitable technique.
Examples Summary Effective therapeutics for SARS-CoV-2 are needed. We sought to use computational protein design to generate high affinity binders to the receptor binding site (RBD) of SARS-Cov-2 that block the interaction with the Ace2 receptor required for cell entry. We generated small protein scaffolds with shape complementary to the Ace2 binding site on the RBD using two strategies: first, scaffolds were built around the helix in Ace2 that makes the majority of the interactions with the RBD, and second, diverse de novo designed scaffolds less than 65 residues in length were docked against this region. In both cases, the scaffold residues at the RBD interface were then optimized for high affinity binding and those in the remainder of the protein, for folding to the target structure and stability. The 50,000 designs predicted to bind most strongly to the virus were encoded in large oligonucleotide arrays, and screened using yeast surface display for binding to the RBD with fluorescence activated cell sorting; deep sequencing of the population before and after sorting identified hundreds of designs that bind the target. The binding modes of the highest affinity (most enriched by sorting) binders were confirmed by high resolution sequence mapping, and the affinities were further increased by combining 1-4 beneficial substitutions. Eight of the optimized designs with different binding sites surrounding the Ace2 interface on the RBD, and completely different sequences, were found to express at high levels in E coli, and to bind the RBD with Kd's ranging from 100pM
to lOnM. The designs blocked infection of vero-6 cells by live virus with IC50' s ranging from lOnM to 20pM. The polypeptides are thus useful, for example, in both intra-nasal and systemic SARS-CoV-2 therapeutics, and, more generally, our results demonstrate the power of computational protein design for rapidly generating potential therapeutic candidates against pandemic threats.
SARS -CoV-2 infection is thought to often start in the nose, with virus replicating there for several before spreading to the broader respiratory system. Delivery of a high concentration of a viral inhibitor into the nose and into the respiratory system generally could therefore potentially provide prophylactic protection, and therapeutic efficacy early in infection, and could be particularly useful for health care workers and others coming into frequent contact with infected individuals. A number of monoclonal antibodies are in development as systemic SARS-CoV-2 therapeutics, but these compounds are not ideal for intranasal delivery as antibodies are large and often not extremely stable molecules, and the density of binding sites is low (two per 150Kd antibody); the Fe domain provides little added benefit. More desirable would be protein inhibitory with the very high affinity for the virus of the monoclonals, but with higher stability and very much smaller size to maximize the density of inhibitory domains and enable direct delivery into the respiratory system through nebulization.
We set out to de novo design high affinity binders to the RBD that compete with Ace2 binding. We explored two strategies: first we attempted to scaffold the alpha helix in Ace2 that makes the majority of the interactions with the RBD in a small designed protein that makes additional interactions with the RBD to attain higher affinity, and second, we sought to design binders completely from scratch that do not incorporate any known binding interaction with the RBD. An advantage of the second approach is that the range of possibilities for design is much larger, and so potentially higher affinity binding modes can be identified. For the first approach, we used the RosettaTm blue print builder to generate small proteins which incorporate the Ace2 helix and for the second approach, RIF docking and design using large miniprotein libraries. The designs interact with distinct regions of the RBD
surface surrounding the Ace2 binding sites (Figure 1). Designs for approach 1, and approach 2, were encoded in long oligonucleotides, and screened for binding to fluorescently tagged RBD on the yeast cell surface. Deep sequencing identified 3 Ace2 helix scaffolded designs (approach 1), and 150 de novo interface designs (approach 2) that were clearly enriched following FACS sorting for RBD binding. Designs were expressed in E. coil and purified, and many were found to be have soluble expression and to bind RBD in biolayer interferometry experiments and could effectively compete with ACE-2 for binding to RBD
(example shown in Figure 2). Based on BLI data (e.g. See Figure 2) the RBD binding affinities of minibinders are: LCB1 <1M, LC133 <1nM. The affinities of LCB2, LCB4, LCB5, LCB6, LCB7, LCB8 range from 1-20nM, with relative strength of different binders being LCB4 >
LCB2 > LCB9 = LCB5 > LCB6 > LCB7.
To determine whether the designs binding the RBD through the designed interfaces, site saturation libraries in which every residue in each design was substituted with each of the 20 amino acids one at a time were constructed, and subjected to FACS sorting for RBD

binding. Deep sequencing showed that the binding interface residues and protein core residues were conserved in many of the designs for which such site saturation libraries (SSM's) were constructed (SSMs were used to define allowable positions for amino acid changes in Table 1). For most of the designs, a small number of substitutions were enriched in the FACS sorting, suggesting they increase binding affinity for RBD. For the highest affinity of the approach 1 designs, and 8 of the approach 2 designs, combinatorial libraries incorporating these substitutions were constructed and again screened for binding with FACS; because of the very high binding affinity the concentrations used in the sorting were as low as 20pM. Each library converged on a small number of closely related sequences, and for each design, one of the optimized variants was expressed in E. coli and purified.
The binding of the 8 optimized designs with different binding modes to RBD
(Figurel) was investigated by biolayer interferometry. For a number of the designs, the Kd's ranged from 1-20nM, and for the remainder, the Kd's were below 1nM, too strong to measure reliably with this technique (See Figure 2). Circular dichroism spectra of the designs were consistent with the design models, and the designs retained full binding activity after a number of days at room temperature (Figure 3).
We investigated the ability of the designs to block infection of human cells by live virus. 100 FFU of SARS-CoV-2 was added to 2.5-3x10^4 vero cells in the presence of varying amounts of the designed binders. Details are provided in the legend to Figure 4. We observed potent inhibition of infection for all of the designs with IC50's ranging from 1 nM
to 0.02 nM.
Details on specific designs are provided in Table 10.
Table 10 Estimated SARS-Level of Estimated CoV-2 Soluble Rd for Neutral Express Productio Estimate Spike ization Construct ion Vecto Expression n (mg / d Rd for (nM) IC50 Name Seq ID Host r Method L) RBD (nM) Avidity (nM) (SEQ ID Autoinduction LC31-1 NO:1) E. coli pET 37 C 10( 0.2 0.1 0.01 (SEQ ID Autoinduction LC31-2 NO:2) E. coli pET 37 C 10i 0.2 0.1 0.01 (SEQ ID Autoinduction LC31 3 NO:3) E. coli pET 37 C 10i 0.2 0.1 0.01 (SEQ ID Autoinduction LC31-4 NO:4) E. coli pET 37 C 7.10 0.2 0.1 0.01 (SEQ ID Autoinduction LC31-5 NO:5) E. coli pET 37 C 10E 0.2 0.1 0.01 LC31_v1.1_Cy (SEQ ID Autoinduction s NO:6) E. coli pET 37 C 10) 0.2 0.1 0.01 (SEQ ID Autoinduction LC31 v1.2 NO:7) E. coli pET 37 C 10) 0.2 0.1 0.01 (SEQ ID Autoinduction LC3l_v1.3 NO:8) E. coli pET 37 C 10: 0.2 0.1 0.01 (SEQ ID Autoinduction LC3l_v1.4 NO:9) E. coli pET 37 C 10) 0.2 0.1 0.01 LC31 v1.5 (LCBTv1.3 _ (SEQ ID
with N-link NO: 10) Glycosylatio Autoinduction n) E. coli pET 37 C 10: 0.2 0.1 0.01 (SEQ ID AuLoinducbion NO:11) E. coli pET 37 C
10i 0.2 0.1 0.01 (SEQ ID Autoinduction NO:12) E. coli pET 37 C
10) 0.2 0.1 0.01 (SEQ ID Autoinduction NO:13) E. coli pET 37 C
10: 0.2 0.1 0.01 (SEQ ID Autoinduction NO:14) E. coli pET 37 C
10) 0.2 0.1 0.01 (SEQ ID Autoinduction NO:15) E. coli pET 37 C
10) 0.2 0.1 0.01 (SEQ ID Autoinduction NO:16) E. coli pET 37 C
10 0.2 0.1 0.01 (SEQ ID Autoinduction LC33_v1.1 NO:17) E. coli pET 37 C
10) 0.2 0.1 0.01 (SEQ ID Autoinduction LC33_v1.2 NO:15) E. coli pET 37 C J.0) 0.2 0.1 0.01 (SEQ ID Autoinduction LC33_v1.3 NO:19) E. coli pET 37 C
10) 0.2 0.1 0.01 (SEQ ID Autoinduction LC33_v1.4 NO:20) E. coil pET 37 C
10) 0.2 0.1 0.01 (SEQ ID Autoinduction LC33_v1.5 NO:21) E. coli pET 37 C
10: 0.2 0.1 0.01 LC33-4 (SEQ ID Autoinduction NO:16) E. coli pET 37 C 10) 0.2 0.1 0.01 _ (SEQ ID Autoinduction NO:23) E. coli pET 37 C
10) 0.2 0.1 0.01 (SEQ ID Autoinduction NO:24) E. coli pET 37 C
10) 0.2 0.1 0.01 _ (SEQ ID Autoinduction NO:25) E. coli pET 37 C
1(1)) 0.2 0.1 0.01 (SEQ ID Autoinduction NO:26) E. coli pET 37 C
10) 0.2 0.1 0.01 (SEQ ID Autoinduction NO:27) E. coli pET 37 C
10) 0.2 0.1 0.01 (SEQ ID Autoinduction NO:28) E. coli pET 37 C
10 0.2 0.1 0.01 (SEQ ID Autoinduction NO:29) E. coli pET 37 C
11:1 0.2 0.1 0.01 (SEQ ID Autoinduction NO:30) E. coli pET 37 C
10) 0.2 0.1 0.01 õ
(SEQ ID Autoinduction NO:31) E. coli pET 37 C
10: 0.2 0.1 0.01 (SEQ ID Autoinduction NO:32) E. coli pET 37 C
10) 0.2 0.1 0.01 _ (SEQ ID Autoinduction NO:33) E. coli pET 37 C
117) 0.2 0.1 0.01 (SEQ ID Autoinduction NO:34) E. coli pET 37 C
10: 0.2 0.1 0.01 _ (SEQ ID Autoinduction NO:100) E. poll pET 37 C 10) 0.2 0.1 0.01 AH32-2 (SEQ ID E. coli pET Autoinduction 10:
0.2 0.1 0.01 NO:101) 37 C
LC31-6GS- (SEQ ID Autoinduction LC31 NO:47) E. coil pET 37 C 10) 0.2 0.1 0.01 LC31-12GS- (SEQ ID Autoinduction LC31 NO:48) E. coil pET 37 C 7.0) 0.2 0.1 0.01 LC31-24GS- (SEQ ID Autoinduction LC31 NO:49) E. coil pET 37 C 10: 0.2 0.1 0.01 LC31 36G5 (SEQ ID Autoinduction LC31 NO:50) E. coil pET 37 C 10( 0.2 0.1 0.01 LC3l_v1.1-(SEQ ID
GSLCB1 v1.1( Autoinduction - NO:51) 1GS1) E. coil pET 37 C 10: 0.2 0.1 0.01 LC3l_v1.1-PRO- (SEQ ID
LC31_v1.1(1P NO:52) Autoinduction R01) E. coli pET 37 C 10: 0.2 0.1 0.01 LC33_v1.2-GS3- (SEQ ID
LC33_v1.2(3G NO:53) Autoinduction 53) E. coli pET 37 C 10( 0.2 0.1 0.01 LC33_v1.2 PRO- (SEQ ID
LC33 v1.2(3P NO:54) Autoinduction R03) E. coil pET 37 C 10( 0.2 0.1 0.01 LC3l_v1.1-GS- (SEQ ID
LC33_v1.2(IG NO:55) Autoinduction 53) E. coil pET 37 C 10: 0.2 0.1 0.01 LC33_v1.2-GS- (SEQ ID
LC31_v1.1(3G NO:56) Autoinduction S1) E. coIi pET 37 C 10 0.2 0.1 0.01 LC33_v1.2-(SEQ ID
LC31 v1.1(LC
- NO:57) 03-GS10- Autoinduction LC31) E. coil pET 37 C 10( 0.2 0.1 0.01 LC3l_v1.1-PRO- (SEQ ID
LC33_v1.2(1P NO:58) Autoinduction R03) E. coil pET 37 C 10' 0.2 0.1 0.01 LC33_v1.2-PRO- (SEQ ID
LC31_v1.1(3P NO:59) Autoinduction R01) E. colt pET 37 C 10i 0.2 0.1 0.01 (5_LCB1_1ink (SEQ ID AuLoinducLion er14) NO:60) E. coil pET 37 C 20.38) 0.2 0.1 0.01141 Mucin_LCBI_v (SEQ ID Autoinduction 1.1_Cys NO:65) E. coil pET 37 C 10( 0.2 0.1 0.01 Mucin_LCB1 v (SEQ ID Autoinduction 1.3 NO:66) E. coil pET 37 C 10: 0.2 0.1 0.01 LC31_v1.3_Mu (SEQ ID Autoinduction cin NO:67) E. coil pET 37 C 10( 0.2 0.1 0.01 LC31-Fcl (BM40 LCB1 GS4-Fc-Opt-WT) The (SEQ ID

NO: 68( sequences =
LC31-1 of Human Transient first 293 Transfection provisional) cells pCMVR 37 C 12: 0.2 0.1 0.01 LC31 Fc2 (SEQ ID Human Transient (BM40-LCB1- NO:69) 293 pCMVR Transfection 12 0.2 0.1 0.01 GS15-Fc-Opt- cells 37 C
WT) (The LE1B1 sequence -LC31-1 of LIrsL
provisional) (BM40-Fc-Opt- GS15-2-LC31-WT) (SKQ ID
(The LC31 NO: 70) sequence =
LC31-1 of Hunan Transient first 293 Transfection provisional) cells pCMVR 37 C 12 0.2 0.1 0.01 LC3i-Fc4 (BM40-LCB1-GS15-Fc-Opt-GS15-2-1,C(-WT) (The (SEQ ID
LC31 NO:71) sequences =
LCB1-1 of Hunan Transient first 293 Transfection provisional) cells pCMVR 37 C 2 0.2 0.1 0.01 LC31 Fc5 (BM40-LCB1-GS4-Fc-Opt-Q38) (The (SEQ ID

NO: 72 sequence =
LCB1-3 of Hunan Transient firsb 293 Transfection provisional) cells pCMVR 37 C 6i 0.2 0.1 0.01 LC31-Fc6 (BM40-LC31-GS15 Fe Opt Q3B) (The (SEQ ID

NO: 73( sequence =
LCB1-3 of Human TransienL
first 293 Transfection provisional) cells pCMVR 37 C 5I 0.2 0.1 0.01 LC31-Fc7 (BM40-Fc-OpL-0315-2-LC31-Q38) (SEQ ID
The LCB1 NO:74) sequence =
LCB1-3 of Hunan Transient first 293 '2ransfection provisional) cells pCMVR 37 C 10i 0.2 0.1 0.01 LC31-Fc8 (BM40-LCB1-Q3B-0515-Fc-Opt-0515-2-(SEQ ID
Q36) (The NO: 75 sequences =
LCB1-3 of Hunan Transient firsL 293 TransfecLion provisional) cells pCMVR 37 C 1 0.2 0.1 0.01 LC31-6M-Fc9 Human Transient (5M40-LCB1- (SEQ ID293 Transfection NO:46) 6M - cells pCMVR 37 C 20( 0.2 0.1 0.01 4N,14K,153',1 844274,384 -GS15-Fc-Opt) Ngly-Fc10 (BM40 LCB1 6M-Ngly -4N,14K,157,1 84,27N,384 GS15-lc-Opt) The LCB1 (SEQ ID
sequence =
NO: 77) LCB1-5 of the original provisional = LC31_v1.1 = LC31-4 with N-link Hunan Transient Glycosylatio 293 Transfection n) cells pCMVR 37 C 21:1 0.2 0.1 0.01 LC33-6M-Fcl1 (131440-LC133-8Q,264,281-I,3 5K,37T,43K -G515-Fc-Opt) (SEQ ID
(LEN NO:78) sequence is the sane as LC33-3 of Hunan Transient First 293 Transfection Provisional) cells pCMVR 37 C 5: 0.2 0.1 0.01 NGly-Fc12 (13M40-LC33-6M-Ngly -84,264,28H,3 5N,37T,43K -G515-Fc-OpL) (LCB
sequence is (SEQ ID
the same as NO:79) LCB3-4 of First Provisional which is LC33-3 with N link Hunan Transient Glycosylatio 293 Bransfection n) cells pCMVR 37 C 5: 0.2 0.1 0.01 GPGcP-Fc13 (BM40 LCB1 4N,14K,157,1 84,274,384 -(SEQ ID
NO: 80) Opt) (LOB
sequence is the same as LCB3-3 of Hunan transient First 293 Transfection Provisional) cells pCMVR 37 C 2 0.2 0.1 0.01 LC33-6M- Hunan Transient GPGcP Fc14 (SEQ ID293 Transfection NO:81) (81.440-LCH3- cells pCMVR 37 C 2) 0.2 0.1 0.01 80,260,28H,3 5K,37T,43K -GPGcP-Fc-OpL) (LCB
sequence is the same as LCB3-3 of First Provisional) GS30-Fc15 (BM40-LCB1-6M - (SEQ ID
4N,145,157,1 NO:82) 8Q,27Q,38Q - Hunan Transient GS30-Fc- 293 Transfection Opt)LCE1-4 cells pCMVR 37 C 1 0.2 0.1 0.01 GS30-Fc16 (BM40-LCB3-8Q,26Q,28H,3 5K,37T,43K -(SEQ ID
GS30-Fc-Opt) NO:83) (LCB
sequence is the same as LCB3-3 of Human Transient First 293 Transfection Provisional) cells pCMVR 37 C 1 0.2 0.1 0.01 LC31 v1.3 Fc17 (BM40-LC31-v1.3 -4N,14K,157,1 (SEQ ID
NO: 84) 7E,18Q,27Q,3 Human Transient 8Q -GS15-Fc- 293 Transfection Opt) cells pCMVR 37 C 0.2 0.1 0.01 LC31-v1.3-Ngly-Fc18 (BM40-LCB1-v1.3 Ngly -4N,14K,157,1 7E,18Q,27N,3 (SEQ ID
8Q -G515-Fc-NO:85) Opt) (>LC131 v1.5 (= LCBl_v1.3 with N-link Hunan Transient Glycosylatio 293 Transfection n) cells pCMVR 37 C 0.2 0.1 0.01 LC31-v1.3-GPGcP-Fc19 (BM40-LCB1-v1.3-Fc19 - (SEQ ID
4N,14K,157,1 NO:86) 7E,18Q,278,3 Human transient 8Q GPGcP Fc 293 Transfection Opt) cells pCMVR 37 C 0.2 0.1 0.01 LC31-v1.3-CS30-Fc20 (BM40-LCB1-(SEQ ID
v1.3 NO:87) 4N,14K,151,1 Hunan transient 7E,18Q,272,3 293 Transfection 8Q -GS30-Fc- cells pCMVR 37 C .5; 0.2 0.1 0.01 Opt) The designed binders have several advantages over antibodies as potential therapeutics. Together, they span a range of binding modes, and in combination viral escape would be quite unlikely. The retention of activity after extended time at elevated temperatures suggests they would not require a cold chain. The designs are 20 fold smaller than a full antibody molecule, and hence in an equal mass have 20 fold more potential neutralizing sites, increasing the potential efficacy of a locally administered drug The cost of goods and the ability to scale to very high production should be lower for the much simpler miniproteins, which unlike antibodies, do not require expression in mammalian cells for proper folding. The small size and high stability should make them amenable to direct delivery into the respiratory system by nebulization. Immunogenicity is a potential problem with any foreign molecule, but for previously characterized small de novo designed proteins little or no immune response has been observed, perhaps because the high solubility and stability together with the small size makes presentation on dendritic cells less likely.
References 1. Yuan M, Wu NC, Zhu X, Lee CD, So RTY, Lv H, Mok CKP, Wilson IA: A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV. Science 2020, 368(6491):630-633.
2. Case JIB, Rothlauf PW, Chen RE, Liu Z, Zhao H, Kim AS, Bloyet L-M, Zeng Q, Tahan S, Droit L et at: Neutralizing antibody and soluble ACE2 inhibition of a replication-competent VSV-SARS-CoV-2 and a clinical isolate of SARS-CoV-2.
bioRxiv 2020:2020.2005.2018.102038.
Ultrapotent miniproteins targeting the receptor-binding domain protect against SARS-CoV-2 infection and disease Despite the introduction of public health measures and spike protein-based vaccines to mitigate the COVID-19 pandemic, SARS-CoV-2 infections and deaths continue to rise..
Here, we investigated the capacity of modified versions of one lead binder, LCB1, to protect against SARS-CoV-2-mediated lung disease in human ACE2-expressing transgenic mice.
Systemic administration of LCB1-Fc reduced viral burden, diminished immune cell infiltration and inflammation, and completely prevented lung disease and pathology. A single intranasal dose of LCB1v1.3 reduced SARS-CoV-2 infection in the lung even when given as many as five days before or two days after virus inoculation. Importantly, LCB
1v1.3 protected in vivo against a historical strain (WA1/2020), an emerging B.1.1.7 strain, and a strain encoding key E484K and N501Y spike protein substitutions. These data support the use of LCB 1v1.3 for prevention or treatment of SARS-CoV-2 infection.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the cause of the Coronavirus Disease 2019 (COVID-19) pandemic, has resulted in global disease, suffering, and economic hardship. Despite implementation of public health measures, SARS-CoV-2 transmission persists principally through human-to-human spread (Day, 2020; Li et al., 2020;
Standl et al., 2020). SARS-CoV-2-induced clinical manifestations range from asymptomatic infection to severe pneumonia, multi-organ failure, and death. Although the underlying mechanisms that dictate disease severity are poorly understood, the immunocompromised, the elderly, and those with specific comorbidities (e.g., history of cardiovascular disease, diabetes, or obesity) are at increased risk for poor outcome (Zhou et al., 2020).
Here, using a stringent model of SARS-CoV-2 disease pathogenesis in human ACE2 (hACE2)-expressing transgenic mice (Golden et al., 2020; Winkler et al., 2020a), we evaluated the efficacy in vivo of exemplary miniprotein binder, LCB1. For our in vivo experiments, we evaluated two versions of LCB1: (a) an Fe-modified bivalent form, LCB1-hIgG-Fc9 (LCB1-Fc) that should extend half-life in vivo and engage effector arms of the immune system; and (b) a further optimized, monomeric form of LCB1 lacking an Fc domain, LCB1v1.3. Intraperitoneal administration of LCB1-Fc at one day pre- or post SARS-CoV-2 exposure conferred substantial protection including an absence of weight loss, reductions in viral burden approaching the limit of detection, and inhibition of lung inflammation and pathology. Intranasal delivery of LCB1v1.3 conferred protection as many as five days before or two days after SARS-CoV-2 inoculation. Dosing experiments revealed that LCB1v1.3 retained efficacy at pharmacologically attainable concentrations and was weakly immunogenic. Most importantly, LCB1v1.3 protected animals against the currently emerging B.1.1.7 United Kingdom variant and a SARS-CoV-2 strain encoding key spike substitutions E484K and N501Y present in both the South Africa (B.1.351) and Brazil (13.1.1.248) variants of concern Overall, these studies establish LCB1-Fc and LC131v1.3 as possible treatments to prevent or mitigate SARS-CoV-2 disease.
RESULTS
LCB1v1.3 prophylaxis limits viral burden and clinical disease. We modified LCB1 to generate two versions for in vivo testing: (a) we introduced polar mutations into LCB1 to increase expression yield and solubility without altering RBD binding (LCB1v1.3) and (b) we modified LCB1 by fusing it to a human IgG1 Fc domain (LCB1-Fc) to enhance bioavailability. LCB 1v1.3 and LCB1-Fc bound avidly to a single RBD within the S trimer (Fig 5A) with dissociation constants (Ku) of less than 625 and 156 pM, respectively (Fig 5B). LCB1v1.3 and LCBI-Fc also potently neutralized an authentic SARS-CoV-2 isolate (2019n-CoV/USA WA1/2020 [WA1/2020]) (EC50 of 14.4 and 71.8 pM, respectively;
Fig 5C).
To determine the protective potential of these miniproteins against SARS-CoV-2, we utilized K18 human hACE2-expressing transgenic mice, which develop severe lung infection and disease after intranasal inoculation of SARS-CoV-2 (Golden et al., 2020;
Winkler et al., 2020a). In prophylaxis studies, a single 250 ug (10 mg/kg) dose of LCB1-Fc administered by intraperitoneal injection (i.p.) one day prior to intranasal (i.n.) inoculation with 103 PFU of SARS-CoV-2 WA1/2020 prevented weight loss compared to animals given a control protein (influenza A virus hemagglutinin minibinder) designed using similar computational methods (Fig 5D) After LCB1-Fc prophylaxis, infectious virus was not detected in the lungs at 4- or 7-days post-infection (dpi), whereas high levels were observed in animals administered control protein (Fig 5E, top and bottom). Similarly, viral RNA levels in the lung, heart, spleen, and brain of LCBI-Fc treated animals were at or near the limit of detection of the assay at 4 or 7 dpi (Fig 5F-I). LCB1-Fc treatment had no effect on viral RNA
levels in nasal wash samples obtained at 4 dpi (Fig 5J), results that are similar to a recent study of a neutralizing human antibody in hamsters (Zhou et al., 2021). However, viral RNA levels were reduced at 7 dpi, suggesting that LCB1-Fc treatment accelerated viral clearance or prevented spread in the upper respiratory tract.
Diffuse alveolar damage, inflammation, and pneumonia are manifestations of COVID-19 lung disease, culminating in respiratory failure and a requirement for mechanical ventilation (Johnson et al., 2020; Kordzadeh-Kermani et al., 2020). We evaluated the capacity of LCB1-Fc to prevent the compromised lung function seen after SARS-CoV-2 infection of K18-hACE2 mice (Winkler et al., 2020a) At 7 dpi, mechanical ventilation tests of lung biomechanics in animals treated with LCB1-Fc showed no difference from naïve animals (Fig 6A), whereas mice receiving the control binder protein showed decreased inspiratory capacity and lung compliance as well as increased pulmonary resistance, elastance, and tissue damping, all consistent with compromised lung function.
These biophysical properties resulted in disparate pressure-volume loops between control binder and LCB1-Fc treated or naive animals. We also assessed the effect of LCB1-Fc treatment on SARS-CoV-2-induced lung pathology. Lung sections of animals collected at 7 dpi with SARS-CoV-2 showed widespread inflammation characterized by a cellular infiltrate and airspace consolidation in control protein-treated but not LCB1-Fc treated or naive mice (Fig 6B). At 4 dpi, inflammatory cytokine and chemokine RNA signatures in the lung were absent in LCB1-Fc treated but not control binder treated animals, suggesting that LCB1-Fc treatment prevents virus infection and inflammation in the lung (Fig 6C and 11).
Post-exposure therapy with anti-RBD binders reduces viral burden. To evaluate its efficacy in a post-exposure setting, we administered LCB1-Fc by i.p.
injection at 1 dpi.
Therapy with LCB1-Fc prevented weight loss (Fig 7A) and reduced viral burden in all tested tissues at 4 and 7 dpi (Fig 7B-G). Infectious virus was not recovered from the lungs of LCB1-Fc treated animals collected at either timepoint. Lung sections confirmed that therapy with LCB1-Fc improved pathological outcome (Fig 7H). At 7 dpi, immune cell infiltrates were absent in the lung sections of LCB1-Fc treated but not control binder-treated animals.
We next tested the efficacy of LCB 1v1.3 as an i.n.-delivered post-exposure therapy.
In. delivery, might enable self-administration of an anti-SARS-CoV-2 biological drug.
Indeed, miniprotein inhibitors against influenza virus have shown efficacy as a nasal mist (Chevalier et al., 2017). For these studies, we used LCB1v1.3 because it can bind an increased number of RBD molecules for a given mass dose, resulting in increased neutralization activity (Fig 5C). Whereas high levels of SARS-CoV-2 RNA were detected in the lungs and other peripheral tissues of control binder-treated animals at 7 dpi, infection was reduced in animals receiving LCB 1v1.3 by i.n. administration at D+1 or D+2 after inoculation with SARS-CoV-2 (Fig 71 and12). Levels of viral RNA were reduced in the nasal washes of animals receiving LCB 1v1.3 after treatment at D+1 but not D+2 compared to control binder-treated animals (Fig 7J).
Intranasal delivery of LCB1v1.3 confers protection against SARS-CoV-2 when administered up to 5 days before infection. We next evaluated the durability of LCB 1v1.3 administered via i.n. prophylaxis. At 5 days, 3 days, 1 day, or 6 hours prior to inoculation with 103 PFU of SARS-CoV-2, K18-hACE2 transgenic mice received a single 50 jig in, dose of LCB1v1.3 or the control binder. At 4 or 7 dpi, viral burden in tissues was determined by RT-qPCR. As expected, protection by LCB1v1.3 was better when administered closer to the time of SARS-CoV-2 exposure, as reflected by greater reductions in viral load and weight loss (Fig 8A-D and S3). However, even mice receiving LCB1v1.3 five days prior to inoculation and collected at 7 dpi showed reduced viral RNA levels in the lung compared to control binder treated animals. Regardless of the collection timepoint, lung viral RNA levels were reduced in animals receiving LCB1v1.3 three days prior to inoculation with SARS-CoV-2.
We tested a range of i.n. doses LCB1v1.3 for efficacy (Fig 8E-J). Treatment with as little as 2 rig (0.1 mg/kg) of LCB1v1.3 prevented SARS-CoV-2-induced weight loss. Doses between 2 and 10 !_ig (0.1 to 0.5 mg/kg) of LCB1v1.3 reduced viral RNA levels in the lung, heart, and spleen at 7 dpi relative to control binder-treated animals.
Moreover, animals receiving a 50 pg dose of LCB1v1.3 showed minimal, if any, lung inflammation (Fig 8K).
Collectively, these results indicate that even low doses of LCB1v1.3, when administered via an i.n. route prior to exposure, can limit SARS-CoV-2 infection and disease in the stringent K18-hACE transgenic mouse model of pathogenesis.
LCB1v1.3 is weakly immunogenic and retains protective activity after repeated dosing. We treated K18-hACE2 transgenic mice with 50 p.g of control binder or LCB 1v1.3 every three days for a total of 18 days (Fig 9A). At this time, we collected sera and assessed the presence of anti-LCB1v1.3 antibodies. Only 1 of 10 mice developed IgG
antibodies against LCB1v1.3 (Fig 9B). To determine if repeated dosing affected LCB1v1.3-mediated protection, we challenged the cohort with 103 PFU of SARS-CoV-2. Again, substantial protection against weight loss (Fig 9C) and viral infection in the lung and other organs was observed in all animals receiving LCB1v1.3 (Fig 9D-H).
LCB1v1.3 protects against emerging SARS-CoV-2 variants. We evaluated the activity of LCB1v1.3 against a B.1.1.7 isolate containing deletions at 69-70 and 144-145, and substitutions at N501Y, A570D, D614G, and P681H, and against a recombinant strain containing key substitutions present in the B.1.351 and B.1.248 variant strains at residues E484K, N501Y, and D614G (Xie et al., 2021a). Although the neutralizing activity of LCB1v1.3 against the B.1 1.7 and E484K/N501Y/D614G strains was approximately 45 to 50-fold lower than for the WA1/2020 strain, the EC 50 values still were ¨800 pM and 667 pM, respectively (Fig 10A). To determine whether LCB1v1.3 could protect in vivo against SARS-CoV-2 strains with concerning spike protein substitutions, we treated K18-hACE2 transgenic mice with a single i.n. 50 jig dose of LCB1v1.3 or control binder one day prior to inoculation with 103 PFU of B.1.1.7 or E484K/N501/D614G SARS-CoV-2. Notably, LCB1v1.3 treatment before challenge with either variant strain protected against weight loss (Fig 10B

and 10H) and viral infection in all tissues collected at 6 dpi (Fig 10C-G and 10I-M). Thus, LCB1v1.3 is effective against both circulating and emerging strains of SARS-CoV-2.
DISCUSSION
Here, using the stringent K18-hACE2 mouse model of SARS-CoV-2 pathogenesis, we show that LCB1-Fc prevented SARS-CoV-2 infection and disease when administered one day before or after virus inoculation. Lung biomechanics of mice treated with LCB1-Fc mirrored those of naïve animals in all parameters tested.
We also evaluated the efficacy of LCB1v1.3, an optimized, monomeric form of without an Fc domain. A single i.n. dose of LCB1v1.3 reduced viral burden when administered as many as five days before or two days after SARS-CoV-2 infection. Our i.n.
delivery approach is unique. I.n, therapy of SARS-CoV-2 has been reported only with type I
interferon in a hamster model of disease (Hoagland et al., 2021) and efficacy was limited.
The K18-hACE2 mouse model recapitulates several aspects of severe COVID-19, including lung inflammation and reduced pulmonary function (Golden et al., 2020; Winkler et al., 2020a). Since K18-hACE2 mice are highly vulnerable to infection, the therapeutic window of treatment is limited (Winkler et al., 2020b) and for our miniproteins, might only curb viral infection. Importantly, our data demonstrate that LCB1v1.3 binder treatment before or after infection limited immune cell infiltration and lung inflammation, which prevented tissue damage and compromise of respiratory function. As part of our proof-of-principle studies for a nasal prophylaxis, we observed little immunogenicity of LCB1v1.3, suggesting that repeated dosing may be possible.
Although several antibody-based therapies demonstrate promise against SARS-CoV-2, and a few have been granted EUA status, viral evolution could jeopardize these interventions as evidenced by the emerging variants in the United Kingdom (B.1.1.7), South Africa (B.1.351), Brazil (B.1.248), and elsewhere. Indeed, we and others have observed that many monoclonal and polyclonal antibodies showed reduced neutralization activity against several of these variant strains (Chen et al., 2021; Wang et al., 2021a; Wang etal., 2021b;
Wibmer et al., 2021; Xie et al., 2021b). In comparison, LCB1v1.3 showed efficacy against historical (WA1/2020) and emerging (B.1.1.7 and E484K/N501Y/D614G) SARS-CoV-2 strains. Based on the cryo-EM structure of the parent LCB1 binder in complex with SARS-CoV-2 RBD (Cao et al., 2020), only the N501Y mutation is expected to affect binding While we observed a decrease in the neutralizing activity of LCB1v1.3 against the emerging variants, EC50 values were still less than 800 pM, suggesting substantial potency was retained.

Compared to other potential SARS-CoV-2 antibody-based treatments, miniproteins have several benefits: (a) due to their smaller size, they can bind each protomer of a single trimeric spike, resulting in greater potency for a given dose; (b) they can be manufactured cost-effectively; and (c) they can be mixed using linker proteins to generate multimerized constructs that limit resistance.
EXPERIMENTAL MODEL AND SUBJECT DETAILS
Cells and viruses. Vero E6 (CRL-1586, American Type Culture Collection (ATCC), Vero CCL81 (ATCC), Vero-furin (Mukherjee et al., 2016), and Vero-hACE2-TMPRSS2 (a gift of A. Creanga and B. Graham, NIH) were cultured at 37 C in Dulbecco's Modified Eagle medium (D1VIEM) supplemented with 10% fetal bovine serum (FBS), 10 mM HEPES pH
7.3, 1 mM sodium pyruvate, 1 x non-essential amino acids, and 100 U/ml of penicillin¨
streptomycin. Additionally, Vero-hACE2-TMPRSS2 cells were cultured in the presence of 5 mg/mL puromycin. The WA1/202 (2019n-CoV/USA WA1/2020) isolate of SARS-CoV-2 was obtained from the US Centers for Disease Control (CDC). The B.1.1.7 and E484K/N501Y/D614G viruses have been described previously (Chen et al., 2021;
Xie et al., 2021a). Infectious stocks were propagated by inoculating Vero CCL81 or Vero-hACE2-TMPRSS2 cells. Supernatant was collected, aliquoted, and stored at -80 C. All work with infectious SARS-CoV-2 was performed in Institutional Biosafety Committee-approved BSL3 and A-BSL3 facilities at Washington University School of Medicine using positive pressure air respirators and protective equipment.
Mouse experiments. Animal studies were carried out in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocols were approved by the Institutional Animal Care and Use Committee at the Washington University School of Medicine (assurance number A3381-01).
Virus inoculations were performed under anesthesia that was induced and maintained with ketamine hydrochloride and xylazine, and all efforts were made to minimize animal suffering.
Heterozygous K18-hACE c57BL/6J mice (strain: 2B6.Cg-Tg(K18-ACE2)2Prlmn/J) were obtained from The Jackson Laboratory. Animals were housed in groups and fed standard chow diets. Mice of different ages and both sexes were administered 103 PFU of SARS-CoV-2 via intranasal administration.
METHOD DETAILS

Miniprotein production. LCB1-Fc was synthesized and cloned by GenScript into pCMVR plasmid, with kanamycin resistance. Plasmids were transformed into the alpha strain of E. coli (New England Biolabs) to recover DNA for transient transfection into Expi293F mammalian cells. Expi293F cells were grown in suspension using Expi293F
expression medium (Life Technologies) at 33 C, 70% humidity, and 8% CO2 rotating at 150 rpm. The cultures were transfected using PEI-MAX (Polyscience) with cells grown to a density of 3 x 106 cells per mL and cultivated for 3 days. Supernatants were clarified by centrifugation (5 min at 4000 x g, addition of PDADMAC solution to a final concentration of 0.0375% (Sigma Aldrich, #409014), and a second spin (5 min at 4000 x g).
Clarified supernatants were purified using a MabSelect PrismATIvi 2.6x5 cm column (Cytiva) on an AKTA Avant150 FPLC (Cytiva). Bound protein was washed with five column volumes of 20 mM NaPO4 and 150 mM NaCl pH 7.2, then five column volumes of 20 mM NaPO4 and 1 M
NaC1 pH 7.4, and eluted with three column volumes of 100 mM glycine at pH 3Ø
The eluate was neutralized with 2 M Tris base to a final concentration of 50 mM. SDS-PAGE
was used to assess protein purity. The protein was passed through a 0.22 !lin filter and stored at 4 C
until use, LCB1v1.3 with polar mutations (4N, 14K, 15T, 17E, 18Q, 27Q, 38Q) relative to the original LCB1 was cloned into a pet29b vector. LCB1v1.3 was expressed in Lemo21(DE3) (NEB) in terrific broth media and grown in 2 L baffled shake flasks. Bacteria were propagated at 37 C to an 0.D.600 of ¨0.8, and then induced with 1 mM IPTG.
Expression temperature was reduced to 18 C, and the cells were shaken for ¨16 h. The cells were harvested and lysed using heat treatment and incubated at 80 C for 10 min with stirring.
Lysates were clarified by centrifugation at 24,000 x g for 30 min and applied to a 2.6x10 cm Ni SepharoseTivi 6 FF column (Cytiva) for purification by IMAC on an AKTA
Avant150 FPLC system (Cytiva). Proteins were eluted over a linear gradient of 30 mM to 500 mM
imidazole in a buffer of 50 mM Tris pH 8.0 and 500 mM NaCl. Peak fractions were pooled, concentrated in 10 kDa MWCO centrifugal filters (Millipore), sterile filtered (0.22p,m) and applied to either a SuperdexTm 200 Increase 10/300, or HiLoad S200 pg GL SEC
column (Cytiva) using 50 mM phosphate pH 7.4, 150 mM NaC1 buffer. After size exclusion chromatography, bacterial-derived components were tested to confirm low levels of endotoxin.
Biolayer interferometry. Biolayer interferometry data were collected using an OctetTm RED96 (ForteBio) and processed using the instrument's integrated software. Briefly, biotinylated RBD (Acro Biosystems) was loaded onto streptavidin-coated biosensors (SA

ForteBio) at 20 nM in binding buffer (10 mM HEPES (pH 7.4), 150 mM NaC1, 3 mM
EDTA, 0.05% surfactant P20, and 0.5% non-fat dry milk) for 360 s. Analyte proteins (LCB1v1.3 or LCB1-Fc) were diluted from concentrated stocks into binding buffer. After baseline measurement in the binding buffer alone, the binding kinetics were monitored by dipping the biosensors in wells containing the target protein at the indicated concentration (association step) for 3,600 s and then dipping the sensors back into baseline/buffer (dissociation) for 7,200 s.
Plaque assay. Vero-furin cells (Mukherjee et al., 2016) were seeded at a density of 2.5x 105 cells per well in flat-bottom 12-well tissue culture plates. The following day, medium was removed and replaced with 200 [IL of 10-fold serial dilutions of the material to be titrated, diluted in DMEM-F2% FBS, and plates incubated at 37 C with rocking at regular intervals. One hour later, 1 mL of methylcellulose overlay was added. Plates were incubated at 37 C for 72 h, then fixed with 4% paraformaldehyde (final concentration) in PBS for 20 min. Fixed cell monolayers were stained with 0.05% (w/v) crystal violet in 20%
methanol and washed twice with distilled, deionized water.
Measurement of viral burden. Tissues were weighed and homogenized with zirconia beads in a MagNA LyserTm instrument (Roche Life Science) in 1,000 I.LL of DMEM
media supplemented with 2% heat-inactivated FBS. Tissue homogenates were clarified by centrifugation at 10,000 rpm for 5 min and stored at ¨80 C. RNA was extracted using the MagMax mirVanalm Total RNA isolation kit (Thermo Scientific) on a Kingfisher Flex extraction robot (Thermo Scientific). RNA was reverse transcribed and amplified using the TaqManTm RNA-to-CT 1-Step Kit (ThermoFisher). Reverse transcription was carried out at 48 C for 15 min followed by 2 min at 95 C. Amplification was accomplished over 50 cycles as follows: 95 C for 15 s and 60 C for 1 min. Copies of SARS-CoV-2 N gene RNA
in samples were determined using a previously published assay (Case et al., 2020;
Hassan et al., 2020). Briefly, a TaqManTm assay was designed to target a highly conserved region of the N
gene (Forward primer: ATGCTGCAATCGTGCTACAA (SEQ ID NO: 190); Reverse primer: GACTGCCGCCTCTGCTC (SEQ ID NO: 191); Probe: /56-FAM/TCAAGGAAC/ZEN/AACATTGCCAA/3IABkFQ/) (SEQ ID NO: 192). This region was included in an RNA standard to allow for copy number determination down to 10 copies per reaction. The reaction mixture contained final concentrations of primers and probe of 500 and 100 nM, respectively.
Cytokine and chemokine mRNA measurements. RNA was isolated from lung homogenates as described above. cDNA was synthesized from DNAse-treated RNA
using the High-Capacity cDNA Reverse Transcription kit (Thermo Scientific) with the addition of RNase inhibitor following the manufacturer's protocol. Cytokine and chemokine expression was determined using TaqManTm Fast Universal PCR master mix (Thermo Scientific) with commercial primers/probe sets specific for IFN-g (IDT: Mm.PT.58.41769240), IL-(Mm.PT.58.10005566), IL-lb (Mm.PT.58.41616450), Tnfa (Mm.PT.58.12575861), CXCLIO
(Mm.PT.58.43575827), CCL2 (Mm.PT.58.42151692), CCL5 (Mm.PT.58.43548565), CXCL11 (Mm.PT.58.10773148.g), /filb (Mm.PT.58.30132453.g), CXCL1 (Mm.PT.58.42076891) and results were normalized to GAPDH(Mm.PT.39a.1) levels.
Fold change was determined using the 2-AA method comparing treated mice to naïve controls.
Lung Pathology. Animals were euthanized before harvest and fixation of tissues. The left lung was first tied off at the left main bronchus and collected for viral RNA analysis. The right lung was inflated with approximately 1.2 mL of 10% neutral buffered formalin using a 3-mL syringe and catheter inserted into the trachea. Tissues were embedded in paraffin, and sections were stained with hematoxylin and eosin. Slides were scanned using a Hamamatsu NanoZoomerTm slide scanning system, and images were viewed using NDP view software (ver.1.2.46).
Respiratory mechanics. Mice were anesthetized with ketamine/xylazine (100 mg/kg and 10 mg/kg, i.p., respectively). The trachea was isolated via dissection of the neck area and cannulated using an 18-gauge blunt metal cannula (typical resistance of 0.18 cmH20.s/mL), which was secured in place with a nylon suture. The mouse then was connected to the flexiVentjm computer-controlled piston ventilator (SCIREQ Inc.) via the cannula, which was attached to the FX adaptor Y-tubing. Mechanical ventilation was initiated, and mice were given an additional 100 mg/kg of ketamine and 0.1 mg/mouse of the paralytic pancuronium bromide via intraperitoneal route to prevent breathing against the ventilator and during measurements. Mice were ventilated using default settings for mice, which consisted in a positive end expiratory pressure at 3 cm H2O, a 10 mL/kg tidal volume (Vt), a respiratory rate at 150 breaths per minute (bpm), and a fraction of inspired oxygen (Fi02) of 0.21 (i.e., room air). Respiratory mechanics were assessed using the forced oscillation technique, as previously described (McGovern et al., 2013), using the latest version of the flexiVentTm operating software (flexiWare v8.1.3). Pressure-volume loops and measurements of inspiratory capacity also were performed.
Neutralization assay. Serial dilutions of binder proteins were incubated with focus-forming units (FFU) of SARS-CoV-2 for 1 h at 37 C. Binder-virus complexes were added to Vero E6 (WA1/2020) or Vero-hACE2-TMPRSS2 (B.1.1.7 and WA1/2020 E484K/N501Y/D614G) cell monolayers in 96-well plates and incubated at 37 C for 1 h.
Subsequently, cells were overlaid with 1% (w/v) methylcellulose in MEM
supplemented with 2% FBS. Plates were harvested 24-30 h later by removing overlays and fixed with 4% PFA in PBS for 20 min at room temperature. Plates were washed and sequentially incubated with an oligoclonal pool of SARS2-2, SARS2-11, SARS2-16, SARS2-31, SARS2-38, SARS2-57, and SARS2-71 anti-spike protein antibodies (Zhou et al., 2021) and 14RP-conjugated goat anti-mouse IgG in PBS supplemented with 0.1% saponin and 0.1% bovine serum albumin.
SARS-CoV-2-infected cell foci were visualized using TrueBlueTm peroxidase substrate (KPL) and quantitated on an ImmunoSpotTm microanalyzer (Cellular Technologies). Data were processed using PrismTm software (GraphPad PrismTm 8.0).
ELISA. C-terminal biotinylated LCB1.1v3 was immobilized on streptavidin-coated plates (RayBiotech #7C-SCP-1) at 2.5 ug/mL in 100 pL total volume per well and incubated at 4 C overnight. Plates were washed with wash buffer (TBS + 0.1% (w/v) BSA +
0.05%
(v/v) Tween20) and blocked with 200 pL/well blocking buffer (TBS + 2% (w/v) BSA +
0.05% (v/v) Tween20) for 1 h at room temperature. Plates were rinsed with wash buffer using 200 uL/well, and 100 pL of 1:100 diluted sera samples in blocking buffer were added to respective wells. For a positive control, Fc-RBD was serially diluted 1:5 starting at 240 ng/mL in 100 uL of blocking buffer. All samples were incubated for 1 hat room temperature. Plates were washed using 200 pL/well of wash buffer. For the serum samples, HRP-conjugated horse anti-mouse IgG antibody (Vector Laboratories #PI-2000-1) was diluted 1:200 in blocking buffer, and 100 uL was incubated in each well at room temperature for 30 min. For the positive control, HRP-conjugated mouse anti-human IgG
antibody (Invitrogen #05-4220) was diluted 1:500 in blocking buffer, and 100 pL was incubated in each well at room temperature for 30 min. Plates were rinsed with wash buffer, and 100 pL
of TMB (SeraCare) was added to each well for 2 min. The reaction was quenched by adding 100 uL of 1N HC1. Optical densities were determined at 450nm on a Synergy Neo2Tm plate reader (BioTek Instruments).
QUANTIFICATION AND STATISTICAL ANALYSIS
Statistical significance was assigned when P values were < 0.05 using PrismTm Version 8 (GraphPad). Tests, number of animals, median values, and statistical comparison groups are indicated in each of the Figure legends. Analysis of weight change was determined by two-way ANOVA. Changes in functional parameters or immune parameters were compared to control binder-treated animals and analyzed by one-way ANOVA
with multiple comparisons tests. Statistical analyses of viral burden between two groups were determined by Mann-Whitney test.
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Multivalent Designs Escape variants of SARS-CoV-2 are threatening to considerably prolong the COVID-19 pandemic. Here we develop multivalent minibinders as potential prophylactic and therapeutic agents to address this problem. We designed multivalent minibinders containing three copies of a minibinder (self-assembled homotrimer), or three linked distinct minibinders (multi-domain fusion) targeting different sites, geometrically matched to the spike trimer and optimized their composition using a rapid cell-free expression and evaluation workflow. The optimized designs have greatly slowed dissociation rates from the SARS-CoV-2-S-glycoprotein with complex half-lives of more than two weeks. Cryo-EM of the structures reveal that both homotrimer and fusion minibinder constructs can engage all three RBDs on a single spike protein. The top trimeric and fusion candidates neutralize the wild-type SARS-CoV-2 virus in addition to the B.1.1.7, B.1.351, B.1.1.28 variants of concern with IC5Os in the low pM range. Additionally, the top homotrimer candidate provided prophylactic protection in a human ACE2-expressing transgenic mice against the same variant strains. Our approach highlights the utility of computational protein design coupled to rapid experimental prototyping to design potent multivalent inhibitors that can broadly neutralize widely circulating variants of concern.
We sought to develop multivalent versions of our computationally designed miniproteins that block the SARS-CoV-2 receptor binding domain (RBD) interaction with its host receptor ACE2. In principle, the small size of the designed minibinders enables simultaneous engagement of multiple RBDs within a single spike protein trimer.
We hypothesized that this multivalent binding would lead to ultra-high affinity inhibitors that are more resistant to escape mutations than their monomeric counterparts. The resulting avidity from these multivalent interactions could ameliorate the effects of mutations that would escape individual domains. Additionally, single proteins containing domains targeting multiple distinct epitopes or containing different sets of contacts with the target epitope could further increase the robustness of the designs to mutational escape. Starting with the LCB1, AHB2, and LCB3 minibinders (hereafter referred to as Ml, M2, and M3 respectively; Table 11) and their known binding modes we pursued two parallel strategies for designing multivalent inhibitors, self-assembled homotrimers and multi-domain fusions.
ID Protein LCB1 "

:

F23-P12 AT-1B2 v2-PAS12-LCB3 v2.2 iF3 -K2i. 'i.CB3 02-PAS12-LCB1 Vini!
F231- AHB2 v2-PAS12-LCB3 y2.2-PAS12-P12 LCB 1 v2.2 F231- Al1B2 v2-PAS24-LCB3 v2.2-PAS24-'' P24 t.CB1 v2.2 F23-G10 AT-1132 v2-GS I 0-LC1:13 v2.2 I -PO
LCB3 *22-GS10-LCW1: MAI*
F231- AHB2_v2-GS10-LCB3_y2.2-GS10-G10 LCB 1 v2.2 WWI infir15-6GS-LCBIA*221 H2-0 AHB2-4GS-lifo git124 'Ok.171132-2GS-SBli*
H3-1 LCB3 v2.2-6GS-SB175 Table 11. List of abbreviations used to describe multivalent minibinders To enable rapid prototyping of the designed proteins, we developed a cell-free DNA
assembly and protein expression workflow enabling a greatly shortened design-build-test cycle better matched to the urgency of a pandemic. The workflow combines a cell-free DNA
assembly step utilizing Gibson assembly followed by PCR to generate linear expression templates that are used to drive cell-free protein synthesis (CFPS) The developed workflow allows us to translate synthetic DNA to purified protein in as little as 6 hours, is easily scaled to high-throughput formats (e.g., 96- or 384-well plates), and is amenable to automated liquid handling. Furthermore, we coupled this cell-free workflow to an AlphaLISATm protein-protein interaction (PPI) competition assay to enable comparison of dissociation rates of the designed proteins against either the monomeric RBD or the trimeric hexapro SARS-CoV-2-S-glycoprotein (S6P). Because multivalency largely only impacts the dissociation rate constant of the interaction, we reasoned that an in-solution off-rate screen would enable us to distinguish mono- from multi-valent binding. The resulting workflow can evaluate hundreds of candidate multivalent proteins per week.
Design and validation of multivalent binders In the first strategy, we designed self-assembling trimeric versions of the Ml, M2, and M3 miniproteins geometrically matched to the three RBDs in the spike trimer (hereafter referred to as H[binding domain #Mhomotrimern for example, H1-1 represents a homotrimer of M1 with homotrimerization domain 1, Table 11). We designed, expressed, and evaluated more than one hundred different proteins containing various homotrimerization domains and linker lengths using our cell-free expression and multivalency screen workflow.
We identified versions of each homotrimer that showed slow dissociation rates potentially indicating multivalent binding (Fig.14).
In the second strategy, we generated two- and three-domain fusions of the Ml, and M3 binding domains separated by flexible linkers (hereafter referred to as F[binding domain #s]-[linker]; for example, F231-P12 represents a fusion of M2 to M3 to M1 all separated by a PAS12 linker, Table 11). We evaluated a range of linker lengths chosen to span the distances between the termini of the domains when bound to the "open-and "closed" states of the RBD. We again expressed and evaluated more than one hundred different designs varying binding domain connectivity and linker length to optimize multivalency. Several identified two- and three-domain fusions show slow dissociation rates comparable to the homo-trimeric constructs described above (Fig.14).
The best candidates from each strategy showed little to no dissociation after 14 days of with competitor, with further measurements being limited by the stability of S6P. From these data we estimate the complex has a dissociation rate constant of slower than lx10-7 To our knowledge, these are the slowest measured dissociation rate constant for a synthetic protein-protein interactions ever reported.
We next used single particle cryo-electron microscopy (cryo-EM) to characterize the complex between S6P and the top candidate minibinders constructs (Fig. 15).
The Cryo-EM

structures of the H2-1, F31-G10, and the F231-P24 constructs were determined at resolutions of 2.6, 4.5, and 3.9 A respectively. H2-1 was found to simultaneously engage all three RBDs, causing all three RBDs to adopt the open state. The design model accurately closely matches the observed structure. F31-G10 bound to two RBDs, both appearing to adopt the open conformation upon binding. The structure indicates this linker length enabled simultaneous binding of two RBDs in their native state. The third free RBD adopted either the open or closed conformation in the structure. F231-P24 bound to three RBDs, with M1 binding a closed conformation RBD and M2 and M3 binding to open conformation RBDs. This suggests the linker length is sufficiently long enough to enable all three binding domains to simultaneously engage all three RBDs without significant distortion of the native state. In both F31-G10 and F231-P24 the maps are highly suggestive of multivalent binding, though the flexible linkers yield no density in the EM map to confirm linkage of the domains.
Multivalent minibinders neutralize widely circulating SARS-CoV-2 variants We next sought to determine ability of the multivalent constructs to neutralize SARS-CoV-2 variants. We screened the off rate of the best multivalent minibinders against a panel of mutant spike proteins (Fig. 16). The homotrimers showed the most mutational resistance, with the H2 homotrimers showing little dissociation after 24 hours against any of the mutant spikes. The two-domain fusions showed little increased resilience to the tested point mutants.
The three-domain fusions showed considerably more consistent binding to the tested point mutants, though some still impacted binding.
We additionally evaluated the potency of these proteins via neutralization assays against both a SARS-CoV-2 WV pseudovirus in addition to authentic SARS-CoV-2 isolates (Fig. 16). The H2-0 and H2-1 homotrimers consistently performed the best across all constructs tested, with IC 50s in the low pM range. The three-domain fusions also performed well, with IC 50s in the sub nM range for all tested variants. The greater neutralization breadth of the H2 homotrimers likely reflects the closer mimicking if the ACE2 binding site by the M2 monomer, a unique advantage enabled by protein design.
Multivalent minibinders resist viral escape In addition to evaluating the top candidate's ability to neutralize currently circulating SARS-CoV-2 mutants, we also tested the ability of the inhibitors to resist escape viral escape (Fig. 17). To do this, plaque assays were performed with a VSV-SARS-CoV-2 chimera virus were replicated on Vero E6 cells. To select mutants that were resistant to the inhibitor, the inhibitor was included in the overlay to halt replication of non-resistant viruses. In positive control neutralizing antibody (2B04), multiple escape mutants were selected per plate. For both F231-P12 and H2-1 no escape mutants were isolated in 35 replicate wells of each inhibitor.
H2-0 provides prophylactic protection in human ACE2-expressing transgenic mice To determine the ability of our multivalent minibinders to protect in an in vivo model, we evaluated them as a pre-exposure prophylactic treatment in human ACE2-expressing transgenic mice (Fig. 17). A single 50 lug dose of H2-0 was administered intranasally (i.n.) one day prior to inoculation with 103 focus forming units of SARS-CoV-2 Variants B.1.1.7, B1.351, B.1.1.24. In all cases, i.n. administration of H2-0 protected the mice against SARS-CoV-2-induced weight loss. At 6 days post infection viral burden was determined via RT-qPCR in a variety in tissues. Notably, viral loads in the lungs were reduced in all cases. These results indicate that H2-0 given via i.n. administration can provide prophylactic protection against SARS-CoV-2 infection in a relevant mouse model.
Conclusions We anticipate that the cell-free protein expression and evaluation workflow will find utility in many different applications where the evaluation of individual protein variants is the limiting process step. In addition, our developed multivalency screen will accelerate the ability of researchers to develop multivalent protein therapeutics.
The designed protein constructs could have a number of advantages over monoclonal antibodies for preventing and treating COVID-19 infection. 1) direct administration into respiratory system, 2) low cost of goods and amenability to very large-scale production, 3) high stability and lack of need for cold chain, and 4) very broad resistance to escape mutants in single compounds. More generally, designed high affinity multivalent minibinders could provide a powerful platform for combating viral pandemics.

Claims (72)

We claim

1. A polypeptide comprising an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to the amino acid sequence selected from the group consisting of SEQ
ID NOS: 1-17, 19-21, 23-34 and 100-101, wherein the polypeptide binds to SARS-CoV-2 Spike glycoprotein receptor binding domain (RBD).

2. The polypeptide of claim 1, wherein amino acid substitutions relative to the reference polypeptide amino acid sequence are selected from the exemplary amino acid substitutions provided in Table 1.

3. The polypeptide of claim 1 or 2, wherein interface residues are identical to those in the reference polypeptide or are conservatively substituted relative to interface residues in the reference polypepti de.

4. The polypeptide of any one of claims 1-3, comprising an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:1-10, 13-17, 19-21, 33-34, and 100-101.

5. The polypeptide of any one of claims 1-4, comprising an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:1-10 and 102-136.

6. The polypeptide of claim 5, wherein the polypeptide comprises an amino acid substitution relative to the amino acid sequence of SEQ ID NO:1 at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18 residues selected from the group consisting of 2, 4, 5, 14, 15, 17, 18, 27, 28, 32, 37, 38, 39, 41, 42, 49, 52, and 55.

7. The polypeptide of claim 6, wherein the substitutions are selected from the substitutions listed in Table 4, either individually or in combinations in a given row.

8. The polypeptide of any one of claims 1-4, comprising an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 13-17, 19-21 and 137-163.

9. The polypeptide of claim 8, wherein the polypeptide comprises an amino acid substitution relative to the amino acid sequence of SEQ ID NO:13 at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or all 20 residues selected from the group consisting 2, 6, 8, 9, 13, 14, 19, 22, 25, 26, 28, 29, 34, 35, 37, 40, 43, 45, 49, and 62.

10. The polypeptide of claim 6, wherein the substitutions are selected from the substitutions listed in Table 6, either individually or in combinations in a given row.

11. The polypeptide of any one of claims 1-4, comprising an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:33-34 and 100-101 and 164.

1 2. The polypeptide of claim 11, wherein the polypeptide comprises an amino acid substitution relative to the amino acid sequence of SEQ ID NO:101 at or both residues selected from the group consisting 63 and 75.

13. The polypeptide of claim 12, wherein the substitutions comprise R63A
and/or K75T.

14. The polypeptide of any one of claims 1-13, further comprising one or more added cysteine residues at the N-terminus and/or C-terminus.

15. The polypeptide of any one of claims 1-14, comprising an N-linked glycosylation site (i.e.: NX(S/T), where X is any amino acid).

16. The polypeptide of any one of claims 1-15, comprising two or more copies of the amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-17, 19-21, 23-34 and 100-101.

17. The polypeptide of claim 16, wherein the two or more copies of the polypeptide are all identical.

18. The polypeptide of claim 16, wherein the two or more copies of the polypeptide are not all identical.

19. The polypeptide of any one of claims 16-18, wherein the two or more copies of the polypeptide are separated by amino acid linker sequences.

20. The polypeptide of claim 9, wherein amino acid linker sequences comprise Gly-Ser rich (at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% Gly-Ser residues) amino acid linkers.

21. The polypeptide of claim 20, wherein the Gly-Ser rich linkers comprise an amino acid sequence selected from the group consisting of GG and SEQ ID NOs:35-46 and 165-

22. The polypeptide of claim 19, wherein amino acid linker sequences comprise Pro-rich (at least 15%, 20%, 25%, or greater Pro residues) amino acid linkers.

23. The polypeptide of claim 22, wherein the Pro-rich amino acid linkers comprise an amino acid sequence selected from the group consisting of SEQ ID NOs:97-98 and 172-176.

24. The polypeptide of claim 19, wherein the amino acid linker comprises the amino acid sequence selected from the group consisting of SEQ ID NOS:99 and 177-178.

25. The polypeptide of any one of claims 19-24, wherein the amino acid linkers are independently between 2-100 amino acids in length.

26. The polypeptide of any one of claims 16-25, wherein the polypeptide comprises the formula Z1-Z2-Z3, wherein:
Z1 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-17, 19-21, 23-34 and 100-164;
Z2 comprises an optional amino acid linker; and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-17, 19-21, 23-34 and 100-164;
Wherein Z1 and Z3 may be identical or different.

27. The polypeptide of claim 26, wherein Z1 and Z3 are identical.

28. The polypeptide of claim 26 wherein Z1 and Z3 are different.

29. The polypeptide of any one of claims 26-28, wherein:
Z1 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-10 and 102-136;
and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-10 and 102-136.

30. The polypeptide of any one of claims 26-28, wherein:
Z1 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 13-17, 19-21 and 137-163; and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 13-17, 19-21 and 137-163.

31. The polypeptide of any one of claims 26-28, wherein:

Z1 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 33-34, 100-100, and 164; and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 33-34, 100-100, and 164.

32. The polypeptide of any one of claims 26-28, wherein:
one of Zl and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to the amino acid sequence selected from the group consisting of SEQ
ID NOS: 1-and 102-136; and the other of Zl and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID
NOS: 13-17, 19-21 and 137-163.

33. The polypeptide of any one of claims 26-28, wherein:
one of Zl and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to the amino acid sequence selected from the group consisting of SEQ
ID NOS: 1-10 and 102-136; and the other of Zl and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID
NOS: 33-34, 100-100, and 164.

34. The polypeptide of any one of claims 26-28, wherein:
one of Z1 and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to the amino acid sequence selected from the group consisting of SEQ
ID NOS: 13-17, 19-21 and 137-163; and the other of Zl and Z3 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID
NOS: 33-34, 100-100, and 164.

35. The polypeptide of any one of claims 26-34, wherein the polypeptide comprises the formula Bl-B2-Z1-Z2-Z3-B3-B4, wherein:
Z1, Z2, and Z3 are as defined in any one of claims 26-34;
B2 and B3 comprise optional amino acid linkers; and one or both of B1 and B4 independently comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-17, 19-21, 23-34 and 100-164, wherein one of Bl and B4 may be absent.

36. The polypeptide of claim 35, wherein one of Bl and B4 is absent.

37. The polypeptide of claim 35, wherein B1 and B4 independently comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-17, 19-21, 23-34 and 100-164.

38. The polypeptide of claim 37, wherein B1 and B4 are identical.

39. The polypeptide of claim 37, wherein B1 and B4 are not identical.

40. The polypeptide of any one of claims 35-39, wherein B1 when present and B4 when present, are identical to one or both of Zl and Z3, or wherein B 1 when present and B4 when present, are not identical to either of Zl and Z3.

41. The polypeptide of any one of claims 35-40, wherein B1 when present, and B4 when present, independently comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-10, 13-17, 19-21, 33-34, and 100-164.

42. The polypeptide of any one of claims 35-40, wherein B1 when present, and B4 when present, independently comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 1-10 and 102-136.

43. The polypeptide of any one of claims 35-40, wherein 131 when present, and B4 when present, independently comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:
13-17, 19-21 and 137-163.

44. The polypeptide of any one of claims 35-40, wherein B1 when present, and B4 when present, independently comprise an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:
33-34, 100-101, and 164.

45. The polypeptide of any one of claims 35-40, wherein both B1 and B4 are present, and wherein = one of Bl and B4 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ
ID NOS: 1-10 and 102-136, and the other comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 13-17, 19-21 and 137-163;
= one of Bl and B4 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ
ID NOS: 1-10 and 102-136, and the other comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 33-34, 100-101, and 164, or = one of B1 and B4 comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ
ID NOS: 13-17, 19-21 and 137-163, and the other comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 33-34, 100-101, and 164.

46. The polypeptide of any one of claims 1-45, comprising an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:47-60,193-355, and 454-588 and a genus selected from those recited in the right hand column of Table 8 wherein genus positions X1, X2, X3, and X4 may be present or absent, and when present may be any sequence of 1 or more amino acids and wherein any N-terminal methionine residues may be present or absent in the polypeptide, preferably wherein the polypeptide comprises and amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID
NOS: 454-588 and most preferably wherein the polypeptide comprises and amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:693-701 wherein any N-terminal methionine residue may be absent or present, and wherein residues in parentheses may be present or absent (preferably absent) and are not considered in determining percent identity.

47. The polypeptide of any one of claims 1-46, further comprising an additional functional peptide domain.

48. The polypeptide of claim 47, wherein the additional functional peptide domain comprises a targeting domain, a detectable domain, a scaffold domain, a secretion signal, an Fc domain, or a further therapeutic peptide domain.

49. The polypeptide of claim 48, wherein the additional functional domain comprises an Fc domain, including but not limited to an Fc domain comprising an amino acid sequence comprising the amino acid sequence of SEQ ID NO:64.

50. The polypeptide of any one of claims 47-49, wherein the added functional domain comprises an oligomerization domain.

51. The polypeptide of claim 50, wherein the oligomerization domain comprises a homotrimerization domain.

52. The polypeptide of claim 50 or 51, wherein the oligomerization domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:179-189 and 589-

53. The polypeptide of any one of claims 50-52, comprising an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 356-453 and 595-692, and a genus selected from those recited in the right hand column of Table 9 wherein genus positions Xl, X2, X3, and X4 may be present or absent, and when present may be any sequence of 1 or more amino acids and wherein any N-terminal methionine residues may be present or absent in the polypeptideõ
preferably wherein the polypeptide comprises and amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID
NOS: 595-692.

54. The polypeptide of any one of claims 1-53, wherein the polypeptide is linked to a stabilization domain, including but not limited to polyethylene glycol (PEG), albumin, hydroxyethyl starch (HES), conformationally disordered polypeptide sequence composed of the amino acids Pro, Ala, and/or Ser ('PASylation'), and/or a mucin diffusivity polypeptide composed of amino acids Lys and Ala, with or without Glu.

55 The polypeptide of any one of claims 1-54, comprising an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS: 65-96, wherein in embodiments where a secretion signal is present (MARAWIFFLLCLAGRALA; SEQ ID NO:63) it can be replaced with any other secretion signal.

56. The polypeptide of any one of claims 1-55, wherein the polypeptide binds to the SARS-CoV-2 Spike glycoprotein with an affinity of at least 10 nM, measured as described in the attached examples.

57. A nucleic acid encoding the polypeptide of any one of claims 1-56.

58. An expression vector comprising the nucleic acid of claim 57 operatively linked to a promoter.

59. A host cell comprising the polypeptide, the nucleic acid, and/or the expression vector of any preceding claim.

60. An oligomer of the polypeptide of any one of claims 1-56.

61. The oligomer of claim 60, wherein the oligomer comprises a trimer, including but not limited to a homotrimer.

62. A composition, comprising 2, 3, 4, or more copies of the polypeptide of any one of claims 1-56 attached to a support, including but not limited to a polypeptide particle support.

63. A pharmaceutical composition, comprising the polypeptide, the nucleic acid, the expression vector, the host cell, the oligomer, and/or the composition of any of the preceding claims, and a pharmaceutically acceptable carrier.

64. A method for treating a severe acute respiratory syndrome (SARS) coronavirus infection (including SARS-Co-V and SARS-CoV-2), comprising administering to a subject in need thereof an amount of the polypeptide, the nucleic acid, the expression vector, the host cell, the oligomer, the composition, and/or the pharmaceutical composition of any of the preceding claims, effective to treat the infection.

65. The method of claim 64, wherein the SARS coronavirus comprises SARS-CoV-2.

66. A method for limiting development of a severe acute respiratory syndrome (SARS) coronavirus infection (including SARS-Co-V and SARS-CoV-2), comprising administering to a subject in need thereof an amount of the polypeptide, the nucleic acid, the expression vector, the host cell, the oligomer, the composition, and/or the pharmaceutical composition of any of the preceding claims, effective to treat the infection.

67. The method of claim 66, wherein the SARS coronavirus comprises SARS-CoV-2.

68. The method of any one of claims 64-67, wherein the polypeptide, the nucleic acid, the expression vector, the host cell, the oligomer, the composition, and/or the pharmaceutical composition is administered intra-nasally.

69. The method of any one of claims 64-67, wherein the polypeptide, the nucleic acid, the expression vector, the host cell, the oligomer, the composition, and/or the pharmaceutical composition is administered systemically.

70. A method for designing polypeptides that bind to the receptor binding site (RBD) of SARS-Cov-2, wherein the methods comprise steps as described in any embodiment or combination of embodiments disclosed herein.

71. The method of claim 70, further comprising cell-free synthesis of the designed polypeptides, and evaluation of the synthesized polypeptides for SARS-Cov-2 RBD binding using any suitable technique.

72. A cell-free system comprising the polypeptide, the nucleic acid, and/or the expression vector of any preceding claim.