Treatment of neurodegenerative diseases

Abstract

The invention relates to a method of treating or preventing a neurodegenerative disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an inhibitor of type I IFN signalling. Also provided are pharmaceutical compositions for use in such methods, and related kits and injection devices.

Description

Treatment of neurodegenerative diseases 1 BACKGROUND

[0001] Degenerative diseases of the nervous system impose a significant worldwide medical and public health burden. The prevalence and incidence of these diseases rise dramatically with age and the number of cases is expected to increase with extended life expectancy in many countries1. Neurodegenerative diseases include, but are not limited to, Alzheimer’s disease (AD), Parkinson’s disease (PD), Lewy body dementia, frontotemporal dementia, Huntington’s disease, prion diseases and amyotrophic lateral sclerosis (ALS). The pathological mechanisms underlying neurodegenerative disease are not fully understood.

[0002] ALS is the most common form of motor neuron disease in adults and is a neurodegenerative disease characterized by the selective and progressive loss of motor neurons in the spinal cord, brain stem and cerebral cortex. It typically results in progressive muscle weakness and neuromuscular respiratory failure. The worldwide approved ALS therapeutic agent is riluzole, which suppresses glutamate release from glutamatergic neurons. While riluzole provides limited survival benefit, it does not significantly affect muscle strength or functional outcome2. Thus, there is a need for new therapeutics for treating ALS and other neurodegenerative disorders.

[0003] The present invention solves one or more of the above-mentioned problems. 2 SUMMARY

[0004] The invention relates to a method of treating, or reducing the risk for development of, a neurodegenerative disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an inhibitor of type I IFN signalling.

[0005] The invention is supported inter alia by data from primary human microglia cultures, data analysis of which are presented herein for the first time. These data show that treatment in a model of ALS with an inhibitor of type I IFN signalling returns expression of aberrant type I IFN signature genes to normal levels. These type I IFN signature genes include ISG20, IFI27 and / or IFIT2. 3 BRIEF DESRIPTION OF THE DRAWINGS

[0006] Figure 1:FIG. 1A is a schematic of a scFv molecule conjugated to the κ-opioid agonist dynorphin. FIG.1B shows the study design for the diuresis model described in the Examples. FIG. 1C shows urine output over time in rats administered dynorphin-conjugated or free Bbbt0241 hIgG1TM, compared to dynorphin-conjugated or free negative control NIP228 hIgG1TM. n=6 for each group. At 1 hr post dose: Bbbt0241 plus dyn significantly different from vehicle ***P<0.001. No significant difference with NIP228-dyn, NIP228 or Bbt0241. Bbbt0241-dyn vs NIP228-dyn: P<0.001 @ 1 hr. Bbbt0241-dyn vs Bbbt0241: P<0.001 @ 1 hr. NIP228-dyn vs NIP228: NS. Data analyzed using 2-way ANOVA with time and treatment as dependent factors. Subsequent statistical significance obtained using Bonferroni’s Post Hoc test.Figure 2:

[0007] FIG. 2A shows urine output results upon administration of selected FC5 mimetic and non- mimetic dynorphin conjugates (IgG format) to rats. n=6. Data analyzed using 2-way ANOVA with time and treatment as dependent factors. Subsequent statistical significance obtained using Bonferroni’s Post Hoc test. When compared to vehicle 1 hr post dose: Bbbt0754-dyn and NIP228- dyn ***P<0.001. Bbbt0674-dyn and Bbbt06540dyn **P<0.05. FIG.2B shows urine output dose response curves upon administration of dynorphin-conjugated NIP228-IgG (black bars) and Bbbt0626-IgG (gray bars) in a rat diuresis model. n=6. Due to the number of animals being tested the experiment was run over 2 days. Results are presented as the combined data from both of those studies. Figure 3:

[0008] FIG.3 is a schematic illustrating surgery performed in the partial sciatic nerve ligation assay. Figure 4:

[0009] FIG.4 shows the effect of FC5 mimetic-IL1Ra fusions on reversal of partial sciatic nerve ligation induced mechanical hyperalgesia in the rat. n=9-10 per group. Data analyzed using 2-way ANOVA with time and treatment as dependent factors. Subsequent statistical significance obtained using Tukey’s Post Hoc test. ***P<0.001 Op+NIP228 vs OP+Bbbt0626-IL1Ra. + P<0.05, +++ P<0.001 Op+NIP228 vs Op+Bbbt0632-IL1Ra. # P<0.05, ### P<0.001 OP+NIP228 vs Op+Bbbt0726-IL1Ra. Figure 5:

[0010] FIG.5 shows the effect of increased doses of a Bbbt0626-IL1Ra fusion on partial nerve ligation- induced mechanical hyperalgesia. n=7-8 per group. All compounds administered i.v. Data analyzed using 2-way ANOVA with time and treatment as dependent factors. Subsequent statistical significance obtained using Bonferroni’s Post Hoc test. Op+NIP228 vs Op+Bbbt062650 mg / kg;mg / kg. Figure 6:

[0011] FIG. 6A and 6B compare the effect of intravenous vs. subcutaneous administration of a Bbbt0626-IL1Ra fusion on partial nerve ligation-induced mechanical hyperalgesia. n=7-8 per group. Data analyzed using 2-way ANOVA with time and treatment as dependent factors. Subsequent statistical significance obtained using Bonferroni’s Post Hoc test. FIG 6A shows data for i.v. dosing only. *** P<0.001 Op+NIP228100mg / kg vs Op+Bbbt0626100 mg / kg. FIG 6B shows data for subcutaneous dosing only. +++ P<0.001 Op+NIP228100mg / kg vs Op+Bbbt0626100mg / kg.Figure 7:

[0012] FIG.7A and 7B compare single and repeat dosing of a Bbbt0626-IL1Ra fusion on partial nerve ligation-induced mechanical hyperalgesia. Data analyzed using 2-way ANOVA with time and treatment as dependent factors. Subsequent statistical significance obtained using Bonferroni’s Post Hoc test. FIG 7A n = 9-10 per group, FIG 7B n = 8-10 per group. *** P<0.001 Op+NIP228 vs Op+BBB-IL1Ra. Figure 8:

[0013] Figure 1:FIG. 1A is a schematic of a scFv molecule conjugated to the κ-opioid agonist dynorphin. FIG.1B shows the study design for the diuresis model described in the Examples. FIG. 1C shows urine output over time in rats administered dynorphin-conjugated or free Bbbt0241 hIgG1TM, compared to dynorphin-conjugated or free negative control NIP228 hIgG1TM. n=6 for each group. At 1 hr post dose: Bbbt0241 plus dyn significantly different from vehicle ***P<0.001. No significant difference with NIP228-dyn, NIP228 or Bbt0241. Bbbt0241-dyn vs NIP228-dyn: P<0.001 @ 1 hr. Bbbt0241-dyn vs Bbbt0241: P<0.001 @ 1 hr. NIP228-dyn vs NIP228: NS. Data analyzed using 2-way ANOVA with time and treatment as dependent factors. Subsequent statistical significance obtained using Bonferroni’s Post Hoc test. Figure 2:

[0014] FIG. 2A shows urine output results upon administration of selected FC5 mimetic and non- mimetic dynorphin conjugates (IgG format) to rats. n=6. Data analyzed using 2-way ANOVA with time and treatment as dependent factors. Subsequent statistical significance obtained using Bonferroni’s Post Hoc test. When compared to vehicle 1 hr post dose: Bbbt0754-dyn and NIP228- dyn ***P<0.001. Bbbt0674-dyn and Bbbt06540dyn **P<0.05. FIG.2B shows urine output dose response curves upon administration of dynorphin-conjugated NIP228-IgG (black bars) and Bbbt0626-IgG (gray bars) in a rat diuresis model. n=6. Due to the number of animals being tested the experiment was run over 2 days. Results are presented as the combined data from both of those studies. Figure 3:

[0015] FIG.3 is a schematic illustrating surgery performed in the partial sciatic nerve ligation assay. Figure 4:

[0016] FIG.4 shows the effect of FC5 mimetic-IL1Ra fusions on reversal of partial sciatic nerve ligation induced mechanical hyperalgesia in the rat. n=9-10 per group. Data analyzed using 2-way ANOVA with time and treatment as dependent factors. Subsequent statistical significance obtained using Tukey’s Post Hoc test. ***P<0.001 Op+NIP228 vs OP+Bbbt0626-IL1Ra. + P<0.05, +++ P<0.001 Op+NIP228 vs Op+Bbbt0632-IL1Ra. # P<0.05, ### P<0.001 OP+NIP228 vs Op+Bbbt0726-IL1Ra.Figure 5:

[0017] FIG.5 shows the effect of increased doses of a Bbbt0626-IL1Ra fusion on partial nerve ligation- induced mechanical hyperalgesia. n=7-8 per group. All compounds administered i.v. Data analyzed using 2-way ANOVA with time and treatment as dependent factors. Subsequent statistical significance obtained using Bonferroni’s Post Hoc test. Op+NIP228 vs Op+Bbbt062650 mg / kg;mg / kg. Figure 6:

[0018] FIG. 6A and 6B compare the effect of intravenous vs. subcutaneous administration of a Bbbt0626-IL1Ra fusion on partial nerve ligation-induced mechanical hyperalgesia. n=7-8 per group. Data analyzed using 2-way ANOVA with time and treatment as dependent factors. Subsequent statistical significance obtained using Bonferroni’s Post Hoc test. FIG 6A shows data for i.v. dosing only. *** P<0.001 Op+NIP228100mg / kg vs Op+Bbbt0626100 mg / kg. FIG 6B shows data for subcutaneous dosing only. +++ P<0.001 Op+NIP228100mg / kg vs Op+Bbbt0626100mg / kg. Figure 7:

[0019] FIG.7A and 7B compare single and repeat dosing of a Bbbt0626-IL1Ra fusion on partial nerve ligation-induced mechanical hyperalgesia. Data analyzed using 2-way ANOVA with time and treatment as dependent factors. Subsequent statistical significance obtained using Bonferroni’s Post Hoc test. FIG 7A n = 9-10 per group, FIG 7B n = 8-10 per group. *** P<0.001 Op+NIP228 vs Op+BBB-IL1Ra.

[0020] Figure 8 shows the measurement of Type I IFN activity in the THP1-Dual Cell line expressing a Lucia luciferase gene under control of an ISG54 minimal promoter and five IFN-stimulated response elements. THP1-Dual Cells were pre-treated with a range of concentrations of IFNAR1 or IFNAR1-BBB and subsequently stimulated with human IFN-α. Secreted luciferase was measured in the supernatant. Abbreviations include: IFNAR1, Anifrolumab; IFNAR1-BBB, Anifrolumab-BBB; IFN-α, interferon-α. Figure 9:

[0021] FIG.9 shows the number of differentially expressed genes upregulated (UP) or downregulated (DOWN) after 24 hours stimulation of human microglia with IFNβ. Upregulation or downregulation was determined by comparing gene expression levels with or without 24 hours stimulation with IFNβ (“Compound IFN vs basal”), or by comparing gene expression levels after 24 hours stimulation with IFNβ with or without 45 minutes pre-treatment with Anifrolumab (“Compound 40 vs microglia stimulated”). 4 DETAILED DESCRIPTION

[0022] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art to which this disclosure belongs. It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such can vary. The terminology used herein is for the purpose of describing particular instances only, and is not intended to limit the scope of the present invention, which is defined solely by the claims. 4.1 Treatment of neurodegenerative disease

[0023] The invention relates to a method of treating, or reducing the risk for development of, a neurodegenerative disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an inhibitor of type I IFN signalling. 4.2 Inhibitor of type I IFN signalling

[0024] The inhibitor of type I IFN mediated signalling may be an IFNAR1 inhibitor. IFNAR1 refers to interferon alpha and beta receptor subunit 1. The inhibitor of type I IFN mediated signalling may be an antibody specific for IFNAR1. The inhibitor of type I IFN mediated signalling may be a human monoclonal antibody specific for IFNAR1. The inhibitor of type I IFN mediated signalling may be a modified IgG1 class human monoclonal antibody specific for IFNAR1.

[0025] Where the inhibitor of type I IFN mediated signalling is an antibody, the antibody may be a murine antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a multispecific antibody, any combination thereof, or any antigen- binding fragment thereof. In certain aspects, the antibody or fragment thereof is a complete IgG immunoglobulin, e.g., a human IgG1 immunoglobulin, comprising two heavy chains and two light chains. In certain aspects the antibody is an antibody fragment, such as an antigen-binding fragment of an antibody, e.g., an Fv fragment, an Fab fragment, an F(ab')2 fragment, an Fab' fragment, a dsFv fragment, a scFv fragment, or an sc(Fv)2 fragment.

[0026] Additionally or alternatively, the type I interferon receptor inhibitor may be a small molecule inhibitor of a type I interferon receptor (e.g. for pharmacological inhibition of type I interferon receptor activity).

[0027] The antibody may comprise a heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 236.The antibody may comprise a heavy chain variable region complementarity determining region (HCDR2) comprising the amino acid sequence of SEQ ID NO: 237. The antibody may comprise a heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 238. The antibody may comprise a light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence SEQ ID NO: 239 The antibody may comprise a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence SEQ ID NO: 240. The antibody may comprise a light chain variable regioncomplementarity determining region 3 (LCDR3) comprising the amino acid sequence SEQ ID NO: 241.

[0028] The antibody may comprise a HCDR1 comprising the amino acid sequence of SEQ ID NO: 236, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 237, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 238, a LCDR1 comprising the amino acid sequence SEQ ID NO: 239, a LCDR2 comprising the amino acid sequence SEQ ID NO: 240 and a LCDR3 comprising the amino acid sequence SEQ ID NO: 241. The antibody may comprise a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 234 and / or a human light chain variable region comprising the amino acid sequence of SEQ ID NO: 235. The antibody may comprise a human light chain constant region comprising the amino acid sequence of SEQ ID NO: 242. The antibody may comprise a human heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 243. The antibody may comprise in the Fc region an amino acid substitution of L234F, as numbered by the EU index as set forth in Kabat and wherein said antibody exhibits reduced affinity for at least one Fc ligand compared to an unmodified antibody. The antibody may comprise a human heavy chain comprising the amino acid sequence of SEQ ID NO: 244 and / or a human light chain comprising the amino acid sequence of SEQ ID NO: 245.

[0029] The antibody may comprise one or more CDRs, e.g. a set of CDRs, within an antibody framework. For example, one or more CDRs or a set of CDRs of the antibody may be grafted into a framework (e.g. human framework) to provide an antibody molecule. Framework regions in the antibody can consist of segments derived from human germline gene sequences. Consequently, the framework may be germlined, meaning that specific residues within it are altered to match the residues found at the corresponding position in the most similar human germline framework. The skilled person can select a germline segment that is closest in sequence to the framework sequence of the antibody before germlining and test the affinity or activity of the antibodies to confirm that germlining does not significantly reduce antigen binding or potency in assays described herein. Human germline gene segment sequences are known to those skilled in the art and can be accessed for example from the VBase compilation.

[0030] The inhibitor of type I IFN mediated signalling or IFNAR1 inhibitor may be Anifrolumab or a functional variant thereof. Anifrolumab is a monoclonal antibody that inhibits binding of type I IFN to IFNAR and inhibits the biologic activity of all type I IFNs. Disclosure related to Anifrolumab can be found in U.S. Patent No.7,662,381, which is incorporated herein by reference. The clone 11E2 referenced in U.S. Patent No.7,662,381 is Anifrolumab.

[0031] The inhibitor of type I IFN mediated signalling or IFNAR1 inhibitor may be isolated. The inhibitor of type I IFN mediated signalling or IFNAR1 inhibitor may be purified. 4.3 Blood brain barrier (BBB) transporter molecule

[0032] The inhibitor of type I IFN mediated signalling or IFNAR1 inhibitor may be capable of crossing the blood-brain barrier (BBB). The inhibitor of type I IFN mediated signalling or IFNAR1 inhibitormay comprise a blood brain barrier (BBB) transporter molecule. The BBB transporter molecule may be capable of crossing brain endothelial cells. The BBB transporter molecule can be part of the inhibitor of type I IFN mediated signalling or INFAR1 inhibitor, e.g. as a fusion polypeptide, or joined to the polypeptide through disulfide bonds or other covalent bonds. Alternatively, the BBB transporter molecule can be associated with the inhibitor of type I IFN mediated signalling or IFNAR1 inhibitor in any way that will allow the transporter molecule to facilitate its transport across the BBB. In certain aspects, the BBB transporter molecule remains part of the inhibitor of type I IFN mediated signalling or IFNAR1 inhibitor following BBB transport, and the inhibitor of type I IFN mediated signalling or IFNAR1 inhibitor retains activity in that form. The blood brain barrier transporter molecule may bind to antigen on the surface of brain capillary endothelial cells.

[0033] The BBB transporter molecule may be capable of binding to brain microvascular endothelial cells (BMVEC). In certain aspects, the BBB transporter molecule can bind to BMVEC in one or more species e.g., mouse BMVEC, rat BMVEC, cynomolgus monkey BMVEC, or human BMVEC, and / or internalize into BMVEC of one or more species.

[0034] In certain aspects, the BMVEC are brain capillary endothelial cells (BCEC). In certain aspects, a transporter molecule as provided herein can pass through a monolayer of BCEC in an in vitro transcytosis assay.

[0035] The BBB transporter molecule may comprise an immunoglobulin-derived polypeptide. The BBB transporter molecule may be a humanized isolated antibody or antigen binding fragment thereof. In certain aspects the polypeptide is a humanized version of the camelid antibody FC5, identified and isolated using Fluorescence Micro-volume Assay Technology (FMAT) to detect binding to brain microvascular endothelial cells (BMVEC), e.g., mouse B.End3 cells. In certain aspects the polypeptide comprises an antibody VH and an antibody VL isolated from a naïve scFv phage library, or a scFv phage library comprising two heavy chain complementarity determining regions (CDRs) from FC5, again identified and isolated using FMAT to detect binding to BMVEC. In certain aspects, the immunoglobulin-derived polypeptide is an antibody or an active fragment thereof, where “active” means that the transporter molecule can, e.g., bind to BMVEC in one or more species, e.g., mouse BMVEC, rat BMVEC, cynomolgus monkey BMVEC, or human BMVEC, internalize into BMVEC of one or more species, and / or cross the blood brain barrier either alone, or associated with a payload. In certain aspects, the transporter molecule comprises one or more of Bbbt0241, Bbbt0351, Bbbt0626, Bbbt0632, Bbbt0654, Bbbt0726, Bbbt0727, Bbbt0732, Bbbt0754, Bbbt0674, Bbbt0755, Bbbt0643, Bbbt0579 or Bbbt0671. Disclosure related to the BBB transporter molecule can be found in U.S. Patent No.10,184,008, which is incorporated herein by reference.

[0036] In certain aspects, the transporter molecule does not bind to BMVEC but is still capable of transporting across the BBB as indicated in the in vitro transcytosis assay. In certain aspects this transporter molecule crosses the BBB with greater efficiency than FC5. In certain aspects this transporter molecule is identical to the FC5 amino acid sequence except for two amino acidsubstitutions, a T97A substitution at Kabat position 97, and a T100aD substitution at Kabat position 100a, and has the amino acid sequence of Bbbt0351 (SEQ ID NO: 200).

[0037] In certain aspects, the immunoglobulin-derived polypeptide comprises immunoglobulin heavy chain complementarity determining regions (CDRs). For example, the immunoglobulin-derived polypeptide can include an immunoglobulin heavy chain complementarity-determining region-1 (H- CDR1), an immunoglobulin heavy chain complementarity-determining region-2 (H-CDR2), an immunoglobulin heavy chain complementarity-determining region-3 (H-CDR3). In certain aspects, the immunoglobulin-derived polypeptide can further comprise, or alternatively comprise, immunoglobulin light chain CDRs. For example, the immunoglobulin-derived polypeptide can include an immunoglobulin complementarity-determining region-1 (L-CDR1), an immunoglobulin light chain complementarity-determining region-2 (L-CDR2), and an immunoglobulin light chain complementarity-determining region-3 (L-CDR3). In certain aspects, the immunoglobulin-derived polypeptide can contain an H-CDR1, an H-CDR2, an H-CDR3, an L-CDR1, an L-CDR2, and an L- CDR3 with the following amino acid sequences, respectively: (a) SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14, the CDRs of Bbbt0241; (b) SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, Q G D S L X2 X3 Y Y X4 X5, S (SEQ ID NO: 260), G X8 X9 261), and N S R D X13 X14 GH; X16=H or P; and X17=V or W, (SEQ ID NO: 262), CDRs similar to those of Bbbt0626; (c) SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 260, SEQ ID NO: 261, and SEQ ID NO: 262, CDRs similar to those of Bbbt0632; (d) SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 66, SEQ ID NO: 67, and SEQ ID NO: 68, the CDRs of Bbbt0654; (e) SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 260, SEQ ID NO: 261, and SEQ ID NO: 262, CDRs similar to those of Bbbt0726; (f) SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 260, SEQ ID NO: 261, and SEQ ID NO: 262, CDRs similar to those of Bbbt0727; (g) SEQ ID NO: 111, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 260, SEQ ID NO: 261, and SEQ ID NO: 262, CDRs similar to those of Bbbt0732; (h) SEQ ID NO: 129, SEQ ID NO: 130, SEQ ID NO: 131, SEQ ID NO: 138, SEQ ID NO: 139, and SEQ ID NO: 140, the CDRs of Bbbt0754; (i) SEQ ID NO: 147, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 156, SEQ ID NO: 157, and SEQ ID NO: 158, the CDRs of Bbbt0674; (j) SEQ ID NO: 165, SEQ ID NO: 166, SEQ ID NO: 167, SEQ ID NO: 174, SEQ ID NO: 175, and SEQ ID NO: 176, the CDRs of Bbbt0755; (k) SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 185, SEQ ID NO: 192, SEQ ID NO: 193, and SEQ ID NO: 194, the CDRs of Bbbt0643; or(l) SEQ ID NO: 210, SEQ ID NO: 211, SEQ ID NO: 212, SEQ ID NO: 219, SEQ ID NO: 220, SEQ ID NO: 221, the CDRs of Bbbt0579.

[0038] In certain alternative embodiments, one or more CDRs as described above are identical to the recited CDRs, except for, e.g., 1, 2, 3, 4, or 5 single amino acid deletions, substitutions, or insertions. In certain embodiments, the transporter molecule as provided above can cross the blood brain barrier. In certain aspects, the H-CDR3 of the Bbbt0241 variant Bbbt0241m comprises two substitutions, a T97A substitution at Kabat position 97, and a T100aD substitution at Kabat position 100a.

[0039] In certain aspects, the immunoglobulin-derived polypeptide can contain an H-CDR1, an H- CDR2, an H-CDR3, an L-CDR1, an L-CDR2, and an L-CDR3 with the following amino acid sequences, respectively: (b) SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 30, SEQ ID NO: 31, and SEQ ID NO: 32, the CDRs of Bbbt0626; (c) SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 48, SEQ ID NO: 49, and SEQ ID NO: 50, the CDRs of Bbbt0632; (e) SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 84, SEQ ID NO: 85, and SEQ ID NO: 86, the CDRs of Bbbt0726; (f) SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 102, SEQ ID NO: 103, and SEQ ID NO: 104, the CDRs of Bbbt0727; or (g) SEQ ID NO: 111, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 120, SEQ ID NO: 121, and SEQ ID NO: 122, the CDRs of Bbbt0732.

[0040] In certain alternative embodiments, one or more CDRs as described above are identical to the recited CDRs, except for, e.g., 1, 2, 3, 4, or 5 single amino acid deletions, substitutions, or insertions.

[0041] In certain aspects, the H-CDR1, the H-CDR2, the H-CDR3, the L-CDR1, the L-CDR2, and the L-CDR3 can be situated in immunoglobulin framework regions to produce an antibody VH and an antibody VL. In certain aspects the framework regions can be human-derived framework regions. In certain aspects the antibody VH and antibody VL are fused together, e.g., through a flexible peptide linker, to form a scFv molecule. In certain aspects the VH and VL further comprise one or more immunoglobulin constant domains, e.g., a CH1 domain, a hinge region, a CH3 domain, a CH3 domain, a CL-kappa domain, and / or a CL lambda domain. In certain aspects the one or more immunoglobulin constant domains are derived from a human immunoglobulin, e.g., a human IgG1 immunoglobulin. In certain aspects the VH, VL, and / or constant domains can comprise mutations to facilitate, e.g., longer or shorter half-life, increased or reduced effector functions.

[0042] In certain aspects, this disclosure provides an isolated transporter molecule comprising an immunoglobulin-derived polypeptide, where the polypeptide comprises an immunoglobulin heavy chain variable region (VH) region, an immunoglobulin light chain variable region (VL) region or an immunoglobulin VH region and an immunoglobulin VL region. In certain aspects the immunoglobulin-derived polypeptide comprises:(a) an VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11, where SEQ ID NO: 2 and SEQ ID NO: 11 encode the VH and VL regions of Bbbt0241; (b) a VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 20 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 29, where SEQ ID NO: 20 and SEQ ID NO: 29 encode the VH and VL regions of Bbbt0626; (c) a VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 38 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 47, where SEQ ID NO: 38 and SEQ ID NO: 47 encode the VH and VL regions of Bbbt0632; (d) a VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 56 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 65, where SEQ ID NO: 56 and SEQ ID NO: 65 encode the VH and VL regions of Bbbt0654; (e) a VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 74 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 83, where SEQ ID NO: 74 and SEQ ID NO: 83 encode the VH and VL regions of Bbbt0726; (f) a VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 92 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 101, where SEQ ID NO: 92 and SEQ ID NO: 101 encode the VH and VL regions of Bbbt0727; (g) a VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 110 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 119 , where SEQ ID NO: 110 and SEQ ID NO: 119 encode the VH and VL regions of Bbbt0732; (h) a VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 128 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 137, where SEQ ID NO: 128 and SEQ ID NO: 137 encode the VH and VL regions of Bbbt0754; (i) a VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 146 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 155, where SEQ ID NO: 146 and SEQ ID NO: 155 encode the VH and VL regions of Bbbt0674; (j) a VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 164 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 173, where SEQ ID NO: 164 and SEQ ID NO: 173 encode the VH and VL regions of Bbbt0755;(k) a VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 182 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 191, where SEQ ID NO: 182 and SEQ ID NO: 191 encode the VH and VL regions of Bbbt0643; (l) an VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 209 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 218, where SEQ ID NO: 209 and SEQ ID NO: 218 encode the VH and VL regions of Bbbt0579; or (m) an VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 226 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 227, where SEQ ID NO: 226 and SEQ ID NO: 227 encode the VH and VL regions of Bbbt0671.

[0043] An overview of sequence information for the different Bbbt clones is provided in Table 1: Bbbt sequences. Table 1: Sequence information for the different Bbbt clones Clone Description SEQ ID NO: Sequence Bbbt0241 DNA encoding SEQ ID NO: 1 gaagttcaactgcaggcgtccggcggtggcctggtgcaggctggcggct VH region ctctgcgtctgtcctgtgctgccagcggctttaaaatcactcactatactatgg gctggttccgccaggcaccgggcaaagagcgtgaattcgtgagccgcat cacctggggcggtgacaacaccttttactccaactccgttaagggtcgtttta ctatctctcgtgataacgctaaaaacaccgtttacctgcagatgaacagcct gaaaccagaggacactgctgactactattgtgctgcaggttccacctctac ggctaccccactgcgcgtcgactattggggcaaaggcacccaggtgacc gtctcgagt VH entire SEQ ID NO: 2 EVQLQASGGGLVQAGGSLRLSCAASGFKITHYTMG WFRQAPGKEREFVSRITWGGDNTFYSNSVKGRFTIS RDNAKNTVYLQMNSLKPEDTADYYCAAGSTSTATPL RVDYWGKGTQVTVSS VH CDR1 SEQ ID NO: 3 HYTMG VH CDR2 SEQ ID NO: 4 RITWGGDNTFYSNSVKG VH CDR3 SEQ ID NO: 5 GSTSTATPLRVDY VH FW1 SEQ ID NO: 6 EVQLQASGGGLVQAGGSLRLSCAASGFKIT VH FW2 SEQ ID NO: 7 WFRQAPGKEREFVS VH FW3 SEQ ID NO: 8 RFTISRDNAKNTVYLQMNSLKPEDTADYYCAA VH FW4 SEQ ID NO: 9 WGKGTQVTVSS DNA encoding SEQ ID NO: 10 gaaacgacactcacgcagtctccagacaccctgtctttgtctccagggga VL region aagagccaccctctcctgccgggccagtcagagtcttagcaacaacttctt agcctggtaccagcagaaatctggccaggctcccaggctcctcatctatg ctgcatccagcagggccactggcatcccagacagattcagtggcagtgg gtctgggacagacttcactctcaccatcagcagactggagcctgaagattt tgcagtttattactgtcagcagtatgctgcctcagcgatcaccttcggccaag ggacacgactggagattaaa VL entire SEQ ID NO: 11 ETTLTQSPDTLSLSPGERATLSCRASQSLSNNFLAW YQQKSGQAPRLLIYAASSRATGIPDRFSGSGSGTDF TLTISRLEPEDFAVYYCQQYAASAITFGQGTRLEIK VL CDR1 SEQ ID NO: 12 RASQSLSNNFLA VL CDR2 SEQ ID NO: 13 AASSRAT VL CDR3 SEQ ID NO: 14 QQYAASAIT VL FW1 SEQ ID NO: 15 ETTLTQSPDTLSLSPGERATLSCVL FW2 SEQ ID NO: 16 WYQQKSGQAPRLLIY VL FW3 SEQ ID NO: 17 GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC VL FW4 SEQ ID NO: 18 FGQGTRLEIK Bbbt0626 DNA encoding SEQ ID NO: 19 ggggtccagctggtgcagtctggggcagagctgaagaagcctgggtcct VH region cggtgaaggtctcctgtaaggcttctggaggcaccttcagcagttatgctat cagctgggtgcgacaggcccctggacaagggcttgagtggatgggaag gatcatccctattcttggtacatcaaactacgcacagaagttccagggcag agtcacgattaccgcggacgaacgtacgagcacagcctacatggagct gagcagcctgagatctgaggacacggccgtatattactgtgcgagaagg agtagtttagcagcagcggataggggggcttttgatatctggggccaggg gacaatggtcaccgtctcgagt VH entire SEQ ID NO: 20 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAIS germline WVRQAPGQGLEWMGRIIPILGTSNYAQKFQGRVTIT ADESTSTAYMELSSLRSEDTAVYYCARRSSLAAADR GAFDIWGQGTMVTVSS VH CDR1 SEQ ID NO: 21 SYAIS VH CDR2 SEQ ID NO: 22 RIIPILGTSNYAQKFQG VH CDR3 SEQ ID NO: 23 RSSLAAADRGAFDI VH FW1 SEQ ID NO: 24 GVQLVQSGAELKKPGSSVKVSCKASGGTFS VH FW2 SEQ ID NO: 25 WVRQAPGQGLEWMG VH FW3 SEQ ID NO: 26 RVTITADERTSTAYMELSSLRSEDTAVYYCAR VH FW4 SEQ ID NO: 27 WGQGTMVTVSS DNA encoding SEQ ID NO: 28 tcgtctgagctgactcaggaccctgctgtgtctgtggccttgggacagaca VL region gtcaggatcacatgccaaggagacagcctcagaagctattatgcaagct ggtaccagcagaagccaggacaggcccctgtacttgtcatctatggtaaa aacaaccggccctcagggatcccagaccgattctctggctccagctcag gaaacacagcttccttgaccatcactggggctcaggcggaagatgaggc tgactattactgtaactcccgggacagcagtggtaaccatgtggtattcggc ggagggaccaagctgaccgtccta VL entire SEQ ID NO: 29 SSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQ QKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASL TITGAQAEDEADYYCNSRDSSGNHVVFGGGTKLTVL VL CDR1 SEQ ID NO: 30 QGDSLRSYYAS VL CDR2 SEQ ID NO: 31 GKNNRPS VL CDR3 SEQ ID NO: 32 NSRDSSGNHVV VL FW1 SEQ ID NO: 33 SSELTQDPAVSVALGQTVRITC VL FW2 SEQ ID NO: 34 WYQQKPGQAPVLVIY VL FW3 SEQ ID NO: 35 GIPDRFSGSSSGNTASLTITGAQAEDEADYYC VL FW4 SEQ ID NO: 36 FGGGTKLTVL Bbbt0632 DNA encoding SEQ ID NO: 37 caggtgcagctggtgcagtctggggctgaggtgaagaagcctgggtcctc VH region ggtgaaggtctcctgcaagacttctggaggcaccttcggcacctattctatc acctgggtgcgacaggcccctggacaagggcttgagtggatgggagac atcgtccctatctttggaacaccaaactacgcacagaatttccagggcaga gtcactatctccgcggacgtatccacggcgacagtctacatggagctgag cagcctaacatccgacgacacggccgtctacttctgtgctaagaggggga gttactacggccggggaggttggttcgacccctggggccgggggacaat ggtcaccgtctcgagt VH entire SEQ ID NO: 38 QVQLVQSGAEVKKPGSSVKVSCKTSGGTFGTYSITW VRQAPGQGLEWMGDIVPIFGTPNYAQNFQGRVTISA DVSTATVYMELSSLTSDDTAVYFCAKRGSYYGRGG WFDPWGRGTMVTVSS VH CDR1 SEQ ID NO: 39 TYSIT VH CDR2 SEQ ID NO: 40 DIVPIFGTPNYAQNFQG VH CDR3 SEQ ID NO: 41 RGSYYGRGGWFDP VH FW1 SEQ ID NO: 42 QVQLVQSGAEVKKPGSSVKVSCKTSGGTFG VH FW2 SEQ ID NO: 43 WVRQAPGQGLEWMG VH FW3 SEQ ID NO: 44 RVTISADVSTATVYMELSSLTSDDTAVYFCAKVH FW4 SEQ ID NO: 45 WGRGTMVTVSS DNA encoding SEQ ID NO: 46 tcttctgagctgactcaggaccctgctgtgtctgtggccttgagacagacag VL region tcaggatcacatgccaaggagacagcctcacaaggtattatacaaactg gtaccagcagaagccaggacaggcccctatacttgtcatctatggtgaaa acaaccggccctcagggatcccagaccgattctctggctccagatcagg aaacacagcttccttgaccatcactggggctcaggcggaagatgaggct gactattactgtaactcccgggacaatactggtaaacattgggtgttcggcg gagggaccaagctgaccgtccta VL entire SEQ ID NO: 47 SSELTQDPAVSVALRQTVRITCQGDSLTRYYTNWYQ QKPGQAPILVIYGENNRPSGIPDRFSGSRSGNTASLT ITGAQAEDEADYYCNSRDNTGKHWVFGGGTKLTVL VL CDR1 SEQ ID NO: 48 QGDSLTRYYTN VL CDR2 SEQ ID NO: 49 GENNRPS VL CDR3 SEQ ID NO: 50 NSRDNTGKHWV VL FW1 SEQ ID NO: 51 SSELTQDPAVSVALRQTVRITC VL FW2 SEQ ID NO: 52 WYQQKPGQAPILVIY VL FW3 SEQ ID NO: 53 GIPDRFSGSRSGNTASLTITGAQAEDEADYYC VL FW4 SEQ ID NO: 54 FGGGTKLTVL Bbbt0654 DNA encoding SEQ ID NO: 55 gaggtgcagctgttggagtctgggggaggcttggtacagcctggggggtc VH region cctgagactctcctgtgcagcctctggattcacctttagcagctatgccatga gctgggtccgccaggctccagggaaggggctggagtgggtctcagctatt agtggtagtggtggtagcacatactacgcagactccgtgaagggccggtt caccatctccagagacaattccaagaacacgctgtatctgcaaatgaaca gcctgagagccgaggacacggccgtgtattactgtgcgaaaaattattact atgatactagtgcttattactacgtagggtccgactactttgactactggggc caagggacaatggtcaccgtctcgagt VH entire SEQ ID NO: 56 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMS WVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTIS RDNSKNTLYLQMNSLRAEDTAVYYCAKNYYYDTSAY YYVGSDYFDYWGQGTMVTVSS VH CDR1 SEQ ID NO: 57 SYAMS VH CDR2 SEQ ID NO: 58 AISGSGGSTYYADSVKG VH CDR3 SEQ ID NO: 59 NYYYDTSAYYYVGSDYFDY VH FW1 SEQ ID NO: 60 EVQLLESGGGLVQPGGSLRLSCAASGFTFS VH FW2 SEQ ID NO: 61 WVRQAPGKGLEWVS VH FW3 SEQ ID NO: 62 RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK VH FW4 SEQ ID NO: 63 WGQGTMVTVSS DNA encoding SEQ ID NO: 64 cagtctgccctgactcagcctgcctccgtgtctgggtctcctggacagtcga VL region taaccatctcctgcactgcaaccagcagtaacgttggcgcttataactttgtc tcctggtaccaacaacacccaggcaaagcccccaaagtcctgatttatag ggtcagtaatcggccttcaggggtttctaatcgcttctctggctccaagtctg gcaacacggcctccctgaccatctctgggctccaggctgacgacgaggc tgattattattgcagctcatatacaaccgactacatttgggtgttcggcggag ggaccaagctgaccgtccta VL entire SEQ ID NO: 65 QSALTQPASVSGSPGQSITISCTATSSNVGAYNFVS WYQQHPGKAPKVLIYRVSNRPSGVSNRFSGSKSGN TASLTISGLQADDEADYYCSSYTTDYIWVFGGGTKLT VL VL CDR1 SEQ ID NO: 66 TATSSNVGAYNFVS VL CDR2 SEQ ID NO: 67 RVSNRPS VL CDR3 SEQ ID NO: 68 SSYTTDYIWV VL FW1 SEQ ID NO: 69 QSALTQPASVSGSPGQSITISC VL FW2 SEQ ID NO: 70 WYQQHPGKAPKVLIY VL FW3 SEQ ID NO: 71 GVSNRFSGSKSGNTASLTISGLQADDEADYYC VL FW4 SEQ ID NO: 72 FGGGTKLTVL Bbbt0726 DNA encoding SEQ ID NO: 73 caggtacagctgcagcagtcaggggctgaggtgaagaagcctgggtcct VH region cggtgagggtctcctgcaaggcttctggaggcaccttcaacagttatgctat caactgggtgcgacaggcccctggacaagggcttgagtggatgggagggatcatcactttctttggtacaacaacctacgcacagaagttccagggcag agtcacgattaccgcggacgaatccacgagcacagcctacatggagctg agcagcctgagatctgacgacacggccgtgtattattgtgcgaggaatcc ccgtattgtgggcggagcttttgatatctgggggaaagggaccacggtcac cgtctcgagt VH entire SEQ ID NO: 74 QVQLQQSGAEVKKPGSSVRVSCKASGGTFNSYAIN WVRQAPGQGLEWMGGIITFFGTTTYAQKFQGRVTIT ADESTSTAYMELSSLRSDDTAVYYCARNPRIVGGAF DIWGKGTTVTVSS VH CDR1 SEQ ID NO: 75 SYAIN VH CDR2 SEQ ID NO: 76 GIITFFGTTTYAQKFQG VH CDR3 SEQ ID NO: 77 NPRIVGGAFDI VH FW1 SEQ ID NO: 78 QVQLQQSGAEVKKPGSSVRVSCKASGGTFN VH FW2 SEQ ID NO: 79 WVRQAPGQGLEWMG VH FW3 SEQ ID NO: 80 RVTITADESTSTAYMELSSLRSDDTAVYYCAR VH FW4 SEQ ID NO: 81 WGKGTTVTVSS DNA encoding SEQ ID NO: 82 tcgtctgagctgactcaggaccctgctgtgtctgtggccttgggacagaca VL region gtcaggatcacatgccaaggagacagcctcagaagctattatgcaagct ggtaccagcagaagccaggacaggcccctgtacttgtcatctatggtaaa aacaaccggccctcaggggtcccagaccgattctctggctccagctcag gaaacacagcttccttgaccatcactggggctcaggcggaagatgaggc tgactattactgtaactcccgggacagcagtggtaaccatgtggtattcggc ggagggaccaagctgaccgtccta VL entire SEQ ID NO: 83 SSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQ QKPGQAPVLVIYGKNNRPSGVPDRFSGSSSGNTASL TITGAQAEDEADYYCNSRDSSGNHVVFGGGTKLTVL VL CDR1 SEQ ID NO: 84 QGDSLRSYYAS VL CDR2 SEQ ID NO: 85 GKNNRPS VL CDR3 SEQ ID NO: 86 NSRDSSGNHVV VL FW1 SEQ ID NO: 87 SSELTQDPAVSVALGQTVRITC VL FW2 SEQ ID NO: 88 WYQQKPGQAPVLVIY VL FW3 SEQ ID NO: 89 GVPDRFSGSSSGNTASLTITGAQAEDEADYYC VL FW4 SEQ ID NO: 90 FGGGTKLTVL Bbbt0727 DNA encoding SEQ ID NO: 91 caggtgcagctggtgcagtctggggctgaggtgaagaagcctgggtcctc VH region ggtgaaggtctcctgcaaggcttctggagacactttccgcagctatattatc agctgggtgcgacaggcccctggacaaggacttgagtgggtgggaggg atcatccctatgtttggcacatcaaattatgcacagcagttccagggcaaa gtcaccattaccgcggacgaatccacgagcacagcctacatggagctga gcagcctgagatctgaggacacggccgtgtattactgtgcgagaggtggg gcccgatactactacatggacgtctggggccgagggacaatggtcaccg tctcttca VH entire SEQ ID NO: 92 QVQLVQSGAEVKKPGSSVKVSCKASGDTFRSYIISW VRQAPGQGLEWVGGIIPMFGTSNYAQQFQGKVTITA DESTSTAYMELSSLRSEDTAVYYCARGGARYYYMD VWGRGTMVTVSS VH CDR1 SEQ ID NO: 93 SYIIS VH CDR2 SEQ ID NO: 94 GIIPMFGTSNYAQQFQG VH CDR3 SEQ ID NO: 95 GGARYYYMDV VH FW1 SEQ ID NO: 96 QVQLVQSGAEVKKPGSSVKVSCKASGDTFR VH FW2 SEQ ID NO: 97 WVRQAPGQGLEWVG VH FW3 SEQ ID NO: 98 KVTITADESTSTAYMELSSLRSEDTAVYYCAR VH FW4 SEQ ID NO: 99 WGRGTMVTVSS DNA encoding SEQ ID NO: 100 tcgtctgagctgactcaggaccctgctgtgtctgtggccttgggacagaca VL region gtcaggatcacatgccaaggagacagcctcagaagctattatgcaagct ggtaccagcagaagccaggacaggcccctgtacttgtcatctatggtaaa aacaaccggccctcagggatcccagaccgattctctggctccagctcag gaaacacagcttccttgaccatcactggggctcaggcggaagatgaggctgactattactgtaactcccgggacagcagtggtaaccatgtggtattcggc ggagggaccaagctgaccgtccta VL entire SEQ ID NO: 101 SSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQ QKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASL TITGAQAEDEADYYCNSRDSSGNHVVFGGGTKLTVL VL CDR1 SEQ ID NO: 102 QGDSLRSYYAS VL CDR2 SEQ ID NO: 103 GKNNRPS VL CDR3 SEQ ID NO: 104 NSRDSSGNHVV VL FW1 SEQ ID NO: 105 SSELTQDPAVSVALGQTVRITC VL FW2 SEQ ID NO: 106 WYQQKPGQAPVLVIY VL FW3 SEQ ID NO: 107 GIPDRFSGSSSGNTASLTITGAQAEDEADYYC VL FW4 SEQ ID NO: 108 FGGGTKLTVL Bbbt0732 DNA encoding SEQ ID NO: 109 gaggtgcagctgttggagtctgggggaggcttggtacagcctggggggtc VH region cctgagactctcctgtgcagcctctggattcacctttagcagctatgccatga gctgggtccgccaggctccagggaaggggctggagtgggtctcagctatt agtggtagtggtggtagcacatactacgcagactccgtgaagggccggtt caccatctccagagacaattccaagaacacgctgtatctgcaaatgaaca gcctgagagccgaggacacggccgtgtattactgtgcgaaacgtcggag ggactactactacgatatggacgtctggggccaagggacaatggtcacc gtctcgagt VH entire SEQ ID NO: 110 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMS WVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTIS RDNSKNTLYLQMNSLRAEDTAVYYCAKRRRDYYYD MDVWGQGTMVTVSS VH CDR1 SEQ ID NO: 111 SYAMS VH CDR2 SEQ ID NO: 112 AISGSGGSTYYADSVKG VH CDR3 SEQ ID NO: 113 RRRDYYYDMDV VH FW1 SEQ ID NO: 114 EVQLLESGGGLVQPGGSLRLSCAASGFTFS VH FW2 SEQ ID NO: 115 WVRQAPGKGLEWVS VH FW3 SEQ ID NO: 116 RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK VH FW4 SEQ ID NO: 117 WGQGTMVTVSS DNA encoding SEQ ID NO: 118 tcttctgagctgactcaggaccctgctgtgtctgtggccttgggacagacag VL region tcaggatcacatgccaaggagacagcctcagaacctattatgcaagctg gtaccagcacaagccaggacaggcccctgtacttgtcatgtatggtaaag ataaccgaccctcagggatcccagaccgattctctggctccagctcagga accacagcttccttgaccatcactggggctcaggcggaagatgaggctg actattactgtaactcccgggacagcagtggtcaccctgtggtattcggcg gagggaccaagctgaccgtccta VL entire SEQ ID NO: 119 SSELTQDPAVSVALGQTVRITCQGDSLRTYYASWYQ HKPGQAPVLVMYGKDNRPSGIPDRFSGSSSGTTASL TITGAQAEDEADYYCNSRDSSGHPVVFGGGTKLTVL VL CDR1 SEQ ID NO: 120 QGDSLRTYYAS VL CDR2 SEQ ID NO: 121 GKDNRPS VL CDR3 SEQ ID NO: 122 NSRDSSGHPVV VL FW1 SEQ ID NO: 123 SSELTQDPAVSVALGQTVRITC VL FW2 SEQ ID NO: 124 WYQHKPGQAPVLVMY VL FW3 SEQ ID NO: 125 GIPDRFSGSSSGTTASLTITGAQAEDEADYYC VL FW4 SEQ ID NO: 126 FGGGTKLTVL Bbbt0754 DNA encoding SEQ ID NO: 127 gaggtgcagctgttggagtctgggggaggcttggtacagcctggggggtc VH region cctgagactctcctgtgcagcctctggattcaaaattacccactatactatgg gctgggtccgccaggctccagggaaggggctggagtgggtctcacgcat cacgtggggcggtgacaacaccttttactccaactccgtgaggggccggtt caccatctccagagacaattccaagaacacgctgtatctgcaaatgaaca gcctgagagccgaggacacggccgtatattactgtgcaacagggacgtt cggggagttattccccgactactttaagtattggggccgggggacaatggt caccgtctcgagt VH entire SEQ ID NO: 128 EVQLLESGGGLVQPGGSLRLSCAASGFKITHYTMG WVRQAPGKGLEWVSRITWGGDNTFYSNSVRGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATGTFGELFP DYFKYWGRGTMVTVSS VH CDR1 SEQ ID NO: 129 HYTMG VH CDR2 SEQ ID NO: 130 RITWGGDNTFYSNSVRG VH CDR3 SEQ ID NO: 131 GTFGELFPDYFKY VH FW1 SEQ ID NO: 132 EVQLLESGGGLVQPGGSLRLSCAASGFKIT VH FW2 SEQ ID NO: 133 WVRQAPGKGLEWVS VH FW3 SEQ ID NO: 134 RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAT VH FW4 SEQ ID NO: 135 WGRGTMVTVSS DNA encoding SEQ ID NO: 136 caggctgtgctgactcagccgtcctcagtgtctggggccccagggcagag VL region ggtcaccatcccctgcactgggagcagctccaacatcggggcaggttatg atgtaaactggtaccagcagcttccaggaacagcccccaaactcctcatc tttcataacaacattcggccctcaggggtccctgaccgattctctggctcca agtctggcacctcagtctccctggccatcactgggctccaggctgaggatg aggctgattattactgccagtcctatgacagcagcctgagtgcttgggtcttc ggcggagggaccaaggtcaccgtccta VL entire SEQ ID NO: 137 QAVLTQPSSVSGAPGQRVTIPCTGSSSNIGAGYDVN WYQQLPGTAPKLLIFHNNIRPSGVPDRFSGSKSGTS VSLAITGLQAEDEADYYCQSYDSSLSAWVFGGGTKV TVL VL CDR1 SEQ ID NO: 138 TGSSSNIGAGYDVN VL CDR2 SEQ ID NO: 139 HNNIRPS VL CDR3 SEQ ID NO: 140 QSYDSSLSAWV VL FW1 SEQ ID NO: 141 QAVLTQPSSVSGAPGQRVTIPC VL FW2 SEQ ID NO: 142 WYQQLPGTAPKLLIF VL FW3 SEQ ID NO: 143 GVPDRFSGSKSGTSVSLAITGLQAEDEADYYC VL FW4 SEQ ID NO: 144 FGGGTKVTVL Bbbt0674 DNA encoding SEQ ID NO: 145 gaggtgcagctgttggagtctgggggaggcttggtacagcctggggggtc VH region cctgagactctcctgtgcagcctctggattcaaaattacccactatactatgg gctgggtccgccaggctccagggaaggggctggagtgggtctcacgcat cacgtggggcggtgacaacaccttttactccaactccgtgaagggccggtt caccatctccagagacaattccaagaacacgctgtatctgcaaatgaaca gcctgagagccgaggacacggccgtatattactgtgcgaaagagactac gaacctctaccactactacggtatgaacgactggggccggggcaccctg gtcaccgtctcgagt VH entire SEQ ID NO: 146 EVQLLESGGGLVQPGGSLRLSCAASGFKITHYTMG WVRQAPGKGLEWVSRITWGGDNTFYSNSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCAKETTNLYHY YGMNDWGRGTLVTVSS VH CDR1 SEQ ID NO: 147 HYTMG VH CDR2 SEQ ID NO: 148 RITWGGDNTFYSNSVKG VH CDR3 SEQ ID NO: 149 ETTNLYHYYGMND VH FW1 SEQ ID NO: 150 EVQLLESGGGLVQPGGSLRLSCAASGFKIT VH FW2 SEQ ID NO: 151 WVRQAPGKGLEWVS VH FW3 SEQ ID NO: 152 RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK VH FW4 SEQ ID NO: 153 WGRGTLVTVSS DNA encoding SEQ ID NO: 154 cagtctgtgttgacgcagccgccctcagtgtctgggacccccgggcagag VL region ggtcaccatctcttgttatggaagcagctccgacatcggcaataatttcgttt actggtaccaacaagtcccaggaatggcccccaaactcctcatctacag gagtcatcagcggccctcaggggtctctgaccgattttcaggctccaagtct ggcacctcagcctccctggccatcagtggactccggtccgaggatgagg ctgattattactgtgcaacatggggtgacaatctgcgtggttgggttttcggc ggagggaccaagctgaccgtccta VL entire SEQ ID NO: 155 QSVLTQPPSVSGTPGQRVTISCYGSSSDIGNNFVYW YQQVPGMAPKLLIYRSHQRPSGVSDRFSGSKSGTS ASLAISGLRSEDEADYYCATWGDNLRGWVFGGGTK LTVLVL CDR1 SEQ ID NO: 156 YGSSSDIGNNFVY VL CDR2 SEQ ID NO: 157 RSHQRPS VL CDR3 SEQ ID NO: 158 ATWGDNLRGWV VL FW1 SEQ ID NO: 159 QSVLTQPPSVSGTPGQRVTISC VL FW2 SEQ ID NO: 160 WYQQVPGMAPKLLIY VL FW3 SEQ ID NO: 161 GVSDRFSGSKSGTSASLAISGLRSEDEADYYC VL FW4 SEQ ID NO: 162 FGGGTKLTVL Bbbt0755 DNA encoding SEQ ID NO: 163 gaggtgcagctgttggagtctgggggaggcttggtacagcctggggggtc VH region cctgagactctcctgtgcagcctctggattcacctttagcagctatgccatga gctgggtccgccaggctccagggaaggggctggagtgggtctcacgcat cacgtggggcggtgacaacaccttttactccaactccgtgaagggccggtt caccatctccagagacaattccaagaacacgctgtatctgcaaatgaaca gcctgagagccgaggacacggccgtatattactgtgccagtcattatggtg gctggatttcactctttgaccactgggggcaggggaccacggtcaccgtct cgagt VH entire SEQ ID NO: 164 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMS WVRQAPGKGLEWVSRITWGGDNTFYSNSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCASHYGGWISL FDHWGQGTTVTVSS VH CDR1 SEQ ID NO: 165 SYAMS VH CDR2 SEQ ID NO: 166 RITWGGDNTFYSNSVKG VH CDR3 SEQ ID NO: 167 HYGGWISLFDH VH FW1 SEQ ID NO: 168 EVQLLESGGGLVQPGGSLRLSCAASGFTFS VH FW2 SEQ ID NO: 169 WVRQAPGKGLEWVS VH FW3 SEQ ID NO: 170 RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAS VH FW4 SEQ ID NO: 171 WGQGTTVTVSS DNA encoding SEQ ID NO: 172 caggctgtgctgactcagccgtcctcaatttctggggccccagggcagag VL region ggtcaccatctcctgcactgggaccagctccaacatcggggcaggtaatg ctgtacactggtaccagcagcttccaggaacagcccccagactcctcatct tcgctgacaaccgtcggccctcaggggtccctgaccgattctccgcctcca agtctgccacctcagcctccctggccatcactgggctccaggttgacgatg aggctgagtattactgccagtcgtatgacaccaggctgcgtgtggtattcgg cggggggaccaaggtcaccgtccta VL entire SEQ ID NO: 173 QAVLTQPSSISGAPGQRVTISCTGTSSNIGAGNAVH WYQQLPGTAPRLLIFADNRRPSGVPDRFSASKSATS ASLAITGLQVDDEAEYYCQSYDTRLRVVFGGGTKVT VL VL CDR1 SEQ ID NO: 174 TGTSSNIGAGNAVH VL CDR2 SEQ ID NO: 175 ADNRRPS VL CDR3 SEQ ID NO: 176 QSYDTRLRVV VL FW1 SEQ ID NO: 177 QAVLTQPSSISGAPGQRVTISC VL FW2 SEQ ID NO: 178 WYQQLPGTAPRLLIF VL FW3 SEQ ID NO: 179 GVPDRFSASKSATSASLAITGLQVDDEAEYYC VL FW4 SEQ ID NO: 180 FGGGTKVTVL Bbbt0643 DNA encoding SEQ ID NO: 181 gaggtgcagctgcaggagtctgggggaggcttggtacagcctggggggt VH region ccctgagactctcctgtgcagcctctggattcaaaattacccactatactatg ggctgggtccgccaggctccagggaaggggctggagtgggtctcagcta ttagtggtagtggtggtagcacatactacgcagactccgtgaagggccggt tcaccatctccagagacaattccaagaacacgctgtatctgcaaatgaac agcctgagagccgaggacacggccgtgtattactgtgcgagagggggtg ggactatatcagctcggttcgacccctgggggcaagggaccacggtcac cgtctcgagt VH entire SEQ ID NO: 182 EVQLQESGGGLVQPGGSLRLSCAASGFKITHYTMG WVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTIS RDNSKNTLYLQMNSLRAEDTAVYYCARGGGTISARF DPWGQGTTVTVSS VH CDR1 SEQ ID NO: 183 HYTMGVH CDR2 SEQ ID NO: 184 AISGSGGSTYYADSVKG VH CDR3 SEQ ID NO: 185 GGGTISARFDP VH FW1 SEQ ID NO: 186 EVQLQESGGGLVQPGGSLRLSCAASGFKIT VH FW2 SEQ ID NO: 187 WVRQAPGKGLEWVS VH FW3 SEQ ID NO: 188 RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR VH FW4 SEQ ID NO: 189 WGQGTTVTVSS DNA encoding SEQ ID NO: 190 tcttctgagctgactcaggaccctgctgtgtctgtggccttgggacagacag VL region tcaggatcacatgccaaggagacagcctcagaagctattatgcaagctg gtaccagcagaagccaggacaggcccctgtacttgtcatctatggtaaaa acaaccggccctcagggatcccagaccgattctctggctccagctcagg aaacacagcttccttgaccatcactggggctcaggcggaagatgaggct gactattactgtaactcccgggacagcagtggtaaccatgtggtattcggc ggagggaccaagctgaccgtccta VL entire SEQ ID NO: 191 SSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQ QKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASL TITGAQAEDEADYYCNSRDSSGNHVVFGGGTKLTVL VL CDR1 SEQ ID NO: 192 QGDSLRSYYAS VL CDR2 SEQ ID NO: 193 GKNNRPS VL CDR3 SEQ ID NO: 194 NSRDSSGNHVV VL FW1 SEQ ID NO: 195 SSELTQDPAVSVALGQTVRITC VL FW2 SEQ ID NO: 196 WYQQKPGQAPVLVIY VL FW3 SEQ ID NO: 197 GIPDRFSGSSSGNTASLTITGAQAEDEADYYC VL FW4 SEQ ID NO: 198 FGGGTKLTVL Bbbt0341 DNA encoding SEQ ID NO: 199 gaagttcaactgcaggcgtccggcggtggcctggtgcaggctggcggct VH region ctctgcgtctgtcctgtgctgccagcggctttaaaatcactcactatactatgg gctggttccgccaggcaccgggcaaagagcgtgaattcgtgagccgcat cacctggggcggtgacaacaccttttactccaactccgttaagggtcgtttta ctatctctcgtgataacgctaaaaacaccgtttacctgcagatgaacagcct gaaaccagaggacactgctgactactattgtgctgcaggttccgcctctac ggctgacccactgcgcgtcgactattggggcaaaggcacccaggtgacc gtttcttcc VH entire SEQ ID NO: 200 EVQLQASGGGLVQAGGSLRLSCAASGFKITHYTMG WFRQAPGKEREFVSRITWGGDNTFYSNSVKGRFTIS RDNAKNTVYLQMNSLKPEDTADYYCAAGSASTADPL RVDYWGKGTQVTVSS VH CDR1 SEQ ID NO: 201 HYTMG VH CDR2 SEQ ID NO: 202 RITWGGDNTFYSNSVKG VH CDR3 SEQ ID NO: 203 GSASTADPLRVDY VH FW1 SEQ ID NO: 204 EVQLQASGGGLVQAGGSLRLSCAASGFKIT VH FW2 SEQ ID NO: 205 WFRQAPGKEREFVS VH FW3 SEQ ID NO: 206 RFTISRDNAKNTVYLQMNSLKPEDTADYYCAA VH FW4 SEQ ID NO: 207 WGKGTQVTVSS Bbbt0579 DNA encoding SEQ ID NO: 208 ggggtgcagctggtgcagtctgggggaggcgtggtccagcctgggaggt VH region ccctgagactctcctgtgcagcctctggattcaccttcagtagctatgctatg cactgggtccgccaggctccaggcaaggggctggagtgggtggcagtta tatcatatgatggaagcaataaatactacgcagactccgtgaagggccga ttcaccatctccagagacaattccaagaacacgctgtatctgcaaatgaac agcctgagagctgaggacacggctgtgtattactgtgcgagagatgatatt gtagtagtaccagctgctaatgcgaactactactactactacatggacgtct ggggccaaggaaccacagtcaccgtctcctca VH entire SEQ ID NO: 209 GVQLVQSGGGVVQPGRSLRLSCAASGFTFSSYAMH WVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTIS RDNSKNTLYLQMNSLRAEDTAVYYCARDDIVVVPAA NANYYYYYMDVWGQGTTVTVSS VH CDR1 SEQ ID NO: 210 SYAMH VH CDR2 SEQ ID NO: 211 VISYDGSNKYYADSVKG VH CDR3 SEQ ID NO: 212 DDIVVVPAANANYYYYYMDVVH FW1 SEQ ID NO: 213 GVQLVQSGGGVVQPGRSLRLSCAASGFTFS VH FW2 SEQ ID NO: 214 WVRQAPGKGLEWVA VH FW3 SEQ ID NO: 215 RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR VH FW4 SEQ ID NO: 216 WGQGTTVTVSS DNA encoding SEQ ID NO: 217 gacatccagatgacccagtctccatccttcctgtctgcatctgtaggagaca VL region gagtcaccatcacttgccgggccagtcagggcattaacaattatttagcct ggtatcagcaaaaaccagggagagcccctaagctcctgatctacgctgc atccagtttacaaagtggggtcccatcaaggttcagcggcagtggatctgg cacagatttcactctcaccatcagcagcctgcagcctgaagattttgcaact tattactgtctccaagattccgattatcccctcactttcggcggagggaccaa gctggagatcaaa VL entire SEQ ID NO: 218 DIQMTQSPSFLSASVGDRVTITCRASQGINNYLAWY QQKPGRAPKLLIYAASSLQSGVPSRFSGSGSGTDFT LTISSLQPEDFATYYCLQDSDYPLTFGGGTKLEIK VL CDR1 SEQ ID NO: 219 RASQGINNYLA VL CDR2 SEQ ID NO: 220 AASSLQS VL CDR3 SEQ ID NO: 221 LQDSDYPLT VL FW1 SEQ ID NO: 222 DIQMTQSPSFLSASVGDRVTITC VL FW2 SEQ ID NO: 223 WYQQKPGRAPKLLIY VL FW3 SEQ ID NO: 224 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC VL FW4 SEQ ID NO: 225 FGGGTKLEIK Bbbt0671 VH entire SEQ ID NO: 226 EVHLLESGGGLVQPGGSLRLSCAASGFTFSSYAMS WVRQAPGKGLEWVSAISGSGGSTYYAHSVKGRFTIS RDNSKNTLYLQMNSLRAEDTAVYYCAKNYYYDTSAY YYVGSDYFDYWGQGTMVTVSS VL entire SEQ ID NO: 227 QSALTQPASVSGSPGQSITISCTATSSNVGAYNFVS WYQQHPGKAPKVLIYRVSNRPSGVSNRFSGSKSGN TASLTISGLQADEEADYYCSSYTTDYIWVFGGGTKLT VL

[0044] Numerous specific IgG constant domain substitutions capable of increasing or decreasing half- life are known in the art. For example, the substitutions 252Y, 254T, 256E, and combinations thereof, as numbered by the EU index as set forth in Kabat have been shown to increase half-life (see, e.g., US 7,083,784). Substitutions at residues 250, 252, 254, 256, 257, 309, 311, 428, 433, 434 and combinations thereof have also been reported to alter half-life (see, e.g., U.S. Patent Nos. 6,277,375, 7,083,784; 7,217,797, 8,088,376; US2002 / 0147311; US2007 / 0148164; WO9823289 and WO09058492). Similarly, IgG constant domain substitutions capable of increasing or decreasing effector functions have been described in the art. For example, the substitutions 239S and / or 332E, as numbered by the EU index as set forth in Kabat have been shown to increase ADCC activity (see, e.g., WO2004099249, US7,317,091), while the substitutions 234F, 235E, 235F, 235Q, 235Y, 239A, 332Q, 331S, 332Q and combinations thereof, as numbered by the EU index as set forth in Kabat have been shown to decrease ADCC. Numerous other substitutions which alter effector function (increase or decrease) can be used, for example, see the mutations described in WO8807089, WO9958572, WO9951642, WO2012175751, WO2011149999, WO2011066501, WO2000042072, WO2011120134.

[0045] In certain embodiments, a transporter molecule as provided herein comprises an antibody scFv fragment, where the scFv comprises a VH domain or region and a VL domain or region, fused to each other either directly or via a linker, e.g., a flexible linker. The VH and VL in a scFv can be arranged such that the VH is at the N terminus and the VL is at the C terminus, or vice versa. Wherethe VH and VL are fused via a linker, the scFv can comprise, from the amino terminus: VH-L-VL, wherein L is the linker, or VL-L-VH, where L is the linker.

[0046] Various linkers suitable for preparing scFvs are known to the person of ordinary skill in the art. Some non-limiting examples include the linker (Gly4Ser)n, where n is a positive integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 (SEQ ID NO: 263-272), Ser(Gly4Ser)n, where n is a positive integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 (SEQ ID NO: 273-282), GGGGSGGGGSGGGGS (SEQ ID NO: 230), GGGGSGGGGSGGGG (SEQ ID NO: 228), GGGGSGGGGSGGGGSAL (SEQ ID NO: 229), or GGGGSGGGGSGGGGSA (SEQ ID NO: 233).

[0047] An overview of sequence information for the different Bbbt clones is provided in Table 2: Bbbt sequences. Table 2: Sequence information for the different Bbbt clones. Description SEQ ID NO: Sequence linker SEQ ID NO: 228 GGGGSGGGGSGGGG linker SEQ ID NO: 229 GGGGSGGGGSGGGGSAL linker SEQ ID NO: 230 GGGGSGGGGSGGGGS linker SEQ ID NO: 233 GGGGSGGGGSGGGGSA 4.4 Delivery device

[0048] The inhibitor of type I IFN mediated signalling, such as an IFNAR1 inhibitor comprising a BBB transporter,may be delivered via an injection device. The inhibitor of type I IFN mediated signalling, such as an IFNAR1 inhibitor comprising a BBB transporter, may be administered subcutaneously using an accessorized pre-filled syringe (APFS), an autoinjector (AI), or a combination thereof. Such devices have been found to be well-tolerated and reliable for administering subcutaneous doses of an antibody and provide further options for optimizing patient care. Indeed, such devices may reduce the burden of frequent clinic visits for patients. An example of a suitable APFS device is described in Ferguson et. al.3, which is incorporated herein by reference in its entirety. The inhibitor of type I IFN mediated signalling may be delivered subcutaneously (SC) or intravenously (IV). The delivery device may be single use, disposable system that is designed to enable manual, SC or IV administration of the dose.

[0049] The invention also relates to an injection device comprising the pharmaceutical composition of the invention. The injection device may be a pre-filled syringe (PFS). The injection device may be an accessorized pre-filed syringe (AFPS). The injection device may be an auto-injector. 4.5 Kit

[0050] The invention also relates to a kit comprising the pharmaceutical composition of the invention or the injection device of the invention and instructions for use. The instructions for use may specify that the injection device and / or pharmaceutical composition are for use in the treatment of neurodegenerative diseases, e.g. ALS or Alzheimer’s Disease. The instructions for use may specify that the injection device and / or pharmaceutical composition are for treating a neurodegenerativedisease in a patient. The instructions for use may specify any features of the method of the invention or the pharmaceutical composition of the invention. The kit may comprise packaging, wherein the packaging is adapted to hold the injection device and the instructions for use. The instructions for use may be attached to the injection device. 4.6 Type I IFN gene signature (IFNGS)

[0051] The patient may have high interferon gene signature expression compared to a healthy subject, or a subject that is not suffering from a type I IFN mediated disease. The type I interferon gene signature may comprise elevated expression of the genes Interferon Alpha Inducible Protein 27 (IFI27), Interferon Induced Protein 44 (IFI44) interferon induced protein 44 like (IFI44L), and Radical S-Adenosyl Methionine Domain Containing 2 (RSAD2), compared to expression levels in a healthy subject, or a subject that is not suffering from a type I IFN mediated disease. The high interferon gene signature expression may be determined by an increased expression of IFI27, IFI44, IFI44L, and RSAD2 relative to expression of one or more control genes.

[0052] In some embodiments, the disclosure provides a method of treating a cardiometabolic disease in a patient comprising administering to the patient a therapeutically effective amount of a type I interferon receptor inhibitor, wherein the patient has high interferon gene signature expression.

[0053] Direct measurement of type I interferon (IFN) remains a challenge. As such, an IFN gene signature (IFNGS) is used to identify patients with low or high levels of IFN inducible gene expression. In some embodiments, the IFNGS comprises Interferon Alpha Inducible Protein 27 (IFI27), Interferon Induced Protein 44 (IFI44) interferon induced protein 44 like (IFI44L), and Radical S-Adenosyl Methionine Domain Containing 2 (RSAD2). Up regulation or overexpression of the genes comprising the IFNGS can be calculated by well-known methods in the art. For example, the overexpression of the signature is calculated as the difference between the mean Ct (cycle threshold) for IFI27, IFI44, IFI44L, and RSAD2 and the mean Ct of three control genes; 18S, ACTB and GAPDH. The degree of increased expression of the IFNGS permits the identification of a fold change cutoff for identifying IFN–high and IFN–low patients. In one embodiment, the cutoff is at least about 2. In another embodiment, the cutoff is at least about 2.5. In another embodiment, the cutoff is at least about 3. In another embodiment, the cutoff is at least about 3.5. In another embodiment, the cutoff is at least about 4. In another embodiment, the cutoff is at least about 4.5. In another embodiment, the cutoff is chosen from at least 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, and 4.5. In another embodiment the cutoff is between about 2 and about 8. The degree of increased expression of the IFNGS also permits the identification of a delta Ct cutoff for identifying IFN–high and IFN–low subpopulations.

[0054] Type I IFN is considered to play a central role SLE disease pathogenesis and inhibition of this pathway is targeted by Anifrolumab. To understand the relationship between type I IFN expression and response to anti-IFN therapy, it is necessary to know if a subject’s disease is driven by type I IFN activation. However, direct measurement of type I IFN remains a challenge. As such, a transcript-based marker was developed to evaluate the effect of over expression of the targetprotein on a specific set of mRNA markers. The expression of these markers is easily detected in whole blood and demonstrates a correlation with expression in diseased tissue such as skin in SLE. The bimodal distribution of the transcript scores for SLE subjects supports defining an IFN test high and low subpopulation . The type I IFN test is described in WO2011028933 A1, which is incorporated herein by reference in its entirety. The type I IFN gene signature may be used to identify a subject that has a type I IFN gene signature (IFNGS)-test high patient or an IFNGS-test low patient. The IFNGS test measures expression of the genes IFI27, IFI44, IFI44L, and RSAD2 compared with 3 reference genes; 18S, ACTB and GAPDH in the whole blood of the subject. The result of the test is a score that is compared with a pre-established cut-off that classifies patients into 2 groups with low or high levels of IFN inducible gene expression .

[0055] The expression of the genes may be measured by RT-PCR. Suitable primers and probes for detection of the genes may be found in WO2011028933. A suitable kit for measuring gene expression for the IFNGS test is the QIAGEN therascreen®IFIGx RGQ RT-PCR kit (IFIGx kit), as described in Brohawn et al.4, which is incorporated herein by reference in its entirety. 4.7 The patient

[0056] The terms “patient” and “subject” are used herein interchangeably to refer to an animal, such as a mammal, that has been or will be the object of treatment, observation, or experiment. The methods described herein may be useful for both human therapy and veterinary applications. The patient may be a human patient. The patient may be an adult. The patient may be a patient with an elevated type I IFN gene signature. The patient may be a type I interferon stimulated gene signature (IFNGS)-test high patient pre-administration with the dose or unit dose. The patient may have elevated of the genes IFI27, IFI44, IFI44L, and RSAD2 in the whole blood. The method may comprise identifying the patient as IFNGS-test high patient pre-treatment with the dose or unit dose. The method may comprise measuring the expression of the genes IFI27, IFI44, IFI44L, and RSAD2 in the whole blood of the patient. The method may comprise measuring the expression of the genes IFI27, IFI44, IFI44L, and RSAD2 in the whole blood of the subject by RT-PCR, as described in WO2022 / 223714 and WO2013 / 188494, which is incorporated herein by reference in its entirety. 4.8 Formulation

[0057] The inhibitor of type I IFN signalling may be comprised within a pharmaceutical composition. In accordance with the invention, the inhibitor of type I IFN signalling may be administered in the form of a pharmaceutical composition. Suitable pharmaceutical compositions may comprise an inhibitor of type I IFN signalling as defined anywhere herein together with a pharmaceutically acceptable excipient. Accordingly the invention provides a pharmaceutical composition suitable for use in a method of the invention, comprising an inhibitor of type I IFN signalling as defined anywhere herein together with a pharmaceutically acceptable excipient.

[0058] The phrase “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial agents and antifungal agents, isotonic agents, and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. Thecompositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions. The pharmaceutical compositions may also be included in a container, pack, or dispenser together with instructions for administration. A pharmaceutical composition as disclosed herein is formulated to be compatible with its intended route of administration. The administration may, for example, be intravenous, intraperitoneal, intramuscular, intracavity, subcutaneous, intradermal or transdermal.

[0059] Pharmaceutical compositions as disclosed herein may be formulated for, but not limited to parenteral delivery, for example intramuscular, subcutaneous or intravenous. Compositions suitable for intramuscular, subcutaneous or intravenous injection include sterile aqueous solutions.

[0060] The pharmaceutical composition may take the form of an aqueous solution and may include physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiologically buffered saline. The pharmaceutical composition may additionally or alternatively contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. The pharmaceutical composition may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Optionally, the pharmaceutical composition may contain suitable stabilisers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0061] Stable formulations suitable for administration to subjects and comprising Anifrolumab are described in detail in US patent 10125195 B1, which is incorporated herein in its in entirety. 5 DEFINITIONS 5.1 Type I IFN inhibitors 5.2 Anifrolumab

[0062] The inhibitor of type I IFN mediated signalling or IFNAR1 inhibitor may be Anifrolumab or a functional variant thereof.

[0063] Anifrolumab (MEDI-546, anifro, ANI) is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody (mAb) directed against subunit 1 of the type I interferon receptor (IFNAR1). Anifrolumab downregulates IFNAR1 signaling and suppresses expression of IFN-inducible genes. Disclosures related to Anifrolumab can be found in U.S. Patent No. 7662381 and U.S. Patent No. 9988459, which are incorporated herein by reference in their entirety. Sequence information for Anifrolumab is provided inTable 3. The inhibitor of type I IFN mediated signalling or IFNAR1 inhibitor may comprise any one or more of the sequences provided in Table 3. The inhibitor of type I IFN mediated signalling or IFNAR1 inhibitor may have any one or more properties or characteristics of Anifrolumab as described herein. Table 3: Sequence information for AnifrolumabSEQ Description Sequence ID 234 EVQLVQSGAEVKKPGESLKISCKGSGYIFTNYWIAWVRQMPGKGLES Anifrolumab VH MGIIYPGDSDIRYSPSFQGQVTISADKSITTAYLQWSSLKASDTAMYY CARHDIEGFDYWGRGTLVTVSS 235 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSFFAWYQQKPGQAPRL Anifrolumab VL LIYGASSRATGIPDRLSGSGSGTDFTLTITRLEPEDFAVYYCQQYDSS AITFGQGTRLEIKHCDR1236NYWIAHCDR2237IIYPGDSDIRYSPSFQGHCDR3238HDIEGFDYLCDR1239RASQSVSSSFFALCDR2240GASSRATLCDR3241QQYDSSAIT242 RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL Light chain QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL constant region SSPVTKSFNRGEC 243 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPE Heavy chain VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS constant region VLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLP PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK 244 EVQLVQSGAEVKKPGESLKISCKGSGYIFTNYWIAWVRQMPGKGLES MGIIYPGDSDIRYSPSFQGQVTISADKSITTAYLQWSSLKASDTAMYY CARHDIEGFDYWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAAL GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP SSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEG Heavy chain GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP ASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNHYTQKS LSLSPGK 245 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSFFAWYQQKPGQAPRL Light chain LIYGASSRATGIPDRLSGSGSGTDFTLTITRLEPEDFAVYYCQQYDSS AITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KVYACEVTHQGLSSPVTKSFNRGEC

[0064] Anifrolumab is a human immunoglobulin G1 kappa monoclonal antibody that binds to subunit 1 of the type I interferon receptor (IFNAR1) with high specificity and affinity. This binding inhibits type I IFN signaling thereby blocking the biologic activity of type I IFNs. Anifrolumab also induces the internalization of IFNAR1, thereby reducing the levels of cell surface IFNAR1 available for receptor assembly. Blockade of receptor mediated type I IFN signaling inhibits IFN responsive gene expression as well as downstream inflammatory and immunological processes.

[0065] Anifrolumab is an immunoglobulin comprising an HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 236, SEQ ID NO: 237, and SEQ ID NO: 238, respectively (or functional variant thereof); and an LCDR1, LCDR2 and LCDR3 of SEQ ID NO: 239, SEQ ID NO: 240, and SEQ ID NO: 241, respectively (or functional variant thereof). Anifrolumab is an immunoglobulin comprising a VH of SEQ ID NO: 234 and a VL of SEQ ID NO: 235.

[0066] The constant region of Anifrolumab has been modified such that Anifrolumab exhibits reduced affinity for at least one Fc ligand compared to an unmodified antibody. Anifrolumab is a modified IgG class monoclonal antibody specific for IFNAR1 comprising in the Fc region an amino acid substitution of L234F, as numbered by the EU index as set forth in Kabat (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Va.). Anifrolumab is a modified IgG class monoclonal antibody specific for IFNAR1 comprising in the Fc region an amino acid substitution of L234F, L235E and / or P331S, as numbered by the EU index as set forth in Kabat (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Va.). Anifrolumab is an antibody comprising a light chain constant region of SEQ ID NO: 242. Anifrolumab is an antibody comprising a heavy chain constant region of SEQ ID NO: 243. Anifrolumab is an antibody comprising a light chain constant region of SEQ ID NO: 242 and a heavy chain constant region of SEQ ID NO: 243. Anifrolumab is an antibody comprising a heavy chain of SEQ ID NO: 244. Anifrolumab is an antibody comprising a light chain of SEQ ID NO: 245. Anifrolumab is an antibody comprising a heavy chain of SEQ ID NO: 244 and a light chain of SEQ ID NO: 245.

[0067] The inhibitor of type I IFN mediated signalling or IFNAR1 inhibitor may be a functional variant of Anifrolumab. Functional variants of Anifrolumab are sequence variants that perform the same function as Anifrolumab. Functional variants of Anifrolumab are variants that bind the same target as Anifrolumab and have the same effector function as Anifrolumab. Functional Anifrolumab variants include antigen-binding fragments of Anifrolumab and antibody and immunoglobulin derivatives of Anifrolumab. Functional variants include biosimilars and interchangeable products. The terms biosimilar and interchangeable product are defined by the FDA and EMA. The term biosimilar refers to a biological product that is highly similar to an approved (e.g. FDA approved) biological product (reference product, e.g. Anifrolumab) in terms of structure and has no clinically meaningful differences in terms of pharmacokinetics, safety and efficacy from the referenceproduct. The presence of clinically meaningful differences of a biosimilar may be assessed in human pharmacokinetic (exposure) and pharmacodynamic (response) studies and an assessment of clinical immunogenicity. An interchangeable product is a biosimilar that is expected to produce the same clinical result as the reference product in any given patient.

[0068] For example, a variant of the reference (Anifrolumab) antibody may comprise: a heavy chain CDR1 having at most 2 amino acid differences when compared to SEQ ID NO: 236; a heavy chain CDR2 having at most 2 amino acid differences when compared to SEQ ID NO: 237; a heavy chain CDR3 having at most 2 amino acid differences when compared to SEQ ID NO: 238; a light chain CDR1 having at most 2 amino acid differences when compared to SEQ ID NO: 239; a light chain CDR2 having at most 2 amino acid differences when compared to SEQ ID NO: 240; and a light chain CDR3 having at most 2 amino acid differences when compared to SEQ ID NO: 241; wherein the variant antibody binds to the target of Anifrolumab (e.g. IFNAR) and preferably with the same affinity.

[0069] A variant of the reference (Anifrolumab) antibody may comprise: a heavy chain CDR1 having at most 1 amino acid difference when compared to SEQ ID NO: 236; a heavy chain CDR2 having at most 1 amino acid difference when compared to SEQ ID NO: 237; a heavy chain CDR3 having at most 1 amino acid difference when compared to SEQ ID NO: 238; a light chain CDR1 having at most 1 amino acid differences when compared to SEQ ID NO: 239; a light chain CDR2 having at most 1 amino acid difference when compared to SEQ ID NO: 240; and a light chain CDR3 having at most 1 amino acid difference when compared to SEQ ID NO: 241; wherein the variant antibody binds to the target of Anifrolumab (e.g. IFNAR) optionally with the same affinity.

[0070] A variant antibody may have at most 5, 4 or 3 amino acid differences total in the CDRs thereof when compared to a corresponding reference (Anifrolumab) antibody, with the proviso that there is at most 2 (optionally at most 1) amino acid differences per CDR. A variant antibody may have at most 2 (optionally at most 1) amino acid differences total in the CDRs thereof when compared to a corresponding reference (Anifrolumab) antibody, with the proviso that there is at most 2 amino acid differences per CDR. A variant antibody may have at most 2 (optionally at most 1) amino acid differences total in the CDRs thereof when compared to a corresponding reference (Anifrolumab) antibody, with the proviso that there is at most 1 amino acid difference per CDR.

[0071] A variant antibody may have at most 5, 4 or 3 amino acid differences total in the framework regions thereof when compared to a corresponding reference (Anifrolumab) antibody, with the proviso that there is at most 2 (optionally at most 1) amino acid differences per framework region. Optionally a variant antibody has at most 2 (optionally at most 1) amino acid differences total in the framework regions thereof when compared to a corresponding reference (Anifrolumab) antibody, with the proviso that there is at most 2 amino acid differences per framework region. Optionally a variant antibody has at most 2 (optionally at most 1) amino acid differences total in the framework regions thereof when compared to a corresponding reference (Anifrolumab) antibody, with the proviso that there is at most 1 amino acid difference per framework region.

[0072] A variant antibody may comprise a variable heavy chain and a variable light chain as described herein, wherein: the heavy chain has at most 14 amino acid differences (at most 2 amino acid differences in each CDR and at most 2 amino acid differences in each framework region) when compared to a heavy chain sequence herein; and the light chain has at most 14 amino acid differences (at most 2 amino acid differences in each CDR and at most 2 amino acid differences in each framework region) when compared to a light chain sequence herein; wherein the variant antibody binds to the same target antigen as the reference (Anifrolumab) antibody (e.g. IFNAR) and preferably with the same affinity.

[0073] The variant heavy or light chains may be referred to as “functional equivalents” of the reference heavy or light chains. A variant antibody may comprise a variable heavy chain and a variable light chain as described herein, wherein: the heavy chain has at most 7 amino acid differences (at most 1 amino acid difference in each CDR and at most 1 amino acid difference in each framework region) when compared to a heavy chain sequence herein; and the light chain has at most 7 amino acid differences (at most 1 amino acid difference in each CDR and at most 1 amino acid difference in each framework region) when compared to a light chain sequence herein; wherein the variant antibody binds to the same target antigen as the reference (Anifrolumab) antibody (e.g. IFNAR) and preferably with the same affinity.

[0074] Functional variants of Anifrolumab include the antibodies described in WO 2018 / 023976 A1, incorporated herein by reference (Table 4). Table 4: anti-IFNAR antibody sequences DescriptionSEQ IDSequenceH15D10 (VH) 246 EVQLVQSGAEVKKPGESLRISCKGSGYTFTNYWVAWVRQMPGK GLESMGIIYPGDSDTRYSPSFQGHVTISADKSISTAY L8C3 (VL) 247 DIQMTQSPSSLSASLGDRVTITCRASQNVGNYLNWYQQKPGKA PKLLIYRASNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQMEHAPPTFGQGTKVEIKR L16C11 (VL) 248 EIVLTQSPGTLSLSPGERATLSCRASQSVIGYYLAWYQQKPGQA PRLLIYSVSTLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQ QYYRFPITFGQGTKVEIK H19B7 (VH) 249 EVQLVQSGAEVKKPGESLRISCKGSGYTFTNYWMAWVRQMPG KGLESMGIIYPSDSDTRYSPSFQGHVTISADKSISTAYLQWSSLK ASDTAMYYCARHDVEGYDYWGQGTLVTVSS

[0075] Functional variants include antibodies comprising the VH amino acid sequence SEQ ID NO: 246. Functional variants include antibodies comprising the VL amino acid sequence SEQ ID NO: 247. Functional variants include antibodies comprising the VL amino acid sequence SEQ ID NO: 248. Functional variants include antibodies comprising the VH amino acid sequence SEQ ID NO: 249. Functional variants include antibodies comprising the VH sequence SEQ ID NO: 246 and VLamino acid sequence SEQ ID NO: 247. Functional variants include antibodies comprising the VH sequence SEQ ID NO: 246 and VL amino acid sequence SEQ ID NO: 248 Functional variants include antibodies comprising the VH sequence SEQ ID NO: 249 and VL amino acid sequence SEQ ID NO: 248. Functional variants include antibodies comprising the VH sequence SEQ ID NO: 249 and VL amino acid sequence SEQ ID NO: 247.

[0076] The inhibitor of type I IFN mediated signalling or IFNAR1 inhibitor may be a monoclonal antibody comprising the VH amino acid sequence SEQ ID NO: 246. The inhibitor of type I IFN mediated signalling or anti-IFNAR antibody may comprise the VH amino acid sequence SEQ ID NO: 249. The inhibitor of type I IFN mediated signalling or anti-IFNAR antibody may comprise the VL amino acid sequence SEQ ID NO: 247. The inhibitor of type I IFN mediated signalling or anti- IFNAR antibody may comprise the VL amino acid sequence SEQ ID NO: 248. The inhibitor of type I IFN mediated signalling or anti-IFNAR antibody may comprise the VH sequence SEQ ID NO: 246 and VL amino acid sequence SEQ ID NO: 247. The inhibitor of type I IFN mediated signalling or anti-IFNAR antibody may comprise the VH sequence SEQ ID NO: 246 and VL amino acid sequence SEQ ID NO: 248. The inhibitor of type I IFN mediated signalling or anti-IFNAR antibody may comprise the VH sequence SEQ ID NO: 249 and VL amino acid sequence SEQ ID NO: 248. The inhibitor of type I IFN mediated signalling or anti-IFNAR antibody may comprise the VH sequence SEQ ID NO: 249 and VL amino acid sequence SEQ ID NO: 247.

[0077] Functional variants of Anifrolumab and other anti-IFNAR antibodies that may be used in the present invention include the QX006N antibody described in CN 11327807, incorporated herein by reference. The inhibitor of type I IFN mediated signalling or IFNAR1 inhibitor may comprise any one or more of the sequences provided in Table 5. The inhibitor of type I IFN mediated signalling or IFNAR1 inhibitor may have any one or more properties or characteristics of QX006N as described herein. Table 5: QX006N antibody sequences Description SEQ ID NO Sequence EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYYMTWVRQAP QX006N (VH) 250 GKGLEWVSVINVYGGTYYASWAKGRFTISRDNSKNTLYLQMN SLRAEDTAVYYCAREDVAVYMAIDLWGQGTLVTVSS AIQMTQSPSSLSASVGDRVTITCQASQSISNQLSWYQQKPGK QX006N (VL) 251 APKLLIYDASSLASGVPSRFSGSRSGTKFTLTISSLQPEDFATY YCLGIYGDGADDGIAFGGGTKVEIK QX006N (HCDR1) 252 SYYMT QX006N (HCDR2) 253 VINVYGGTYYASWAKG QX006N (HCDR3) 254 EDVAVYMAIDL QX006N (LCDR1) 255 QASQSISNQLS QX006N (LCDR2) 256 DASSLASQX006N (LCDR3) 257 LGIYGDGADDGIA

[0078] The inhibitor of type I IFN mediated signalling or IFNAR1 inhibitor or anti-IFNAR antibody may be a monoclonal antibody comprising the VH amino acid sequence SEQ ID NO: 250. The inhibitor of type I IFN mediated signalling or IFNAR1 inhibitor or anti-IFNAR antibody may comprise the VL amino acid sequence SEQ ID NO: 251.

[0079] QX006N is an immunoglobulin comprising an HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 252, SEQ ID NO: 253, and SEQ ID NO: 254, respectively (or functional variant thereof); and an LCDR1, LCDR2 and LCDR3 of SEQ ID NO: 255, SEQ ID NO: 256, and SEQ ID NO: 257, respectively (or functional variant thereof). QX006N is an immunoglobulin comprising a VH amino acid sequence SEQ ID NO: 250 the VL amino acid sequence SEQ ID NO: 251. 5.2.1 Sifalimumab

[0080] Sifalimumab (MEDI-545) is a fully human, immunoglobulin G1 κ monoclonal antibody that binds to and neutralizes the majority of IFN-α subtypes5. Sifalimumab is described US patent 7,741,449, which is incorporated herein by reference in its entirety. The inhibitor of type I IFN mediated signalling may be sifalimubab or a functional variant thereof. 5.2.2 Other inhibitors of type I IFN signalling

[0081] In addition to the inhibitors described above, inhibition of type I IFN signalling may be achieved by directly targeting the ligands binding to the type I IFN receptor. For example, PF 06823859 is a recombinant humanized antibody that binds and neutralizes the Type I IFN receptor ligand IFN-β. Rontalizumab is a humanized monoclonal antibody inhibiting the Type I IFN receptor ligand IFN-α.

[0082] Alternatively, type I IFN signalling may be inhibited by targeting molecules downstream of the type I IFN receptor. LABP-104 is a small molecule agonist of the surface membrane-associated receptor LanC-like Glutathione S-Transferase 2 (LANCL2). SAR443122, also called Eclitasertib, is a small molecule inhibitor of receptor-interacting protein kinase 1 (RIPK1). Litifilimab is a humanized IgG1 monoclonal antibody inhibiting blood dendritic cell antigen 2 (BDCA2). The small molecule Deucravacitinib is a selective allosteric tyrosine kinase 2 (TYK2) inhibitor. ABBV-599 is a combination of small molecule inhibitors of Bruton’s Tyrosine Kinase (BTK) and Janus kinase 1 (JAK1). The small molecule Baricitinib is an JAK1 and Janus kinase 2 (JAK2) tyrosine kinase inhibitor. 5.3 Blood Brain Barrier Transporter Molecules

[0083] This disclosure provides compositions for delivery of an inhibitor of Type I IFN signalling across the blood-brain-barrier (BBB) using a transporter molecule that can cross brain endothelial cells while associated with the payload, e.g., while fused or conjugated to the payload. The inhibitor of Type I IFN signalling can be part of a transporter molecule, e.g., as a fusion polypeptide, or joined to the polypeptide through disulfide bonds or other covalent bonds. Alternatively, the Type I IFNsignalling inhibitor can be associated with the transporter molecule in any way that will allow the transporter molecule to facilitate its transport across the BBB, as further described below. In certain aspects the Type I IFN signalling inhibitor remains part of the transporter molecule following BBB transport, and retains central nervous system (CNS) activity in that form. The disclosure further provides methods for the treatment of a disease or disorder of the CNS, comprising the use of such transporter molecules.

[0084] In certain aspects, the transporter molecule is an immunoglobulin-derived polypeptide. In certain aspects the polypeptide is a humanized version of the camelid antibody FC5, identified and isolated using Fluorescence Micro-volume Assay Technology (FMAT) to detect binding to brain microvascular endothelial cells (BMVEC), e.g., mouse B.End3 cells. In certain aspects the polypeptide comprises an antibody VH and an antibody VL isolated from a naïve scFv phage library, or a scFv phage library comprising two heavy chain complementarity determining regions (CDRs) from FC5, again identified and isolated using FMAT to detect binding to BMVEC. In certain aspects, the immunoglobulin-derived polypeptide is an antibody or an active fragment thereof, where “active” means that the transporter molecule can, e.g., bind to BMVEC in one or more species, e.g., mouse BMVEC, rat BMVEC, cynomolgus monkey BMVEC, or human BMVEC, internalize into BMVEC of one or more species, and / or cross the blood brain barrier either alone, or associated with a payload. In certain aspects, the transporter molecule comprises one or more of Bbbt0241, Bbbt0351, Bbbt0626, Bbbt0632, Bbbt0654, Bbbt0726, Bbbt0727, Bbbt0732, Bbbt0754, Bbbt0674, Bbbt0755, Bbbt0643, Bbbt0579 or Bbbt0671.

[0085] In certain aspects, the transporter molecule does not bind to BMVEC but is still capable of transporting across the BBB as indicated in the in vitro transcytosis assay. In certain aspects this transporter molecule crosses the BBB with greater efficiency than FC5. In certain aspects this transporter molecule is identical to the FC5 amino acid sequence except for two amino acid substitutions, a T97A substitution at Kabat position 97, and a T100aD substitution at Kabat position 100a, and has the amino acid sequence of Bbbt0351 (SEQ ID NO: 200).

[0086] In certain aspects, the immunoglobulin-derived polypeptide comprises immunoglobulin heavy chain complementarity determining regions (CDRs). For example, the immunoglobulin-derived polypeptide can include an immunoglobulin heavy chain complementarity-determining region-1 (H- CDR1), an immunoglobulin heavy chain complementarity-determining region-2 (H-CDR2), an immunoglobulin heavy chain complementarity-determining region-3 (H-CDR3). In certain aspects, the immunoglobulin-derived polypeptide can further comprise, or alternatively comprise, immunoglobulin light chain CDRs. For example, the immunoglobulin-derived polypeptide can include an immunoglobulin complementarity-determining region-1 (L-CDR1), an immunoglobulin light chain complementarity-determining region-2 (L-CDR2), and an immunoglobulin light chain complementarity-determining region-3 (L-CDR3). In certain aspects, the immunoglobulin-derived polypeptide can contain an H-CDR1, an H-CDR2, an H-CDR3, an L-CDR1, an L-CDR2, and an L- CDR3 with the following amino acid sequences, respectively:(a) SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14, the CDRs of Bbbt0241; (b) SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, Q G D S L X2 X3 Y Y X4 X5, S (SEQ ID NO: 260), G X8 X9 261), and N S R D X13 X14 GH; X16=H or P; and X17=V or W, (SEQ ID NO: 262), CDRs similar to those of Bbbt0626; (c) SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 260, SEQ ID NO: 261, and SEQ ID NO: 262, CDRs similar to those of Bbbt0632; (d) SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 66, SEQ ID NO: 67, and SEQ ID NO: 68, the CDRs of Bbbt0654; (e) SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 260, SEQ ID NO: 261, and SEQ ID NO: 262, CDRs similar to those of Bbbt0726; (f) SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 260, SEQ ID NO: 261, and SEQ ID NO: 262, CDRs similar to those of Bbbt0727; (g) SEQ ID NO: 111, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 260, SEQ ID NO: 261, and SEQ ID NO: 262, CDRs similar to those of Bbbt0732; (h) SEQ ID NO: 129, SEQ ID NO: 130, SEQ ID NO: 131, SEQ ID NO: 138, SEQ ID NO: 139, and SEQ ID NO: 140, the CDRs of Bbbt0754; (i) SEQ ID NO: 147, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 156, SEQ ID NO: 157, and SEQ ID NO: 158, the CDRs of Bbbt0674; (j) SEQ ID NO: 165, SEQ ID NO: 166, SEQ ID NO: 167, SEQ ID NO: 174, SEQ ID NO: 175, and SEQ ID NO: 176, the CDRs of Bbbt0755; (k) SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 185, SEQ ID NO: 192, SEQ ID NO: 193, and SEQ ID NO: 194, the CDRs of Bbbt0643; or (l) SEQ ID NO: 210, SEQ ID NO: 211, SEQ ID NO: 212, SEQ ID NO: 219, SEQ ID NO: 220, SEQ ID NO: 221, the CDRs of Bbbt0579.

[0087] In certain alternative embodiments, one or more CDRs as described above are identical to the recited CDRs, except for, e.g., 1, 2, 3, 4, or 5 single amino acid deletions, substitutions, or insertions. In certain embodiments, the transporter molecule as provided above can cross the blood brain barrier. In certain aspects, the H-CDR3 of the Bbbt0241 variant Bbbt0241m comprises two substitutions, a T97A substitution at Kabat position 97, and a T100aD substitution at Kabat position 100a.

[0088] In certain aspects, the immunoglobulin-derived polypeptide can contain an H-CDR1, an H- CDR2, an H-CDR3, an L-CDR1, an L-CDR2, and an L-CDR3 with the following amino acid sequences, respectively: (b) SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 30, SEQ ID NO: 31, and SEQ ID NO: 32, the CDRs of Bbbt0626;(c) SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 48, SEQ ID NO: 49, and SEQ ID NO: 50, the CDRs of Bbbt0632; (e) SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 84, SEQ ID NO: 85, and SEQ ID NO: 86, the CDRs of Bbbt0726; (f) SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 102, SEQ ID NO: 103, and SEQ ID NO: 104, the CDRs of Bbbt0727; or (g) SEQ ID NO: 111, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 120, SEQ ID NO: 121, and SEQ ID NO: 122, the CDRs of Bbbt0732.

[0089] In certain alternative embodiments, one or more CDRs as described above are identical to the recited CDRs, except for, e.g., 1, 2, 3, 4, or 5 single amino acid deletions, substitutions, or insertions. In certain embodiments, the transporter molecule as provided above can cross the blood brain barrier.

[0090] In certain aspects, the H-CDR1, the H-CDR2, the H-CDR3, the L-CDR1, the L-CDR2, and the L-CDR3 can be situated in immunoglobulin framework regions to produce an antibody VH and an antibody VL. In certain aspects the framework regions can be human-derived framework regions. In certain aspects the antibody VH and antibody VL are fused together, e.g., through a flexible peptide linker, to form a scFv molecule. In certain aspects the VH and VL further comprise one or more immunoglobulin constant domains, e.g., a CH1 domain, a hinge region, a CH3 domain, a CH3 domain, a CL-kappa domain, and / or a CL lambda domain. In certain aspects the one or more immunoglobulin constant domains are derived from a human immunoglobulin, e.g., a human IgG1 immunoglobulin. In certain aspects the VH, VL, and / or constant domains can comprise mutations to facilitate, e.g., longer or shorter half-life, increased or reduced effector functions, or the ability to attach a payload molecule either via peptide fusion, a disulfide bond, or chemical conjugation.

[0091] In certain aspects, this disclosure provides a transporter molecule comprising an immunoglobulin-derived polypeptide, where the polypeptide comprises an immunoglobulin heavy chain variable region (VH) region, an immunoglobulin light chain variable region (VL) region or an immunoglobulin VH region and an immunoglobulin VL region. In certain aspects the immunoglobulin-derived polypeptide comprises: (a) an VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 11, where SEQ ID NO: 2 and SEQ ID NO: 11 encode the VH and VL regions of Bbbt0241; (b) a VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 20 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 29, where SEQ ID NO: 20 and SEQ ID NO: 29 encode the VH and VL regions of Bbbt0626; (c) a VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 38 and a VL amino acid sequence at least 80%,84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 47, where SEQ ID NO: 38 and SEQ ID NO: 47 encode the VH and VL regions of Bbbt0632; (d) a VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 56 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 65, where SEQ ID NO: 56 and SEQ ID NO: 65 encode the VH and VL regions of Bbbt0654; (e) a VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 74 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 83, where SEQ ID NO: 74 and SEQ ID NO: 83 encode the VH and VL regions of Bbbt0726; (f) a VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 92 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 101, where SEQ ID NO: 92 and SEQ ID NO: 101 encode the VH and VL regions of Bbbt0727; (g) a VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 110 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 119, where SEQ ID NO: 110 and SEQ ID NO: 119 encode the VH and VL regions of Bbbt0732; (h) a VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 128 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 137, where SEQ ID NO: 128 and SEQ ID NO: 137 encode the VH and VL regions of Bbbt0754; (i) a VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 146 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 155, where SEQ ID NO: 146 and SEQ ID NO: 155 encode the VH and VL regions of Bbbt0674; (j) a VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 164 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 173, where SEQ ID NO: 164 and SEQ ID NO: 173 encode the VH and VL regions of Bbbt0755; (k) a VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 182 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 191, where SEQ ID NO: 182 and SEQ ID NO: 191 encode the VH and VL regions of Bbbt0643; (l) an VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 209 and a VL amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 218, where SEQ ID NO: 209 and SEQ ID NO: 218 encode the VH and VL regions of Bbbt0579; or (m) an VH amino acid sequence at least 80%, 84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 226 and a VL amino acid sequence at least 80%,84%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 227, where SEQ ID NO: 226 and SEQ ID NO: 227 encode the VH and VL regions of Bbbt0671.

[0092] In certain aspects, the transporter molecule provided above has transporter activity, e.g., it can bind to BMVEC from one or more species, e.g., mouse, rat, cynomolgus monkey, or human BMVEC, it can internalize into BMVEC of one or more species, or it can cross the blood brain barrier.

[0093] In certain aspects, this disclosure provides an isolated transporter molecule comprising an immunoglobulin-derived polypeptide, where the polypeptide comprises a VH region and a VL region, where: (a) the VH comprises SEQ ID NO: 2 and the VL comprises SEQ ID NO: 11; (b) the VH comprises SEQ ID NO: 20 and the VL comprises S S E L T Q D P A V S V A L X1 Q T V R I T C Q G D S L X2 X3 Y Y X4 X5 W Y Q X6 K P G Q A P V L V X7 Y G X8 X9 N R P S G X10 P D R F S G S X11 S G X12 T A S L T I T G A Q A E D E A Dand X17=V or W (SEQ ID NO: 283) or SEQ ID NO: 29; (c) the VH comprises SEQ ID NO: 38 and the VL comprises SEQ ID NO: 283 or SEQ ID NO: 47; (d) the VH comprises SEQ ID NO: 56 and the VL comprises SEQ ID NO: 65; (e) the VH comprises SEQ ID NO: 74 and the VL comprises SEQ ID NO: 283 or SEQ ID NO: 83; (f) the VH comprises SEQ ID NO: 92 and the VL comprises SEQ ID NO: 283 or SEQ ID NO: 101; (g) the VH comprises SEQ ID NO: 110 and the VL comprises SEQ ID NO: 283 or SEQ ID NO: 119; (h) the VH comprises SEQ ID NO: 128 and the VL comprises SEQ ID NO: 137; (i) the VH comprises SEQ ID NO: 146 and the VL comprises SEQ ID NO: 155; (j) the VH comprises SEQ ID NO: 164 and the VL comprises SEQ ID NO: 173; or (k) the VH comprises SEQ ID NO: 182 and the VL comprises SEQ ID NO: 191.

[0094] In certain aspects, the transporter molecule provided above has transporter activity, e.g., it can bind to BMVEC from one or more species, e.g., mouse, rat, cynomolgus monkey, or human BMVEC, it can internalize into BMVEC of one or more species, or it can cross the blood brain barrier.

[0095] In certain aspects, this disclosure provides an isolated transporter molecule comprising an immunoglobulin-derived polypeptide, where the polypeptide comprises a VH region and a VL region, where: (a) the VH comprises SEQ ID NO: 2 and the VL comprises SEQ ID NO: 11;(b) the VH comprises SEQ ID NO: 20 and the VL comprises S S E L T Q D P A V S V A L X1 Q T V R I T C Q G D S L X2 X3 Y Y X4 X5 W Y Q X6 K P G Q A P V L V X7 Y G X8 X9 N R P S G X10 P D R F S G S X11 S G X12 T A S L T I T G A Q A E D E A Dand X17=V or W (SEQ ID NO: 283) or SEQ ID NO: 29; (c) the VH comprises SEQ ID NO: 38 and the VL comprises SEQ ID NO: 283 or SEQ ID NO: 47; (d) the VH comprises SEQ ID NO: 56 and the VL comprises SEQ ID NO: 65; (e) the VH comprises SEQ ID NO: 74 and the VL comprises SEQ ID NO: 283 or SEQ ID NO: 83; (f) the VH comprises SEQ ID NO: 92 and the VL comprises SEQ ID NO: 283 or SEQ ID NO: 101; (g) the VH comprises SEQ ID NO: 110 and the VL comprises SEQ ID NO: 283 or SEQ ID NO: 119; (h) the VH comprises SEQ ID NO: 128 and the VL comprises SEQ ID NO: 137; (i) the VH comprises SEQ ID NO: 146 and the VL comprises SEQ ID NO: 155; (j) the VH comprises SEQ ID NO: 164 and the VL comprises SEQ ID NO: 173; or (k) the VH comprises SEQ ID NO: 182 and the VL comprises SEQ ID NO: 191. In certain aspects, the transporter molecule provided above has transporter activity, e.g., it can bind to BMVEC from one or more species, e.g., mouse, rat, cynomolgus monkey, or human BMVEC, it can internalize into BMVEC of one or more species, or it can cross the blood brain barrier.

[0096] In certain aspects, a transporter molecule as provided herein comprises an immunoglobulin- derived polypeptide, where the immunoglobulin-derived polypeptide comprises an antibody or a BBB-penetrable fragment thereof. A “BBB-penetrable fragment” as described herein is a fragment of the transporter molecule that can specifically bind to BMVEC of one or more species and cross through BMVEC in vitro or in vivo from the peripheral vasculature into the CNS vasculature. Whether a given fragment is a BBB-penetrable fragment can be tested by a variety of in vitro or in vivo assays known to persons of ordinary skill in the art. For example, the transporter molecule can be tested in the in vitro transcytosis assay described elsewhere herein, or in an in vivo assay such as the diuresis assay described elsewhere herein. Other assays that could be used to measure in vivo delivery of payloads across the BBB include, without limitation, chronic constriction injury (CCI); spared nerve injury model (SNI) or spinal nerve ligation (SNL), all of which can be measured via paw flick, or the Hargreaves method6.

[0097] In certain aspects, a transporter molecule as provided herein comprises an antibody or BBB- penetrable fragment thereof that comprises or consists of two or more subunits, e.g., a heavy chain or fragment thereof and a light chain or fragment thereof, where the heavy chain and light chain are associated, e.g., as a single fusion protein (e.g., a scFv), or as two subunits held together by oneor more disulfide bonds. In certain aspects the heavy chain comprises a VH domain or region and the light chain comprises a VL domain or region.

[0098] In certain aspects the heavy chain further comprises a heavy chain constant domain, e.g., a CH1 domain, a hinge, a CH2 domain, and / or a CH3 domain, or fragment thereof. In certain aspects the heavy chain constant domain is an IgG constant domain or fragment thereof, e.g., a human IgG constant domain, e.g., a human IgG1, IgG2, IgG3 or IgG4 constant domain. In certain aspects, the IgG constant domain or fragment thereof comprises an altered glycosylation and / or one or more amino acid substitutions relative to a wild-type IgG constant domain wherein the modified IgG has a particular property, e.g., an increased or decreased half-life compared to the half-life of an IgG having the wild-type IgG constant domain, either increased or decreased effector functions relative to a wild-type IgG constant domain, or the ability to attach heterologous moieties via, e.g., a peptide bond, a disulfide bond, or a chemical conjugation. In certain aspects, the IgG constant domain or fragment thereof has an altered glycosylation relative to a wild-type IgG constant domain wherein the modified IgG has a particular property, e.g., an increased or decreased half-life compared to the half-life of an IgG having the wild-type IgG constant domain, either increased or decreased effector functions relative to a wild-type IgG constant domain.

[0099] Numerous specific IgG constant domain substitutions capable of increasing or decrease half- life are known in the art. For example, the substitutions 252Y, 254T, 256E, and combinations thereof, as numbered by the EU index as set forth in Kabat have been shown to increase half-life (see, e.g., US 7,083,784). Substitutions at residues 250, 252, 254, 256, 257, 309, 311, 428, 433, 434 and combinations thereof have also been reported to alter half-life (see, e.g., U.S. Patent Nos. 6,277,375, 7,083,784; 7,217,797, 8,088,376; US2002 / 0147311; US2007 / 0148164; WO9823289 and WO09058492). Similarly, IgG constant domain substitutions capable of increasing or decreasing effector functions have been described in the art. For example, the substitutions 239S and / or 332E, as numbered by the EU index as set forth in Kabat have been shown to increase ADCC activity (see, e.g., WO2004099249, US7,317,091), while the substitutions 234F, 235E, 235F, 235Q, 235Y, 239A, 332Q, 331S, 332Q and combinations thereof, as numbered by the EU index as set forth in Kabat have been shown to decrease ADCC. Numerous other substitutions which alter effector function (increase or decrease) can be used, for example, see the mutations described in WO8807089, WO9958572, WO9951642, WO2012175751, WO2011149999, WO2011066501, WO2000042072, WO2011120134.

[0100] In certain aspects, a transporter molecule as provided herein comprises an IgG constant domain or fragment thereof comprising an altered glycosylation and / or one or more amino acid substitutions relative to a wild-type IgG constant domain wherein at least one effector function (e.g., ADCC) of the transporter molecule is reduced or eliminated. In a specific aspect ADCC activity, CDC activity, or both ADCC and CDC activity are reduced or eliminated.

[0101] In certain aspects the light chain further comprise a light chain constant domain or fragment thereof, e.g., a Ckappa domain or a Clambda domain, e.g., a human kappa constant domain or fragment thereof, or a human lambda constant region or fragment thereof.

[0102] In certain aspects, a transporter molecule as provided herein comprises an antibody or BBB- penetrable fragment thereof that comprises or consists of a murine antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a multispecific antibody, any combination thereof, or any antigen-binding fragment thereof. In certain aspects, the antibody or fragment thereof is a complete IgG immunoglobulin, e.g., a human IgG1 immunoglobulin, comprising two heavy chains and two light chains. In certain aspects the transporter molecule comprises or consists of an antibody fragment, e.g., an Fv fragment, an Fab fragment, an F(ab')2 fragment, an Fab' fragment, a dsFv fragment, a scFv fragment, or an sc(Fv)2 fragment.

[0103] In certain embodiments, a transporter molecule as provided herein comprises an antibody scFv fragment, where the scFv comprises a VH domain or region and a VL domain or region, fused to each other either directly or via a linker, e.g., a flexible linker. The VH and VL in a scFv can be arranged such that the VH is at the N terminus and the VL is at the C terminus, or vice versa. Where the VH and VL are fused via a linker, the scFv can comprise, from the amino terminus: VH-L-VL, wherein L is the linker, or VL-L-VH, where L is the linker.

[0104] Various linkers suitable for preparing scFvs are known to the person of ordinary skill in the art. Some non-limiting examples include the linker (Gly4Ser)n, where n is a positive integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 (SEQ ID NO: 263-272), Ser(Gly4Ser)n, where n is a positive integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 (SEQ ID NO: 273-282), GGGGSGGGGSGGGGS (SEQ ID NO: 230), GGGGSGGGGSGGGG (SEQ ID NO: 228), GGGGSGGGGSGGGGSAL (SEQ ID NO: 229), or GGGGSGGGGSGGGGSA (SEQ ID NO: 233).

[0105] In certain aspects the transporter molecule provided herein comprises a scFv, where the scFv comprises the VH and VL of Bbbt0241, the Bbbt0626, Bbbt0632, Bbbt0654, Bbbt0726, Bbbt0727, Bbbt0732, Bbbt0754, Bbbt0674, Bbbt0755, Bbbt0643, Bbbt0579, or Bbbt0671.

[0106] This disclosure provides transporter molecules comprising an immunoglobulin-derived polypeptide fused, or otherwise associated with an inhibitor of Type I IFN signalling. The inhibitor of Type I IFN signalling can be attached to a transporter molecule as described herein by any suitable means, for example the inhibitor of Type I IFN signalling can be fused to t immunoglobulin- derived polypeptide as provided herein, at the N-terminus or at the C terminus of either the heavy chain or the light chain. For example, this disclosure provides a transporter molecule fused to Anifrolumab, comprising a VH having the amino acid sequence SEQ ID NO: 20 (Bbbt0626) fused to the C terminus of the CH having the amino acid sequence SEQ ID NO: 243 (Anifrolumab) via a linker having the amino acid sequence SEQ ID NO: 228. Based on this disclosure, a person of ordinary skill in the art could contemplate myriad other transporter molecules comprising animmunoglobulin-derived polypeptide provided herein fused to Anifrolumab, such that the transporter molecule retains activity, e.g., the transporter molecule can specifically bind to BMVEC, can internalize into BMVEC, or can transport across BMVEC either in vivo or in vitro. 5.4 Cell and cell lines

[0107] Microglia cells are ubiquitously distributed in the brain and are key regulator of inflammatory responses in the central nervous system. They have been shown to exhibit a neuroprotective role in early stages of ALS, but progress to a neurotoxic role in later stages of the disease. However, studies investigating the role of microglia in ALS have been hampered by difficulties associated with isolation and culturing of human microglia cells7. For these reasons, recent approaches have focused on the use of pluripotent stem cell (PSC)-derived microglia cells as a model for ALS.

[0108] The THP-1 cell line designates a spontaneously immortalized monocyte-like cell line, derived from the peripheral blood of a childhood case of acute monocytic leukemia (M5 subtype)8. THP-1 cells and their derivatives have been used extensively in research and are well-known to the skilled person. 5.5 Neurodegenerative disease

[0109] As used herein, a "neurodegenerative disease" refers to a disease or disorder that results from progressive damage to cells and nervous system connections that are essential for mobility, coordination, sensation, and cognition. Neurodegenerative disease include, but are not limited to, Alzheimer’s disease (AD), Parkinson’s disease (PD), Lewy body dementia, frontotemporal lobar degeneration, Huntington’s disease, prion diseases and amyotrophic lateral sclerosis (ALS). Neurodegenerative disease are commonly associated with the accumulation of intracellular or extracellular protein aggregates, such as β-amyloid in Alzheimer’s disease, α-synuclein in Parkinson’s disease, huntingtin in Huntington’s disease and prion protein in transmissible prior encephalopathies9. However, it is unclear if these protein aggregates are driving the disease or are themselves consequences of other underlying processes.

[0110] Alzheimer’s disease (AD) is the most common cause of dementia and has a long preclinical phase characterized by neuronal loss in subcortical nuclei, followed by involvement of limbic regions with associated cognitive decline and neuropsychiatric symptoms10. Familial AD accounts for less than 1% of all AD cases, and is mainly caused by rare, dominantly inherited PSEN1, PSEN2, or APP mutations.

[0111] Parkinson’s disease (PD) is the most common clinical representation of synucleinopathies, which are characterized by the aggregation of α-synuclein in the form of Lewy bodies starting subcortically, spreading in to limbic and neocortical regions11. Synucleinopathies generally present as PD, PD dementia, or dementia with Lewy bodies, all with varying degrees of behavioural, cognitive, and autonomous symptoms on top of motor dysfunction12.

[0112] Frontotemporal lobar degeneration (FTLD) represents a spectrum of diseases characterized by vacuolation, gliosis, and neuronal loss in the external cortical layers of predominantly frontal andtemporal neocortices. FTLD is associated with a spectrum of frontotemporal dementia (FTD) syndromes ranging from behavioural, language, to motor variants. Amyotrophic lateral sclerosis (ALS) and other motor neuron disease can be considered as falling within the FTLD spectrum due to the presence of common neuropathologic and genetic features10

[0113] Huntington’s disease (HD) is characterized by progressive neuronal loss and astrogliosis in the striatum as well as significant degeneration of the cortical regions, cerebellum, and brainstem nuclei. HD is an autosomal dominant diseases with a very low incidence.

[0114] Prion disease is characterized by aggregation of the prion protein (PrP) encoded by the PRNP gene, resulting in spongiform encephalopathy with underlying neuronal loss and gliosis. A multitude of genetic, sporadic and acquired / zoonotic forms of prion diseases exist with sporadic Creutzfeldt- Jakob disease (sCJD) accounting for roughly 85% of cases13,14.

[0115] Amyotrophic lateral sclerosis (ALS is the most common form of motor neuron disease in adults and is a neurodegenerative disease characterized by the selective and progressive loss of motor neurons in the spinal cord, brain stem and cerebral cortex. It typically results in progressive muscle weakness and neuromuscular respiratory failure. 5.6 Treatment

[0116] As used herein, the term “treating” or “treatment” refers to an amelioration of a disease or disorder, or at least one discernable symptom thereof. "Treatment" or "treating" may refer to an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient. "Treatment" or "treating" may refer to inhibiting, reducing, or delaying the progression of a disease or disorder, either physically, e.g., stabilization of a discernible symptom, physiologically, e.g., stabilization of a physical parameter, or both. For example, “treating” or “treatment” may refer to reducing the progression of a neurodegenerative disease in a subject compared to the progression that would be expected for a subject having that neurodegenerative disease or compared to the progression that would be expected in a subject at that stage of the neurodegenerative disease. "Treatment" or "treating" may refer to delaying the onset of a disease or disorder.

[0117] As used herein, the terms "treatment" or "treat" refer to both therapeutic treatment and prophylactic or preventative measures. As used herein, the term “preventing” or “prevention” refers to a reduction of the risk of acquiring a given disease or disorder. “Preventing” or “prevention” may refer to preventing or delaying the onset of one or more symptoms of a disease or disorder, e.g., compared to an untreated control or placebo.

[0118] Those in need of treatment include patients having a neurodegenerative disease as well as those prone to having neurodegenerative disease or those in which neurodegenerative disease is to be prevented. In some embodiments, the methods disclosed herein can be used to treat neurodegenerative disease. The present disclosure may be applied to other diseases in addition to neurodegenerative diseases such as diseases affiliated with neurodegenerative diseases.

[0119] Where methods of treatment are described herein, they are also intended to refer to the equivalent products for use in such methods, uses in the manufacture of medicaments for such treatments and other equivalent medical uses, methods and compositions. 5.7 Administration

[0120] As used herein, the terms "administration" or "administering" refer to providing, contacting, and / or delivering a compound or compounds by any appropriate route to achieve the desired effect. Administration may include, but is not limited to, oral, sublingual, parenteral (e.g., intravenous, subcutaneous, intracutaneous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection), transdermal, topical, buccal, rectal, vaginal, nasal, ophthalmic, via inhalation, and implants. 6 EXAMPLE 1: Generation of Anifrolumab-BBB

[0121] To make anifro-BBB, Anifrolumab was expressed as a fusion construct with BBBt0626-scFv fused to the C-terminus of the heavy chain constant region via a linker. Construction of this fusion protein from these or similar building blocks is well within the knowledge of a person of ordinary skill in the art. The fusion construct was expressed in CHO-EBNA cells15according to standard methods, and the resulting proteins were purified by protein-A affinity and gel filtration. The resulting antibody comprises the heavy chain of Bbbt0626, comprising SEQ ID NO: 20, the light chain of Bbbt0626, comprising SEQ ID NO:29, a linker comprising SEQ ID NO: 228; the heavy chain of Anifrolumab comprising SEQ ID: 234 and SEQ ID: 243; and the light chain of Anifrolumab comprising SEQ ID: 235 and SEQ ID: 242. Description SEQ ID NO: Sequence VH entire SEQ ID NO: 20 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQA Bbbt0626 PGQGLEWMGRIIPILGTSNYAQKFQGRVTITADESTSTAYME germline LSSLRSEDTAVYYCARRSSLAAADRGAFDIWGQGTMVTVS S VL entire SEQ ID NO: 29 SSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPG Bbbt0626 QAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDE ADYYCNSRDSSGNHVVFGGGTKLTVL linker SEQ ID NO: 228 GGGGSGGGGSGGGG VH SEQ ID NO: 234 EVQLVQSGAEVKKPGESLKISCKGSGYIFTNYWIAWVRQMP Anifrolumab GKGLESMGIIYPGDSDIRYSPSFQGQVTISADKSITTAYLQW SSLKASDTAMYYCARHDIEGFDYWGRGTLVTVSS VL SEQ ID NO: 235 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSFFAWYQQKP Anifrolumab GQAPRLLIYGASSRATGIPDRLSGSGSGTDFTLTITRLEPED FAVYYCQQYDSSAITFGQGTRLEIKCL SEQ ID NO: 242 RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQW Anifrolumab KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KVYACEVTHQGLSSPVTKSFNRGEC CH SEQ ID NO: 243 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW Anifrolumab NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK VH entire SEQ ID NO: 258 GVQLVQSGAELKKPGSSVKVSCKASGGTFSSYAISWVRQA Bbbt0626 PGQGLEWMGRIIPILGTSNYAQKFQGRVTITADERTSTAYME LSSLRSEDTAVYYCARRSSLAAADRGAFDIWGQGTMVTVS S VH entire SED ID NO: 259 caggtccagctggtgcagtctggggcagaggtgaagaagcctgggtcctcggtgaa Bbbt0626 ggtctcctgtaaggcttctggaggcaccttcagcagttatgctatcagctgggtgcgac germline aggcccctggacaagggcttgagtggatgggaaggatcatccctattcttggtacatc aaactacgcacagaagttccagggcagagtcacgattaccgcggacgaatctacg agcacagcctacatggagctgagcagcctgagatctgaggacacggccgtatatta ctgtgcgagaaggagtagtttagcagcagcggataggggggcttttgatatctgggg ccaggggacaatggtcaccgtctcctca 7 EXAMPLE 2: Transport molecules enable transport of a payload across the blood brain barrier 7.1 Transport across BBB in rat diuresis model

[0122] The efficacy of the transporter polypeptides of the disclosure in transporting a payload comprising an analgesic agent across the BBB was demonstrated using a rat diuresis model as follows.

[0123] Dynorphins are a class of endogenous opioid peptides that arise from the precursor protein prodynorphin. They exhibit 6-10 times more potency than morphine on a per mole basis, exerting their effects primarily through the κ-opioid receptor (KOR). Dynorphins have been shown to be modulators of pain response: injecting dynorphin peptides into the subarachnoid space of the rat spinal cord produced dose-dependent analgesia, which was partially eliminated by naloxone treatment (Han JS et al., Sci. Sin., Ser. B, Chem. Biol. Agric. Med. Earth Sci.27(2):169–77. (1984)). Dynorphin peptides are peripherally restricted in animals and cannot cross the BBB. However, adynorphin peptide coupled to a BBB targeting moiety could be delivered across the BBB after i.v. administration and result in pain relief.

[0124] Towards that end, Bbbt0241 (both scFv and IgG format) was expressed, purified and coupled to a κ-opioid peptide (dynorphin) (FIG. 1A) by coupling the dynorphin peptide using a chloromethylketone active group on the to a cysteine residue on the Bbbt0241 scFv or hIgG. The scFv-dynorphin conjugates were injected (i.v.) into rats and diuresis measured hourly over a period of 4 hours. The study design is shown in FIG.1B. If the dynorphin is transported across the BBB then an increase in diuresis is observed. Peripheral administration of dynorphin alone shows no effect. FIG. 1C shows a significant increase in urine output observed upon administration of dynorphin-conjugated Bbbt0241 to rats.

[0125] Both scFv and IgG formats for the FC5 mimetics and non-mimetics were tested in the rat diuresis model. FIG 2A shows a significant increase in urine output upon administration of IgG versions of Bbbt0643, Bbbt0674, Bbbt0754, and Bbbt0654 over vehicle. The IgG compounds were administered at 4mls per 1kg body weight. FIG 2B shows the effect of different doses of Bbbt0626 hIgG as compared to control (doses are shown on graphs in mgs / ml.). The results show that the effect increases with the dose of dynorphin-conjugated Bbbt0626. Subsequent assays demonstrated that all of the FC5 mimetics in Table 3 and all of the FC5 non-mimetics in Table 4 were positive in the diuresis model (data not shown). 7.2 Transport across BBB in mouse Partial Sciatic nerve ligation model

[0126] Neuropathic pain is centrally mediated and therefore a drug must reach the CNS to allow pain relief. A neuropathic pain model has been described (Seltzer Z et al., Pain 43: 205-218 (1990)) whereby the sciatic nerve of one leg of a mouse is partially ligated, resulting in the paw pressure pain threshold on the injured paw being reduced. An analgesic drug will reduce pain if it is able to reach the CNS and paw pressure ratio will become more equal. A schematic of the model is shown in FIG.3.

[0127] The use of IL-1 receptor antagonism as a strategy for relieving neuropathic pain has been demonstrated (Gabay et al, Eur J Pain.2011 Mar;15(3):242-8 (2011). IL-1Ra is a naturally occurring IL-1 receptor antagonist. The protein does not cross the BBB, and must be delivered intrathecally to achieve pain reduction as measured by the Seltzer model. However, IL-1Ra coupled to a BBB targeting moiety could be delivered across the BBB after i.v. administration and result in pain relief.

[0128] To this end Bbbt0241, Bbbt0632, Bbbt0626, and Bbbt0726 (and NIP228 control IgG) were expressed as fusion constructs with IL-1Ra fused to the C-terminus of the heavy chain constant regions via a linker. Construction of any of these fusion proteins from these or similar building blocks is well within the knowledge of a person of ordinary skill in the art. The fusion constructs were expressed in CHO-EBNA cells (Daramola et al., Biotechnol Prog. 201430:132-41) according to standard methods, and the resulting proteins were purified by protein-A affinity and gel filtration. The constructs were shown to retain IL1Ra activity in an in vitro assay (data not shown).

[0129] Animal subjects underwent surgery on day 0 and were tested for mechanical hyperalgesia on day 7 and day 10 post-operation. Following administration of the IL-1Ra fusion proteins or controls on day 13 post surgery the animals were again tested for mechanical hyperalgesia at 2 hours (some experiments), 4 hours, 1 day, 2 days and 4 days post-dose.

[0130] Mechanical hyperalgesia was determined using an analgysemeter (Randall LO et al., Arch Int Pharmacodyn Ther.111:409-19 (1957)) (Ugo Basile). An increasing force was applied to the dorsal surface of each hind paw in turn until a withdrawal response was observed. The application of force was halted at this point and the weight in grams recorded. Data was expressed as withdrawal threshold in grams for ipsilateral and contralateral paws. Following the establishment of baseline readings mice were divided into 2 groups with approximately equal ipsilateral / contralateral ratios and underwent surgery. Mice were anaesthetized with 3% isoflurane. Following this approximately 1 cm of the left sciatic nerve was exposed by blunt dissection through an incision at the level of the mid-thigh. A suture (10 / 0 Virgin Silk: Ethicon) was then passed through the dorsal third of the nerve and tied tightly. The incision was closed using glue and the mice were allowed to recover for at least seven days prior to commencement of testing. Sham operated mice underwent the same protocol but following exposure of the nerve the wound was glued and allowed to recover.

[0131] Preliminary dose response studies in mice shown that intravenous (i.v.) administration of 40 mg / kg or 100 mg / kg of Bbbt0241 and Bbbt0632-IL-1Ra fusions showed significant analgesia model system (data note shown). FIG. 4 shows that significant analgesia was observed upon i.v. administration of 100 mg / kg of Bbbt0632, Bbbt0626, and Bbbt0726 IL-1Ra fusions, with the effect lasting more than two days post dose. Additional in vivo studies were carried out with the Bbbt0626 IL-1Ra fusion protein. The fusion protein was administered i.v. at 25 mg / kg, 50 mg / kg, and 100 mg / kg demonstrated a statistically significant dose-related effect (FIG.5). Moreover, a comparison of i.v. administration to subcutaneous (s.c.) administration showed no difference in effect between the two delivery routes (FIG.6A and 6B).

[0132] Finally, the effect of repeat administrations was studied. In this study, the animals underwent surgery on day 0 and were tested for mechanical hyperalgesia on day 7 and day 10 post-operation. All animals were dosed with either Bbbt0626-IL-1Ra or NIP228-IL-1Ra on day 13, and were tested for mechanical hyperalgesia at 4 hours and 1 day post-dose. Some animals were re-dosed with either Bbbt0626-IL-1Ra or NIP228-IL-1Ra on day 14 and retested 4 hours later. The study was run in two identical halves due to the large number of animals. Animals were then tested up to 4 days post-dose.

[0133] The results (from the combined studies) are shown in FIG. 7A and 7B. In the single-dosed animals a peak analgesic effect was between at 4 hours and 1 day post dose as in the earlier studies. In the animals that received two doses the levels of analgesia increased further showing peak analgesia at 4 hours after the second dose. The effect remained statistically significant through 4 days after the second dose. In a further study in which the second dose was administeredfour days after the first dose (day 17), an increased effect was still observed, lasting out to at least 4 days after the second dose (data not shown). 8 EXAMPLE 3: Anifrolumab-BBB retains the ability to neutralise the type I IFN gene signature 8.1 Aim

[0134] The ability of BBB-anifro to inhibit type I IFN gene signalling was assessed using a type I IFN gene expression luciferase reporter cell line. 8.2 Methods

[0135] Human THP1-Dual Cells (InvivoGen) expressing a Lucia luciferase gene under the control of an ISG54 minimal promoter and five IFN-stimulated response elements were pretreated with a range of concentrations of Anifrolumab (IFNAR1) or Anifrolumab-BBB (IFNAR1-BBB) for 30 minutes in a 96 well plate. The cells were subsequently stimulated with 1000 Units / mL of Human IFN Alpha Hybrid Protein (PBL Assay Science) (IFN- ^) for 24 hours. Secreted luciferase activity in 20 μL of supernatant was quantified using the QUANTI-Luc (InvivoGen) reagent, using a luminescence plate reader (PerkinElmer). 8.3 Results

[0136] As expected, in the absence of stimulation with IFN- ^no Luciferase Activity was detected. In the presence of low concentrations of Anifrolumab or Anifrolumab-BBB, treatment with IFN-alpha activated Luciferase expression. As the concentration of either Anifrolumab or Anifrolumab-BBB was increased, IFN-alpha stimulated luciferase activity was inhibited (FIG 8). The EC50 values for both values were within the nanomolar range, with the EC50 for Anifrolumab determined at 4.125E- 09 M and the EC50 for Anifrolumab-BBB determined at 1.151E-09 M. 8.4 Conclusions

[0137] The data provided herein show that Anifrolumab-BBB retains the functional ability of Anifrolumab to downregulate type I IFN stimulated genes through engagement and internalisation of the type I IFN receptor (IFNAR1) to inhibit type I IFN gene signalling. Previous data have demonstrated the ability of the BBB molecule to transport a monoclonal antibody payload across the BBB. Anifrolumab-BBB can therefore be expected to inhibit type I IFN signalling in the brain. 9 EXAMPLE 4: Anifrolumab suppresses the type I IFN gene signature in human microglia cells and significantly links to verified human ALS signatures 9.1 Aim

[0138] The effects of Anifrolumab were assessed in human microglia cells, which are a disease relevant cell type for ALS. 9.2 Methods

[0139] Human microglia (wild-type (AHN) iCell Microglia, FUJIFILM Cellular Dynamics, Inc) cryovials were thawed in a 37ºC water bath with constant agitation for 3 minutes, followed by cleaning of the cryovial with 70% ethanol. The thawed microglia cells were transferred to a centrifuge tube containing 3ml of Complete Maintenance Medium (iCell Microglia Media Kit, FUJIFILM Cellular Dynamics, Inc). The cryovial was further rinsed with 1 mL of Complete Maintenance Medium which was then added to the centrifuge tube. The centrifuge tube was gently inverted to mix the contents. The cells were then centrifuged at 1000 x g for 10 minutes and the supernatant was then removed.

[0140] The cells were resuspended in 1 ml of Complete Maintenance Medium. A viability count was performed via mixing 10 µL of trypan blue with 10 µL of cell suspension in an Eppendorf. Cell density was calculated using a C-chip haemocytometer.

[0141] 8 wells within a 96-well plate were seeded at 50K cells per well in 100 μL Complete Maintenance Medium and the cells were grown for 24 hours. Wells were then treated as set out in Table 7. Accordingly, 24 hours post-plating wells were treated with 10 µL of 120 µg / mL Anifrolumab or 10 µL of 120 µg / mL NIP228 IgG1TM isotype control. 45 minutes later, 10 µL of vehicle or 10 µL of 60 ng / mL human IFNβ (activating stimulus) was added. 6 or 24 hours later, samples were harvested for RNA isolation. The experiment was performed in three independent plates. Table 7: Layout for treatments in 8 wells. 6 h 24 h Isotype / vehicle Anifro / vehicle Isotype / vehicle Anifro / vehicle Isotype / IFNβ Anifro / IFNβ Isotype / IFNβ Anifro / IFNβ

[0142] 95 µL of the treated cells from each well was removed and transferred to -80ºC storage. Prior to RNAseq analysis, RNA extraction was completed using the RNAdvance Cell v2 kit (Beckman Coulter). RNA libraries were then prepared from the extracted RNA utilising the Kapa HyperPrep Kit (Roche). Following library preparation, the libraries were loaded onto a flow cell and sequenced using next generation sequencing (Illumina).

[0143] Gene expression levels in different samples were compared to identify Differentially Expressed Genes (DEGs), which may correspond to an increase or a decrease in expression levels (e.g. RNA levels) between two samples. A gene is declared differentially expressed if a difference or change observed in read counts or expression levels between two experimental conditions is statistically significant. Strict thresholds to define DEGs were set: Abs (LogFC) > 1 and a false discovery rate (FDR) < 0.05. The data generated via RNAseq which pass these strict thresholds corresponds to a transcriptomic signature of the gene expression in the cells. In the present case, the signaturereflects the effects on the cellular transcriptome of the treatment utilised on the microglial cells. Transcriptomic signatures corresponding to treatment of the microglia with Anifrolumab, IFNβ, or Anifrolumab+IFNβ compared to the relevant controls were therefore generated.

[0144] The transcriptomic signatures obtained were also compared computationally to verified human ALS transcriptomic signatures disclosed in Tam et al., 2019 (referred to herein as the TAM-2019 dataset) which incorporates transcriptomes of 148 ALS post-mortem cortex samples. Tam et al.2019, stratified these transcriptomes to reveal three distinct molecular subtypes associated with signatures of oxidative and proteotoxic stress (ALS-Ox), glial activation or dysfunction (ALS-Glia), or retrotransposon reactivation / elevated transposable element and signatures of TARDBP / TDP-43 dysfunction (ALS-TE).

[0145] Mapping of the Anifrolumab+IFNβ transcriptomic signature to the verified human ALS signatures of the TAM-2019 dataset was completed following the methods discussed in Ahangari et al., 2022. Briefly, a “connectivity score” was calculated by comparing the verified ALS signature to the Anifrolumab signature. The Connectivity score provides various measures of confidence such as a nominal p-value derived by comparing the similarity between the query and reference signature and a false discovery rate (FDR) that adjusts the p-value to account for multiple hypothesis testing. Connectivity scores can range from -1 to 1, where a score of >0 indicates a positive connection of gene signatures with the reference profile, while a score of <0 indicates a negative connection. 9.3 Results

[0146] IFNβ treatment (6 or 24 hours) altered the transcription levels of a wide range of RNAs in microglial cells, leading to the generation of a Type I IFN transcriptomic signature for these cells. This IFN signature showed significant connection to known IFN inducible / stimulated genes and inflammatory and metabolic regulation linked genes.

[0147] Treatment of microglial cells with Anifrolumab prior to stimulation with IFNβ broadly suppressed the IFN signature seen based on IFN stimulation alone. As illustrated in FIG.9, after 24 hours IFN stimulation, Anifrolumab pre-treatment suppressed 2683 of 3474 genes that had been upregulated in the IFN signature, and upregulated 2085 of 3028 genes that had been downregulated in the IFN signature. There was a strong concordance between the gene expression patterns 6hr and 24hr after IFN stimulation for microglial cells treated under equivalent conditions. However, there was more significant suppression in gene expression for some RNAs expected to be upregulated by IFN when observed at the 24hr time point in comparison to microglial cells treated with equivalent conditions for 6 hours. This highlights the potential advantage of longer treatment times with Anifrolumab.

[0148] Table 8 shows genes found to have the highest log fold change in RNA levels based on the presence or absence of Anifrolumub treatments prior to stimulation with IFNβ for 6 hours or 24 hours. Genes belonging to the IFI family are known to be IFN inducible and ISG family genes are commonly referred to as IFN-stimulated genes. ISG20, IFI27 and IFIT2 showed the largestdecrease in gene expression level. All three of these genes have been associated with various pathways in ALS phenotypes (Wang et al., 2011). Table 8: Exemplary differentially expressed genes exhibiting the greatest difference in gene expression levels after IFNβ stimulation in the presence and absence of Anifrolumab 6 Hours 24 Hours n oiPn oiPe d e d C s e s e F g s 2areruletC a s F g suulets j e 2areraue g e o v pxVdulg ev pxVjdulL A E P A a v o L A E P A a v IFI44L -1.16 5.07 3.10E-07 3.39E-06 -1.74 5.07 1.05E-08 2.84E-07 IFI44 -1.48 5.47 1.61E-10 3.93E-09 -2.03 5.47 3.43E-11 2.06E-09 IFI27 -1.48 5.47 1.61E-10 3.93E-09 -5.28 3.28 1.07E-16 2.54E-13 IFI16 -1.32 8.1 1.28E-15 2.246-13 -1.22 8.1 5.60E-13 6.89E-11 IFI35 -1.38 6.4 1.39E-13 8.95E-12 -2.32 6.4 1.72E-15 1.43E-12 IRF6 -1.45 2.89 4.33E-06 3.54E-05 -0.62 2.89 2.96E-02 7.48E-02 IFIH1 -2.29 6.91 1.01E-14 1.07E-12 -2.37 6.91 1.37E-12 1.37E-10 IFIT3 -3.12 7.25 6.69E-16 1.416-13 -3.37 7.25 6.356-14 1.41E-11 ISG20 -3.18 2.89 2.14E-15 3.21E-13 -6.04 2.89 1.39E-14 5.02E-12 IFIT1 -3.32 6.65 1.81E-13 1.11E-11 -4.19 6.65 4.006E-11 2.34E-09 IFIT2 -4.48 6.03 3.24E-16 7.93E-14 -5.12 6.03 1.87E-14 5.93E-12 IFITM1 -2.02 2.17 1.89E-10 4.536-09 -4.85 2.17 1.26E-14 4.88E-12 IFITM3 -1.55 5.96 9.35E-11 2.46E-09 -3.55 5.96 1.49E-15 1.30E-12 GBP2 -3.02 4.19 1.15E-16 3.48E-14 -3.19 4.19 8.33E-14 1.67E-11 IFITM2 -1.7 4.68 5.33E-11 1.49E-09 -3.12 4.68 1.94E-14 5.93E-12 IRF7 -1.61 6.72 3.11E-12 1.24E-10 -2.02 6.72 3.856-12 3.29E-10 IRF1 -2.2 6.1 1.55E-19 5.14E-16 -1.82 6.1 7.68E-17 2.54E-13 IFI6 -0.71 9.42 6.85E-06 5.33E-05 -1.59 9.42 1.54E-11 1.05E-09 IFIT5 -1.53 4.62 9.21E-13 4.43E-11 -1.49 4.62 7.176-11 3.84E-09 IRF2 -1.64 5.96 1.15E-16 3.48E-14 -1.13 5.96 4.09E-12 3.42E-10

[0149] Following from the observation above that Anifrolumab treatment suppresses the type I IFN transcriptome signature in human microglia cells, the gene expression signatures obtained were mapped to verified ALS human signatures (Tam et al., 2019). Table 9 shows how transcriptomic signatures obtained above mapped to three verified human ALS signatures. The negative connectivity scores in Table 9 indicate that the signatures obtained from Anifrolumab treatment are inversely related to the ALS human signatures. Genes that were upregulated in the ALS signatures were downregulated in the Anifrolumab signatures. Table 9: Connectivity scores mapping microglial Anifrolumab transcriptomic signatures to verified human ALS signatures. Disease Condition** Score P-Value Adjusted Signature* P-ValueALS-Glia_UP Anifro / IFNβ vs Isotype / IFNβ -0.167 1.0822E-06 4.3289E-06 (6hrs) ALS-Glia_UP Anifro / IFNβ vs Isotype / IFNβ -0.126 0.0018 0.0024 (24hrs) ALS-Glia_UP Anifro / vehicle vs -0.116 0.0068 0.0068 Isotype / vehicle (6hrs) ALS-Ox_UP Anifro / vehicle vs -0.233 0.0250 0.0250 Isotype / vehicle (6hrs) ALS-TE_UP Anifro / vehicle vs -0.133 0.0422 0.0422 Isotype / vehicle (6hrs) * Disease gene expression signatures from ALS subtypes as identified in Tam et al., 2019: ALS-Glial = Glial Dysfunction, ALS-Ox = Oxidative Stress Signatures, ALS-TE = Retrotransposon Reactivated. ** Gene expression signatures from Anifrolumab treatment of microglia, obtained as above: signatures obtained from IFN stimulated human microglia based on comparison of Anifrolumab pre-treatment vs isotype control; signatures obtained from unstimulated human microglia (vehicle) based on comparison of Anifrolumab pre-treatment vs isotype control. 9.4 Conclusions

[0150] As discussed above, interferons such as IFNβ are pro-inflammatory cytokines involved in the induction of interferon inducible or stimulated genes. The type I IFN signalling pathways have been shown to be elevated as a result of these interferons in ALS patients, making them key markers in the progression of ALS and they may play a pivotal role in the pathogenesis, through neuron degeneration. It was found that expression levels of a large number of genes are altered in human microglial cells by the presence of IFNβ for 6 or 24 hours. However, treatment with Anifrolumab prior to the addition of IFNβ broadly suppresses the IFNβ-induced gene expression signature in those human microglial cells. This confirms that Anifrolumab can be expected to inhibit type I IFN signalling in the brain, and in particular in microglia, which are a disease relevant cell type for ALS.

[0151] In addition, mapping of Anifrolumab gene expression signatures to verified human ALS transcriptomic profiles showed significant linkage, with connectivity scores indicating that genes having increased expression in the ALS signatures are decreased in the presence of Anifrolumab.

[0152] These results indicate that Anifrolumab can be expected to inhibit type I IFN signalling in the brain and thus remedy aberrant type I IFN signalling in e.g. ALS. REFERENCES All publications mentioned in the specification are herein incorporated by reference. (1) Checkoway, H.; Lundin, J. I.; Kelada, S. N. Neurodegenerative Diseases. IARC Sci Publ 2011, No.163, 407–419.(2) Habib, A. A.; Mitsumoto, H. Emerging Drugs for Amyotrophic Lateral Sclerosis. Expert Opin Emerg Drugs 2011, 16 (3), 537–558. https: / / doi.org / 10.1517 / 14728214.2011.604312. (3) Ferguson, G. T.; Mansur, A. H.; Jacobs, J. S.; Hebert, J.; Clawson, C.; Tao, W.; Wu, Y.; Goldman, M. Assessment of an Accessorized Pre-Filled Syringe for Home-Administered Benralizumab in Severe Asthma. J Asthma Allergy 2018, 11, 63–72. https: / / doi.org / 10.2147 / JAA.S157762. (4) Interferon-Inducible Gene Expression Kit As a Potential Diagnostic Test for Anifrolumab: Analytical Validation for Use in Clinical Trials. ACR Meeting Abstracts. (5) Khamashta, M.; Merrill, J. T.; Werth, V. P.; Furie, R.; Kalunian, K.; Illei, G. G.; Drappa, J.; Wang, L.; Greth, W. Sifalimumab, an Anti-Interferon-α Monoclonal Antibody, in Moderate to Severe Systemic Lupus Erythematosus: A Randomised, Double-Blind, Placebo-Controlled Study. Ann Rheum Dis 2016, 75 (11), 1909–1916. https: / / doi.org / 10.1136 / annrheumdis-2015-208562. (6) Hargreaves, K.; Dubner, R.; Brown, F.; Flores, C.; Joris, J. A New and Sensitive Method for Measuring Thermal Nociception in Cutaneous Hyperalgesia. Pain 1988, 32 (1), 77–88. (7) Quek, H.; Cuní-López, C.; Stewart, R.; Colletti, T.; Notaro, A.; Nguyen, T. H.; Sun, Y.; Guo, C. C.; Lupton, M. K.; Roberts, T. L.; Lim, Y. C.; Oikari, L. E.; La Bella, V.; White, A. R. ALS Monocyte- Derived Microglia-like Cells Reveal Cytoplasmic TDP-43 Accumulation, DNA Damage, and Cell- Specific Impairment of Phagocytosis Associated with Disease Progression. Journal of Neuroinflammation 2022, 19 (1), 58. https: / / doi.org / 10.1186 / s12974-022-02421-1. (8) Bosshart, H.; Heinzelmann, M. THP-1 Cells as a Model for Human Monocytes. Ann Transl Med 2016, 4 (21), 438. https: / / doi.org / 10.21037 / atm.2016.08.53. (9) Brundin, P.; Melki, R.; Kopito, R. Prion-like Transmission of Protein Aggregates in Neurodegenerative Diseases. Nat Rev Mol Cell Biol 2010, 11 (4), 301–307. https: / / doi.org / 10.1038 / nrm2873. (10) Ehrenberg, A. J.; Khatun, A.; Coomans, E.; Betts, M. J.; Capraro, F.; Thijssen, E. H.; Senkevich, K.; Bharucha, T.; Jafarpour, M.; Young, P. N. E.; Jagust, W.; Carter, S. F.; Lashley, T.; Grinberg, L. T.; Pereira, J. B.; Mattsson-Carlgren, N.; Ashton, N. J.; Hanrieder, J.; Zetterberg, H.; Schöll, M.; Paterson, R. W. Relevance of Biomarkers across Different Neurodegenerative Diseases. Alzheimers Res Ther 2020, 12 (1), 56. https: / / doi.org / 10.1186 / s13195-020-00601-w. (11) Braak, H.; Ghebremedhin, E.; Rüb, U.; Bratzke, H.; Del Tredici, K. Stages in the Development of Parkinson’s Disease-Related Pathology. Cell Tissue Res 2004, 318 (1), 121–134. https: / / doi.org / 10.1007 / s00441-004-0956-9. (12) Vonsattel, J. P.; Myers, R. H.; Stevens, T. J.; Ferrante, R. J.; Bird, E. D.; Richardson, E. P. Neuropathological Classification of Huntington’s Disease. J Neuropathol Exp Neurol 1985, 44 (6), 559– 577. https: / / doi.org / 10.1097 / 00005072-198511000-00003.(13) Hsiao, K.; Baker, H. F.; Crow, T. J.; Poulter, M.; Owen, F.; Terwilliger, J. D.; Westaway, D.; Ott, J.; Prusiner, S. B. Linkage of a Prion Protein Missense Variant to Gerstmann-Sträussler Syndrome. Nature 1989, 338 (6213), 342–345. https: / / doi.org / 10.1038 / 338342a0. (14) Mackenzie, G.; Will, R. Creutzfeldt-Jakob Disease: Recent Developments. F1000Res 2017, 6, 2053. https: / / doi.org / 10.12688 / f1000research.12681.1. (15) Daramola, O.; Stevenson, J.; Dean, G.; Hatton, D.; Pettman, G.; Holmes, W.; Field, R. A High- Yielding CHO Transient System: Coexpression of Genes Encoding EBNA-1 and GS Enhances Transient Protein Expression. Biotechnol Prog.2013, 30 (1), 132–141. (16) Yao, Y.; Higgs, B. W.; Morehouse, C.; de Los Reyes, M.; Trigona, W.; Brohawn, P.; White, W.; Zhang, J.; White, B.; Coyle, A. J.; Kiener, P. A.; Jallal, B. Development of Potential Pharmacodynamic and Diagnostic Markers for Anti-IFN-α Monoclonal Antibody Trials in Systemic Lupus Erythematosus. Hum Genomics Proteomics 2009, 2009. https: / / doi.org / 10.4061 / 2009 / 374312. (17) Yao, Y.; Richman, L.; Higgs, B. W.; Morehouse, C. A.; Reyes, M. de los; Brohawn, P.; Zhang, J.; White, B.; Coyle, A. J.; Kiener, P. A.; Jallal, B. Neutralization of Interferon-α / β–Inducible Genes and Downstream Effect in a Phase I Trial of an Anti–Interferon-α Monoclonal Antibody in Systemic Lupus Erythematosus. Arthritis & Rheumatism 2009, 60 (6), 1785–1796. https: / / doi.org / 10.1002 / art.24557. (18) Tam, O. H., Rozhkov, N. V., Shaw, R., Kim, D., Hubbard, I., Fennessey, S., Propp, N., NYGC ALS Consortium, Fagegaltier, D., Harris, B. T., Ostrow, L. W., Phatnani, H., Ravits, J., Dubnau, J., & Gale Hammell, M. (2019). Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia. Cell reports, 29(5), 1164–1177.e5. https: / / doi.org / 10.1016 / j.celrep.2019.09.066. (19) Wang, R., Yang, B., & Zhang, D. (2011). Activation of interferon signalling pathways in spinal cord astrocytes from an ALS mouse model. Glia, 59(6), 946–958.(20) Ahangari, F., Becker, C., Foster, D. G., Chioccioli, M., Nelson, M., Beke, K., Wang, X., Justet, A., Adams, T., Readhead, B., Meador, C., Correll, K., Lili, L. N., Roybal, H. M., Rose, K. A., Ding, S., Barnthaler, T., Briones, N., DeIuliis, G., Schupp, J. C., … Downey, G. P. (2022). Saracatinib, a Selective Src Kinase Inhibitor, Blocks Fibrotic Responses in Preclinical Models of Pulmonary Fibrosis. American journal of respiratory and critical care medicine, 206(12), 1463–1479. https: / / doi.org / 10.1164 / rccm.202010-3832OC.Sequence Listing Information: DTD Version: V1_3 File Name: I32733.xml Software Name: WIPO Sequence Software Version: 2.3.0 Production Date: 2023-07-03 General Information: Current application / IP Office: US Current application / Applicant file reference: I32733 Applicant name: Astrazeneca Applicant name / Language: en Invention title: Treatment of neurodegenerative diseases ( en ) Sequence Total Quantity: 283 Sequences: Sequence Number (ID): 1 Length: 366 Molecule Type: DNA Features Location / Qualifiers: - source, 1..366 > mol_type, other DNA > organism, synthetic construct Residues: gaagttcaac tgcaggcgtc cggcggtggc ctggtgcagg ctggcggctc tctgcgtctg 60 tcctgtgctg ccagcggctt taaaatcact cactatacta tgggctggtt ccgccaggca 120 ccgggcaaag agcgtgaatt cgtgagccgc atcacctggg gcggtgacaa caccttttac 180 tccaactccg ttaagggtcg ttttactatc tctcgtgata acgctaaaaa caccgtttac 240 ctgcagatga acagcctgaa accagaggac actgctgact actattgtgc tgcaggttcc 300 acctctacgg ctaccccact gcgcgtcgac tattggggca aaggcaccca ggtgaccgtc 360 tcgagt 366 Sequence Number (ID): 2 Length: 122 Molecule Type: AA Features Location / Qualifiers: - source, 1..122 > mol_type, protein > organism, synthetic construct Residues: EVQLQASGGG LVQAGGSLRL SCAASGFKIT HYTMGWFRQA PGKEREFVSR ITWGGDNTFY 60 SNSVKGRFTI SRDNAKNTVY LQMNSLKPED TADYYCAAGS TSTATPLRVD YWGKGTQVTV 120 SS 122 Sequence Number (ID): 3 Length: 5Molecule Type: AA Features Location / Qualifiers: - source, 1..5 > mol_type, protein > organism, synthetic construct Residues: HYTMG Sequence Number (ID): 4 Length: 17 Molecule Type: AA Features Location / Qualifiers: - source, 1..17 > mol_type, protein > organism, synthetic construct Residues: RITWGGDNTF YSNSVKG Sequence Number (ID): 5 Length: 13 Molecule Type: AA Features Location / Qualifiers: - source, 1..13 > mol_type, protein > organism, synthetic construct Residues: GSTSTATPLR VDY Sequence Number (ID): 6 Length: 30 Molecule Type: AA Features Location / Qualifiers: - source, 1..30 > mol_type, protein > organism, synthetic construct Residues: EVQLQASGGG LVQAGGSLRL SCAASGFKIT Sequence Number (ID): 7 Length: 14 Molecule Type: AA Features Location / Qualifiers: - source, 1..14 > mol_type, protein > organism, synthetic construct Residues: WFRQAPGKER EFVS Sequence Number (ID): 8Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: RFTISRDNAK NTVYLQMNSL KPEDTADYYC AA 32 Sequence Number (ID): 9 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: WGKGTQVTVS S 11 Sequence Number (ID): 10 Length: 324 Molecule Type: DNA Features Location / Qualifiers: - source, 1..324 > mol_type, other DNA > organism, synthetic construct Residues: gaaacgacac tcacgcagtc tccagacacc ctgtctttgt ctccagggga aagagccacc 60 ctctcctgcc gggccagtca gagtcttagc aacaacttct tagcctggta ccagcagaaa 120 tctggccagg ctcccaggct cctcatctat gctgcatcca gcagggccac tggcatccca 180 gacagattca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240 cctgaagatt ttgcagttta ttactgtcag cagtatgctg cctcagcgat caccttcggc 300 caagggacac gactggagat taaa 324 Sequence Number (ID): 11 Length: 108 Molecule Type: AA Features Location / Qualifiers: - source, 1..108 > mol_type, protein > organism, synthetic construct Residues: ETTLTQSPDT LSLSPGERAT LSCRASQSLS NNFLAWYQQK SGQAPRLLIY AASSRATGIP 60 DRFSGSGSGT DFTLTISRLE PEDFAVYYCQ QYAASAITFG QGTRLEIK 108Sequence Number (ID): 12 Length: 12 Molecule Type: AA Features Location / Qualifiers: - source, 1..12 > mol_type, protein > organism, synthetic construct Residues: RASQSLSNNF LA Sequence Number (ID): 13 Length: 7 Molecule Type: AA Features Location / Qualifiers: - source, 1..7 > mol_type, protein > organism, synthetic construct Residues: AASSRAT Sequence Number (ID): 14 Length: 9 Molecule Type: AA Features Location / Qualifiers: - source, 1..9 > mol_type, protein > organism, synthetic construct Residues: QQYAASAIT Sequence Number (ID): 15 Length: 23 Molecule Type: AA Features Location / Qualifiers: - source, 1..23 > mol_type, protein > organism, synthetic construct Residues: ETTLTQSPDT LSLSPGERAT LSC Sequence Number (ID): 16 Length: 15 Molecule Type: AA Features Location / Qualifiers: - source, 1..15 > mol_type, protein > organism, synthetic construct Residues:WYQQKSGQAP RLLIY 15 Sequence Number (ID): 17 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: GIPDRFSGSG SGTDFTLTIS RLEPEDFAVY YC 32 Sequence Number (ID): 18 Length: 10 Molecule Type: AA Features Location / Qualifiers: - source, 1..10 > mol_type, protein > organism, synthetic construct Residues: FGQGTRLEIK 10 Sequence Number (ID): 19 Length: 369 Molecule Type: DNA Features Location / Qualifiers: - source, 1..369 > mol_type, other DNA > organism, synthetic construct Residues: ggggtccagc tggtgcagtc tggggcagag ctgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgtaagg cttctggagg caccttcagc agttatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta ttcttggtac atcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggacg aacgtacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtat attactgtgc gagaaggagt 300 agtttagcag cagcggatag gggggctttt gatatctggg gccaggggac aatggtcacc 360 gtctcgagt 369 Sequence Number (ID): 20 Length: 123 Molecule Type: AA Features Location / Qualifiers: - source, 1..123 > mol_type, protein> organism, synthetic construct Residues: QVQLVQSGAE VKKPGSSVKV SCKASGGTFS SYAISWVRQA PGQGLEWMGR IIPILGTSNY 60 AQKFQGRVTI TADESTSTAY MELSSLRSED TAVYYCARRS SLAAADRGAF DIWGQGTMVT 120 VSS 123 Sequence Number (ID): 21 Length: 5 Molecule Type: AA Features Location / Qualifiers: - source, 1..5 > mol_type, protein > organism, synthetic construct Residues: SYAIS 5 Sequence Number (ID): 22 Length: 17 Molecule Type: AA Features Location / Qualifiers: - source, 1..17 > mol_type, protein > organism, synthetic construct Residues: RIIPILGTSN YAQKFQG 17 Sequence Number (ID): 23 Length: 14 Molecule Type: AA Features Location / Qualifiers: - source, 1..14 > mol_type, protein > organism, synthetic construct Residues: RSSLAAADRG AFDI 14 Sequence Number (ID): 24 Length: 30 Molecule Type: AA Features Location / Qualifiers: - source, 1..30 > mol_type, protein > organism, synthetic construct Residues: GVQLVQSGAE LKKPGSSVKV SCKASGGTFS 30 Sequence Number (ID): 25Length: 14 Molecule Type: AA Features Location / Qualifiers: - source, 1..14 > mol_type, protein > organism, synthetic construct Residues: WVRQAPGQGL EWMG 14 Sequence Number (ID): 26 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: RVTITADERT STAYMELSSL RSEDTAVYYC AR 32 Sequence Number (ID): 27 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: WGQGTMVTVS S 11 Sequence Number (ID): 28 Length: 324 Molecule Type: DNA Features Location / Qualifiers: - source, 1..324 > mol_type, other DNA > organism, synthetic construct Residues: tcgtctgagc tgactcagga ccctgctgtg tctgtggcct tgggacagac agtcaggatc 60 acatgccaag gagacagcct cagaagctat tatgcaagct ggtaccagca gaagccagga 120 caggcccctg tacttgtcat ctatggtaaa aacaaccggc cctcagggat cccagaccga 180 ttctctggct ccagctcagg aaacacagct tccttgacca tcactggggc tcaggcggaa 240 gatgaggctg actattactg taactcccgg gacagcagtg gtaaccatgt ggtattcggc 300 ggagggacca agctgaccgt ccta 324 Sequence Number (ID): 29Length: 108 Molecule Type: AA Features Location / Qualifiers: - source, 1..108 > mol_type, protein > organism, synthetic construct Residues: SSELTQDPAV SVALGQTVRI TCQGDSLRSY YASWYQQKPG QAPVLVIYGK NNRPSGIPDR 60 FSGSSSGNTA SLTITGAQAE DEADYYCNSR DSSGNHVVFG GGTKLTVL 108 Sequence Number (ID): 30 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: QGDSLRSYYA S 11 Sequence Number (ID): 31 Length: 7 Molecule Type: AA Features Location / Qualifiers: - source, 1..7 > mol_type, protein > organism, synthetic construct Residues: GKNNRPS 7 Sequence Number (ID): 32 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: NSRDSSGNHV V 11 Sequence Number (ID): 33 Length: 22 Molecule Type: AA Features Location / Qualifiers: - source, 1..22 > mol_type, protein > organism, synthetic construct Residues:SSELTQDPAV SVALGQTVRI TC 22 Sequence Number (ID): 34 Length: 15 Molecule Type: AA Features Location / Qualifiers: - source, 1..15 > mol_type, protein > organism, synthetic construct Residues: WYQQKPGQAP VLVIY 15 Sequence Number (ID): 35 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: GIPDRFSGSS SGNTASLTIT GAQAEDEADY YC 32 Sequence Number (ID): 36 Length: 10 Molecule Type: AA Features Location / Qualifiers: - source, 1..10 > mol_type, protein > organism, synthetic construct Residues: FGGGTKLTVL 10 Sequence Number (ID): 37 Length: 366 Molecule Type: DNA Features Location / Qualifiers: - source, 1..366 > mol_type, other DNA > organism, synthetic construct Residues: caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaaga cttctggagg caccttcggc acctattcta tcacctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggagac atcgtcccta tctttggaac accaaactac 180 gcacagaatt tccagggcag agtcactatc tccgcggacg tatccacggc gacagtctac 240 atggagctga gcagcctaac atccgacgac acggccgtct acttctgtgc taagaggggg 300agttactacg gccggggagg ttggttcgac ccctggggcc gggggacaat ggtcaccgtc 360 tcgagt 366 Sequence Number (ID): 38 Length: 122 Molecule Type: AA Features Location / Qualifiers: - source, 1..122 > mol_type, protein > organism, synthetic construct Residues: QVQLVQSGAE VKKPGSSVKV SCKTSGGTFG TYSITWVRQA PGQGLEWMGD IVPIFGTPNY 60 AQNFQGRVTI SADVSTATVY MELSSLTSDD TAVYFCAKRG SYYGRGGWFD PWGRGTMVTV 120 SS 122 Sequence Number (ID): 39 Length: 5 Molecule Type: AA Features Location / Qualifiers: - source, 1..5 > mol_type, protein > organism, synthetic construct Residues: TYSIT 5 Sequence Number (ID): 40 Length: 17 Molecule Type: AA Features Location / Qualifiers: - source, 1..17 > mol_type, protein > organism, synthetic construct Residues: DIVPIFGTPN YAQNFQG 17 Sequence Number (ID): 41 Length: 13 Molecule Type: AA Features Location / Qualifiers: - source, 1..13 > mol_type, protein > organism, synthetic construct Residues: RGSYYGRGGW FDP 13 Sequence Number (ID): 42Length: 30 Molecule Type: AA Features Location / Qualifiers: - source, 1..30 > mol_type, protein > organism, synthetic construct Residues: QVQLVQSGAE VKKPGSSVKV SCKTSGGTFG 30 Sequence Number (ID): 43 Length: 14 Molecule Type: AA Features Location / Qualifiers: - source, 1..14 > mol_type, protein > organism, synthetic construct Residues: WVRQAPGQGL EWMG 14 Sequence Number (ID): 44 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: RVTISADVST ATVYMELSSL TSDDTAVYFC AK 32 Sequence Number (ID): 45 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: WGRGTMVTVS S 11 Sequence Number (ID): 46 Length: 324 Molecule Type: DNA Features Location / Qualifiers: - source, 1..324 > mol_type, other DNA > organism, synthetic construct Residues: tcttctgagc tgactcagga ccctgctgtg tctgtggcct tgagacagac agtcaggatc 60acatgccaag gagacagcct cacaaggtat tatacaaact ggtaccagca gaagccagga 120 caggccccta tacttgtcat ctatggtgaa aacaaccggc cctcagggat cccagaccga 180 ttctctggct ccagatcagg aaacacagct tccttgacca tcactggggc tcaggcggaa 240 gatgaggctg actattactg taactcccgg gacaatactg gtaaacattg ggtgttcggc 300 ggagggacca agctgaccgt ccta 324 Sequence Number (ID): 47 Length: 108 Molecule Type: AA Features Location / Qualifiers: - source, 1..108 > mol_type, protein > organism, synthetic construct Residues: SSELTQDPAV SVALRQTVRI TCQGDSLTRY YTNWYQQKPG QAPILVIYGE NNRPSGIPDR 60 FSGSRSGNTA SLTITGAQAE DEADYYCNSR DNTGKHWVFG GGTKLTVL 108 Sequence Number (ID): 48 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: QGDSLTRYYT N 11 Sequence Number (ID): 49 Length: 7 Molecule Type: AA Features Location / Qualifiers: - source, 1..7 > mol_type, protein > organism, synthetic construct Residues: GENNRPS 7 Sequence Number (ID): 50 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues:NSRDNTGKHW V Sequence Number (ID): 51 Length: 22 Molecule Type: AA Features Location / Qualifiers: - source, 1..22 > mol_type, protein > organism, synthetic construct Residues: SSELTQDPAV SVALRQTVRI TC Sequence Number (ID): 52 Length: 15 Molecule Type: AA Features Location / Qualifiers: - source, 1..15 > mol_type, protein > organism, synthetic construct Residues: WYQQKPGQAP ILVIY Sequence Number (ID): 53 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: GIPDRFSGSR SGNTASLTIT GAQAEDEADY YC Sequence Number (ID): 54 Length: 10 Molecule Type: AA Features Location / Qualifiers: - source, 1..10 > mol_type, protein > organism, synthetic construct Residues: FGGGTKLTVL Sequence Number (ID): 55 Length: 384 Molecule Type: DNA Features Location / Qualifiers: - source, 1..384 > mol_type, other DNA > organism, synthetic constructResidues: gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggtag cacatactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gaaaaattat 300 tactatgata ctagtgctta ttactacgta gggtccgact actttgacta ctggggccaa 360 gggacaatgg tcaccgtctc gagt 384 Sequence Number (ID): 56 Length: 128 Molecule Type: AA Features Location / Qualifiers: - source, 1..128 > mol_type, protein > organism, synthetic construct Residues: EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYAMSWVRQA PGKGLEWVSA ISGSGGSTYY 60 ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKNY YYDTSAYYYV GSDYFDYWGQ 120 GTMVTVSS 128 Sequence Number (ID): 57 Length: 5 Molecule Type: AA Features Location / Qualifiers: - source, 1..5 > mol_type, protein > organism, synthetic construct Residues: SYAMS 5 Sequence Number (ID): 58 Length: 17 Molecule Type: AA Features Location / Qualifiers: - source, 1..17 > mol_type, protein > organism, synthetic construct Residues: AISGSGGSTY YADSVKG 17 Sequence Number (ID): 59Length: 19 Molecule Type: AA Features Location / Qualifiers: - source, 1..19 > mol_type, protein > organism, synthetic construct Residues: NYYYDTSAYY YVGSDYFDY Sequence Number (ID): 60 Length: 30 Molecule Type: AA Features Location / Qualifiers: - source, 1..30 > mol_type, protein > organism, synthetic construct Residues: EVQLLESGGG LVQPGGSLRL SCAASGFTFS Sequence Number (ID): 61 Length: 14 Molecule Type: AA Features Location / Qualifiers: - source, 1..14 > mol_type, protein > organism, synthetic construct Residues: WVRQAPGKGL EWVS Sequence Number (ID): 62 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: RFTISRDNSK NTLYLQMNSL RAEDTAVYYC AK Sequence Number (ID): 63 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: WGQGTMVTVS SSequence Number (ID): 64 Length: 330 Molecule Type: DNA Features Location / Qualifiers: - source, 1..330 > mol_type, other DNA > organism, synthetic construct Residues: cagtctgccc tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gataaccatc 60 tcctgcactg caaccagcag taacgttggc gcttataact ttgtctcctg gtaccaacaa 120 cacccaggca aagcccccaa agtcctgatt tatagggtca gtaatcggcc ttcaggggtt 180 tctaatcgct tctctggctc caagtctggc aacacggcct ccctgaccat ctctgggctc 240 caggctgacg acgaggctga ttattattgc agctcatata caaccgacta catttgggtg 300 ttcggcggag ggaccaagct gaccgtccta 330 Sequence Number (ID): 65 Length: 110 Molecule Type: AA Features Location / Qualifiers: - source, 1..110 > mol_type, protein > organism, synthetic construct Residues: QSALTQPASV SGSPGQSITI SCTATSSNVG AYNFVSWYQQ HPGKAPKVLI YRVSNRPSGV 60 SNRFSGSKSG NTASLTISGL QADDEADYYC SSYTTDYIWV FGGGTKLTVL 110 Sequence Number (ID): 66 Length: 14 Molecule Type: AA Features Location / Qualifiers: - source, 1..14 > mol_type, protein > organism, synthetic construct Residues: TATSSNVGAY NFVS 14 Sequence Number (ID): 67 Length: 7 Molecule Type: AA Features Location / Qualifiers: - source, 1..7 > mol_type, protein > organism, synthetic construct Residues:RVSNRPS Sequence Number (ID): 68 Length: 10 Molecule Type: AA Features Location / Qualifiers: - source, 1..10 > mol_type, protein > organism, synthetic construct Residues: SSYTTDYIWV Sequence Number (ID): 69 Length: 22 Molecule Type: AA Features Location / Qualifiers: - source, 1..22 > mol_type, protein > organism, synthetic construct Residues: QSALTQPASV SGSPGQSITI SC Sequence Number (ID): 70 Length: 15 Molecule Type: AA Features Location / Qualifiers: - source, 1..15 > mol_type, protein > organism, synthetic construct Residues: WYQQHPGKAP KVLIY Sequence Number (ID): 71 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: GVSNRFSGSK SGNTASLTIS GLQADDEADY YC Sequence Number (ID): 72 Length: 10 Molecule Type: AA Features Location / Qualifiers: - source, 1..10 > mol_type, protein > organism, synthetic constructResidues: FGGGTKLTVL 10 Sequence Number (ID): 73 Length: 360 Molecule Type: DNA Features Location / Qualifiers: - source, 1..360 > mol_type, other DNA > organism, synthetic construct Residues: caggtacagc tgcagcagtc aggggctgag gtgaagaagc ctgggtcctc ggtgagggtc 60 tcctgcaagg cttctggagg caccttcaac agttatgcta tcaactgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaggg atcatcactt tctttggtac aacaacctac 180 gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgacgac acggccgtgt attattgtgc gaggaatccc 300 cgtattgtgg gcggagcttt tgatatctgg gggaaaggga ccacggtcac cgtctcgagt 360 Sequence Number (ID): 74 Length: 120 Molecule Type: AA Features Location / Qualifiers: - source, 1..120 > mol_type, protein > organism, synthetic construct Residues: QVQLQQSGAE VKKPGSSVRV SCKASGGTFN SYAINWVRQA PGQGLEWMGG IITFFGTTTY 60 AQKFQGRVTI TADESTSTAY MELSSLRSDD TAVYYCARNP RIVGGAFDIW GKGTTVTVSS 120 Sequence Number (ID): 75 Length: 5 Molecule Type: AA Features Location / Qualifiers: - source, 1..5 > mol_type, protein > organism, synthetic construct Residues: SYAIN 5 Sequence Number (ID): 76 Length: 17 Molecule Type: AA Features Location / Qualifiers: - source, 1..17> mol_type, protein > organism, synthetic construct Residues: GIITFFGTTT YAQKFQG Sequence Number (ID): 77 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: NPRIVGGAFD I Sequence Number (ID): 78 Length: 30 Molecule Type: AA Features Location / Qualifiers: - source, 1..30 > mol_type, protein > organism, synthetic construct Residues: QVQLQQSGAE VKKPGSSVRV SCKASGGTFN Sequence Number (ID): 79 Length: 14 Molecule Type: AA Features Location / Qualifiers: - source, 1..14 > mol_type, protein > organism, synthetic construct Residues: WVRQAPGQGL EWMG Sequence Number (ID): 80 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: RVTITADEST STAYMELSSL RSDDTAVYYC AR Sequence Number (ID): 81 Length: 11 Molecule Type: AA Features Location / Qualifiers:- source, 1..11 > mol_type, protein > organism, synthetic construct Residues: WGKGTTVTVS S 11 Sequence Number (ID): 82 Length: 324 Molecule Type: DNA Features Location / Qualifiers: - source, 1..324 > mol_type, other DNA > organism, synthetic construct Residues: tcgtctgagc tgactcagga ccctgctgtg tctgtggcct tgggacagac agtcaggatc 60 acatgccaag gagacagcct cagaagctat tatgcaagct ggtaccagca gaagccagga 120 caggcccctg tacttgtcat ctatggtaaa aacaaccggc cctcaggggt cccagaccga 180 ttctctggct ccagctcagg aaacacagct tccttgacca tcactggggc tcaggcggaa 240 gatgaggctg actattactg taactcccgg gacagcagtg gtaaccatgt ggtattcggc 300 ggagggacca agctgaccgt ccta 324 Sequence Number (ID): 83 Length: 108 Molecule Type: AA Features Location / Qualifiers: - source, 1..108 > mol_type, protein > organism, synthetic construct Residues: SSELTQDPAV SVALGQTVRI TCQGDSLRSY YASWYQQKPG QAPVLVIYGK NNRPSGVPDR 60 FSGSSSGNTA SLTITGAQAE DEADYYCNSR DSSGNHVVFG GGTKLTVL 108 Sequence Number (ID): 84 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: QGDSLRSYYA S 11 Sequence Number (ID): 85 Length: 7Molecule Type: AA Features Location / Qualifiers: - source, 1..7 > mol_type, protein > organism, synthetic construct Residues: GKNNRPS Sequence Number (ID): 86 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: NSRDSSGNHV V Sequence Number (ID): 87 Length: 22 Molecule Type: AA Features Location / Qualifiers: - source, 1..22 > mol_type, protein > organism, synthetic construct Residues: SSELTQDPAV SVALGQTVRI TC Sequence Number (ID): 88 Length: 15 Molecule Type: AA Features Location / Qualifiers: - source, 1..15 > mol_type, protein > organism, synthetic construct Residues: WYQQKPGQAP VLVIY Sequence Number (ID): 89 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: GVPDRFSGSS SGNTASLTIT GAQAEDEADY YC Sequence Number (ID): 90Length: 10 Molecule Type: AA Features Location / Qualifiers: - source, 1..10 > mol_type, protein > organism, synthetic construct Residues: FGGGTKLTVL 10 Sequence Number (ID): 91 Length: 357 Molecule Type: DNA Features Location / Qualifiers: - source, 1..357 > mol_type, other DNA > organism, synthetic construct Residues: caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggaga cactttccgc agctatatta tcagctgggt gcgacaggcc 120 cctggacaag gacttgagtg ggtgggaggg atcatcccta tgtttggcac atcaaattat 180 gcacagcagt tccagggcaa agtcaccatt accgcggacg aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaggtggg 300 gcccgatact actacatgga cgtctggggc cgagggacaa tggtcaccgt ctcttca 357 Sequence Number (ID): 92 Length: 119 Molecule Type: AA Features Location / Qualifiers: - source, 1..119 > mol_type, protein > organism, synthetic construct Residues: QVQLVQSGAE VKKPGSSVKV SCKASGDTFR SYIISWVRQA PGQGLEWVGG IIPMFGTSNY 60 AQQFQGKVTI TADESTSTAY MELSSLRSED TAVYYCARGG ARYYYMDVWG RGTMVTVSS 119 Sequence Number (ID): 93 Length: 5 Molecule Type: AA Features Location / Qualifiers: - source, 1..5 > mol_type, protein > organism, synthetic construct Residues: SYIIS 5Sequence Number (ID): 94 Length: 17 Molecule Type: AA Features Location / Qualifiers: - source, 1..17 > mol_type, protein > organism, synthetic construct Residues: GIIPMFGTSN YAQQFQG Sequence Number (ID): 95 Length: 10 Molecule Type: AA Features Location / Qualifiers: - source, 1..10 > mol_type, protein > organism, synthetic construct Residues: GGARYYYMDV Sequence Number (ID): 96 Length: 30 Molecule Type: AA Features Location / Qualifiers: - source, 1..30 > mol_type, protein > organism, synthetic construct Residues: QVQLVQSGAE VKKPGSSVKV SCKASGDTFR Sequence Number (ID): 97 Length: 14 Molecule Type: AA Features Location / Qualifiers: - source, 1..14 > mol_type, protein > organism, synthetic construct Residues: WVRQAPGQGL EWVG Sequence Number (ID): 98 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues:KVTITADEST STAYMELSSL RSEDTAVYYC AR 32 Sequence Number (ID): 99 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: WGRGTMVTVS S 11 Sequence Number (ID): 100 Length: 324 Molecule Type: DNA Features Location / Qualifiers: - source, 1..324 > mol_type, other DNA > organism, synthetic construct Residues: tcgtctgagc tgactcagga ccctgctgtg tctgtggcct tgggacagac agtcaggatc 60 acatgccaag gagacagcct cagaagctat tatgcaagct ggtaccagca gaagccagga 120 caggcccctg tacttgtcat ctatggtaaa aacaaccggc cctcagggat cccagaccga 180 ttctctggct ccagctcagg aaacacagct tccttgacca tcactggggc tcaggcggaa 240 gatgaggctg actattactg taactcccgg gacagcagtg gtaaccatgt ggtattcggc 300 ggagggacca agctgaccgt ccta 324 Sequence Number (ID): 101 Length: 108 Molecule Type: AA Features Location / Qualifiers: - source, 1..108 > mol_type, protein > organism, synthetic construct Residues: SSELTQDPAV SVALGQTVRI TCQGDSLRSY YASWYQQKPG QAPVLVIYGK NNRPSGIPDR 60 FSGSSSGNTA SLTITGAQAE DEADYYCNSR DSSGNHVVFG GGTKLTVL 108 Sequence Number (ID): 102 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein> organism, synthetic construct Residues: QGDSLRSYYA S Sequence Number (ID): 103 Length: 7 Molecule Type: AA Features Location / Qualifiers: - source, 1..7 > mol_type, protein > organism, synthetic construct Residues: GKNNRPS Sequence Number (ID): 104 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: NSRDSSGNHV V Sequence Number (ID): 105 Length: 22 Molecule Type: AA Features Location / Qualifiers: - source, 1..22 > mol_type, protein > organism, synthetic construct Residues: SSELTQDPAV SVALGQTVRI TC Sequence Number (ID): 106 Length: 15 Molecule Type: AA Features Location / Qualifiers: - source, 1..15 > mol_type, protein > organism, synthetic construct Residues: WYQQKPGQAP VLVIY Sequence Number (ID): 107 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32> mol_type, protein > organism, synthetic construct Residues: GIPDRFSGSS SGNTASLTIT GAQAEDEADY YC 32 Sequence Number (ID): 108 Length: 10 Molecule Type: AA Features Location / Qualifiers: - source, 1..10 > mol_type, protein > organism, synthetic construct Residues: FGGGTKLTVL 10 Sequence Number (ID): 109 Length: 360 Molecule Type: DNA Features Location / Qualifiers: - source, 1..360 > mol_type, other DNA > organism, synthetic construct Residues: gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggtag cacatactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gaaacgtcgg 300 agggactact actacgatat ggacgtctgg ggccaaggga caatggtcac cgtctcgagt 360 Sequence Number (ID): 110 Length: 120 Molecule Type: AA Features Location / Qualifiers: - source, 1..120 > mol_type, protein > organism, synthetic construct Residues: EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYAMSWVRQA PGKGLEWVSA ISGSGGSTYY 60 ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKRR RDYYYDMDVW GQGTMVTVSS 120 Sequence Number (ID): 111 Length: 5 Molecule Type: AAFeatures Location / Qualifiers: - source, 1..5 > mol_type, protein > organism, synthetic construct Residues: SYAMS Sequence Number (ID): 112 Length: 17 Molecule Type: AA Features Location / Qualifiers: - source, 1..17 > mol_type, protein > organism, synthetic construct Residues: AISGSGGSTY YADSVKG Sequence Number (ID): 113 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: RRRDYYYDMD V Sequence Number (ID): 114 Length: 30 Molecule Type: AA Features Location / Qualifiers: - source, 1..30 > mol_type, protein > organism, synthetic construct Residues: EVQLLESGGG LVQPGGSLRL SCAASGFTFS Sequence Number (ID): 115 Length: 14 Molecule Type: AA Features Location / Qualifiers: - source, 1..14 > mol_type, protein > organism, synthetic construct Residues: WVRQAPGKGL EWVS Sequence Number (ID): 116 Length: 32Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: RFTISRDNSK NTLYLQMNSL RAEDTAVYYC AK 32 Sequence Number (ID): 117 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: WGQGTMVTVS S 11 Sequence Number (ID): 118 Length: 324 Molecule Type: DNA Features Location / Qualifiers: - source, 1..324 > mol_type, other DNA > organism, synthetic construct Residues: tcttctgagc tgactcagga ccctgctgtg tctgtggcct tgggacagac agtcaggatc 60 acatgccaag gagacagcct cagaacctat tatgcaagct ggtaccagca caagccagga 120 caggcccctg tacttgtcat gtatggtaaa gataaccgac cctcagggat cccagaccga 180 ttctctggct ccagctcagg aaccacagct tccttgacca tcactggggc tcaggcggaa 240 gatgaggctg actattactg taactcccgg gacagcagtg gtcaccctgt ggtattcggc 300 ggagggacca agctgaccgt ccta 324 Sequence Number (ID): 119 Length: 108 Molecule Type: AA Features Location / Qualifiers: - source, 1..108 > mol_type, protein > organism, synthetic construct Residues: SSELTQDPAV SVALGQTVRI TCQGDSLRTY YASWYQHKPG QAPVLVMYGK DNRPSGIPDR 60 FSGSSSGTTA SLTITGAQAE DEADYYCNSR DSSGHPVVFG GGTKLTVL 108Sequence Number (ID): 120 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: QGDSLRTYYA S Sequence Number (ID): 121 Length: 7 Molecule Type: AA Features Location / Qualifiers: - source, 1..7 > mol_type, protein > organism, synthetic construct Residues: GKDNRPS Sequence Number (ID): 122 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: NSRDSSGHPV V Sequence Number (ID): 123 Length: 30 Molecule Type: AA Features Location / Qualifiers: - source, 1..30 > mol_type, protein > organism, synthetic construct Residues: EVQLLESGGG LVQPGGSLRL SCAASGFKIT Sequence Number (ID): 124 Length: 14 Molecule Type: AA Features Location / Qualifiers: - source, 1..14 > mol_type, protein > organism, synthetic construct Residues: WVRQAPGKGL EWVSSequence Number (ID): 125 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: RFTISRDNSK NTLYLQMNSL RAEDTAVYYC AT 32 Sequence Number (ID): 126 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: WGRGTMVTVS S 11 Sequence Number (ID): 127 Length: 366 Molecule Type: DNA Features Location / Qualifiers: - source, 1..366 > mol_type, other DNA > organism, synthetic construct Residues: gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caaaattacc cactatacta tgggctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcacgc atcacgtggg gcggtgacaa caccttttac 180 tccaactccg tgaggggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc aacagggacg 300 ttcggggagt tattccccga ctactttaag tattggggcc gggggacaat ggtcaccgtc 360 tcgagt 366 Sequence Number (ID): 128 Length: 122 Molecule Type: AA Features Location / Qualifiers: - source, 1..122 > mol_type, protein > organism, synthetic construct Residues:EVQLLESGGG LVQPGGSLRL SCAASGFKIT HYTMGWVRQA PGKGLEWVSR ITWGGDNTFY 60 SNSVRGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCATGT FGELFPDYFK YWGRGTMVTV 120 SS 122 Sequence Number (ID): 129 Length: 5 Molecule Type: AA Features Location / Qualifiers: - source, 1..5 > mol_type, protein > organism, synthetic construct Residues: HYTMG 5 Sequence Number (ID): 130 Length: 17 Molecule Type: AA Features Location / Qualifiers: - source, 1..17 > mol_type, protein > organism, synthetic construct Residues: RITWGGDNTF YSNSVRG 17 Sequence Number (ID): 131 Length: 13 Molecule Type: AA Features Location / Qualifiers: - source, 1..13 > mol_type, protein > organism, synthetic construct Residues: GTFGELFPDY FKY 13 Sequence Number (ID): 132 Length: 30 Molecule Type: AA Features Location / Qualifiers: - source, 1..30 > mol_type, protein > organism, synthetic construct Residues: EVQLLESGGG LVQPGGSLRL SCAASGFKIT 30 Sequence Number (ID): 133 Length: 14 Molecule Type: AAFeatures Location / Qualifiers: - source, 1..14 > mol_type, protein > organism, synthetic construct Residues: WVRQAPGKGL EWVS 14 Sequence Number (ID): 134 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: RFTISRDNSK NTLYLQMNSL RAEDTAVYYC AT 32 Sequence Number (ID): 135 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: WGRGTMVTVS S 11 Sequence Number (ID): 136 Length: 333 Molecule Type: DNA Features Location / Qualifiers: - source, 1..333 > mol_type, other DNA > organism, synthetic construct Residues: caggctgtgc tgactcagcc gtcctcagtg tctggggccc cagggcagag ggtcaccatc 60 ccctgcactg ggagcagctc caacatcggg gcaggttatg atgtaaactg gtaccagcag 120 cttccaggaa cagcccccaa actcctcatc tttcataaca acattcggcc ctcaggggtc 180 cctgaccgat tctctggctc caagtctggc acctcagtct ccctggccat cactgggctc 240 caggctgagg atgaggctga ttattactgc cagtcctatg acagcagcct gagtgcttgg 300 gtcttcggcg gagggaccaa ggtcaccgtc cta 333 Sequence Number (ID): 137 Length: 111 Molecule Type: AAFeatures Location / Qualifiers: - source, 1..111 > mol_type, protein > organism, synthetic construct Residues: QAVLTQPSSV SGAPGQRVTI PCTGSSSNIG AGYDVNWYQQ LPGTAPKLLI FHNNIRPSGV 60 PDRFSGSKSG TSVSLAITGL QAEDEADYYC QSYDSSLSAW VFGGGTKVTV L 111 Sequence Number (ID): 138 Length: 14 Molecule Type: AA Features Location / Qualifiers: - source, 1..14 > mol_type, protein > organism, synthetic construct Residues: TGSSSNIGAG YDVN 14 Sequence Number (ID): 139 Length: 7 Molecule Type: AA Features Location / Qualifiers: - source, 1..7 > mol_type, protein > organism, synthetic construct Residues: HNNIRPS 7 Sequence Number (ID): 140 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: QSYDSSLSAW V 11 Sequence Number (ID): 141 Length: 22 Molecule Type: AA Features Location / Qualifiers: - source, 1..22 > mol_type, protein > organism, synthetic construct Residues: QAVLTQPSSV SGAPGQRVTI PC 22Sequence Number (ID): 142 Length: 15 Molecule Type: AA Features Location / Qualifiers: - source, 1..15 > mol_type, protein > organism, synthetic construct Residues: WYQQLPGTAP KLLIF 15 Sequence Number (ID): 143 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: GVPDRFSGSK SGTSVSLAIT GLQAEDEADY YC 32 Sequence Number (ID): 144 Length: 10 Molecule Type: AA Features Location / Qualifiers: - source, 1..10 > mol_type, protein > organism, synthetic construct Residues: FGGGTKVTVL 10 Sequence Number (ID): 145 Length: 366 Molecule Type: DNA Features Location / Qualifiers: - source, 1..366 > mol_type, other DNA > organism, synthetic construct Residues: gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caaaattacc cactatacta tgggctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcacgc atcacgtggg gcggtgacaa caccttttac 180 tccaactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagagact 300 acgaacctct accactacta cggtatgaac gactggggcc ggggcaccct ggtcaccgtc 360tcgagt 366 Sequence Number (ID): 146 Length: 122 Molecule Type: AA Features Location / Qualifiers: - source, 1..122 > mol_type, protein > organism, synthetic construct Residues: EVQLLESGGG LVQPGGSLRL SCAASGFKIT HYTMGWVRQA PGKGLEWVSR ITWGGDNTFY 60 SNSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKET TNLYHYYGMN DWGRGTLVTV 120 SS 122 Sequence Number (ID): 147 Length: 5 Molecule Type: AA Features Location / Qualifiers: - source, 1..5 > mol_type, protein > organism, synthetic construct Residues: HYTMG 5 Sequence Number (ID): 148 Length: 17 Molecule Type: AA Features Location / Qualifiers: - source, 1..17 > mol_type, protein > organism, synthetic construct Residues: RITWGGDNTF YSNSVKG 17 Sequence Number (ID): 149 Length: 13 Molecule Type: AA Features Location / Qualifiers: - source, 1..13 > mol_type, protein > organism, synthetic construct Residues: ETTNLYHYYG MND 13 Sequence Number (ID): 150 Length: 30 Molecule Type: AAFeatures Location / Qualifiers: - source, 1..30 > mol_type, protein > organism, synthetic construct Residues: EVQLLESGGG LVQPGGSLRL SCAASGFKIT 30 Sequence Number (ID): 151 Length: 14 Molecule Type: AA Features Location / Qualifiers: - source, 1..14 > mol_type, protein > organism, synthetic construct Residues: WVRQAPGKGL EWVS 14 Sequence Number (ID): 152 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: RFTISRDNSK NTLYLQMNSL RAEDTAVYYC AK 32 Sequence Number (ID): 153 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: WGRGTLVTVS S 11 Sequence Number (ID): 154 Length: 330 Molecule Type: DNA Features Location / Qualifiers: - source, 1..330 > mol_type, other DNA > organism, synthetic construct Residues: cagtctgtgt tgacgcagcc gccctcagtg tctgggaccc ccgggcagag ggtcaccatc 60 tcttgttatg gaagcagctc cgacatcggc aataatttcg tttactggta ccaacaagtc 120ccaggaatgg cccccaaact cctcatctac aggagtcatc agcggccctc aggggtctct 180 gaccgatttt caggctccaa gtctggcacc tcagcctccc tggccatcag tggactccgg 240 tccgaggatg aggctgatta ttactgtgca acatggggtg acaatctgcg tggttgggtt 300 ttcggcggag ggaccaagct gaccgtccta 330 Sequence Number (ID): 155 Length: 110 Molecule Type: AA Features Location / Qualifiers: - source, 1..110 > mol_type, protein > organism, synthetic construct Residues: QSVLTQPPSV SGTPGQRVTI SCYGSSSDIG NNFVYWYQQV PGMAPKLLIY RSHQRPSGVS 60 DRFSGSKSGT SASLAISGLR SEDEADYYCA TWGDNLRGWV FGGGTKLTVL 110 Sequence Number (ID): 156 Length: 13 Molecule Type: AA Features Location / Qualifiers: - source, 1..13 > mol_type, protein > organism, synthetic construct Residues: YGSSSDIGNN FVY 13 Sequence Number (ID): 157 Length: 7 Molecule Type: AA Features Location / Qualifiers: - source, 1..7 > mol_type, protein > organism, synthetic construct Residues: RSHQRPS 7 Sequence Number (ID): 158 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: ATWGDNLRGW V 11Sequence Number (ID): 159 Length: 22 Molecule Type: AA Features Location / Qualifiers: - source, 1..22 > mol_type, protein > organism, synthetic construct Residues: QSVLTQPPSV SGTPGQRVTI SC Sequence Number (ID): 160 Length: 15 Molecule Type: AA Features Location / Qualifiers: - source, 1..15 > mol_type, protein > organism, synthetic construct Residues: WYQQVPGMAP KLLIY Sequence Number (ID): 161 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: GVSDRFSGSK SGTSASLAIS GLRSEDEADY YC Sequence Number (ID): 162 Length: 10 Molecule Type: AA Features Location / Qualifiers: - source, 1..10 > mol_type, protein > organism, synthetic construct Residues: FGGGTKLTVL Sequence Number (ID): 163 Length: 360 Molecule Type: DNA Features Location / Qualifiers: - source, 1..360 > mol_type, other DNA > organism, synthetic construct Residues:gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcacgc atcacgtggg gcggtgacaa caccttttac 180 tccaactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc cagtcattat 300 ggtggctgga tttcactctt tgaccactgg gggcagggga ccacggtcac cgtctcgagt 360 Sequence Number (ID): 164 Length: 120 Molecule Type: AA Features Location / Qualifiers: - source, 1..120 > mol_type, protein > organism, synthetic construct Residues: EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYAMSWVRQA PGKGLEWVSR ITWGGDNTFY 60 SNSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCASHY GGWISLFDHW GQGTTVTVSS 120 Sequence Number (ID): 165 Length: 5 Molecule Type: AA Features Location / Qualifiers: - source, 1..5 > mol_type, protein > organism, synthetic construct Residues: SYAMS 5 Sequence Number (ID): 166 Length: 17 Molecule Type: AA Features Location / Qualifiers: - source, 1..17 > mol_type, protein > organism, synthetic construct Residues: RITWGGDNTF YSNSVKG 17 Sequence Number (ID): 167 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein> organism, synthetic construct Residues: HYGGWISLFD H Sequence Number (ID): 168 Length: 30 Molecule Type: AA Features Location / Qualifiers: - source, 1..30 > mol_type, protein > organism, synthetic construct Residues: EVQLLESGGG LVQPGGSLRL SCAASGFTFS Sequence Number (ID): 169 Length: 14 Molecule Type: AA Features Location / Qualifiers: - source, 1..14 > mol_type, protein > organism, synthetic construct Residues: WVRQAPGKGL EWVS Sequence Number (ID): 170 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: RFTISRDNSK NTLYLQMNSL RAEDTAVYYC AS Sequence Number (ID): 171 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: WGQGTTVTVS S Sequence Number (ID): 172 Length: 330 Molecule Type: DNA Features Location / Qualifiers: - source, 1..330> mol_type, other DNA > organism, synthetic construct Residues: caggctgtgc tgactcagcc gtcctcaatt tctggggccc cagggcagag ggtcaccatc 60 tcctgcactg ggaccagctc caacatcggg gcaggtaatg ctgtacactg gtaccagcag 120 cttccaggaa cagcccccag actcctcatc ttcgctgaca accgtcggcc ctcaggggtc 180 cctgaccgat tctccgcctc caagtctgcc acctcagcct ccctggccat cactgggctc 240 caggttgacg atgaggctga gtattactgc cagtcgtatg acaccaggct gcgtgtggta 300 ttcggcgggg ggaccaaggt caccgtccta 330 Sequence Number (ID): 173 Length: 110 Molecule Type: AA Features Location / Qualifiers: - source, 1..110 > mol_type, protein > organism, synthetic construct Residues: QAVLTQPSSI SGAPGQRVTI SCTGTSSNIG AGNAVHWYQQ LPGTAPRLLI FADNRRPSGV 60 PDRFSASKSA TSASLAITGL QVDDEAEYYC QSYDTRLRVV FGGGTKVTVL 110 Sequence Number (ID): 174 Length: 14 Molecule Type: AA Features Location / Qualifiers: - source, 1..14 > mol_type, protein > organism, synthetic construct Residues: TGTSSNIGAG NAVH 14 Sequence Number (ID): 175 Length: 7 Molecule Type: AA Features Location / Qualifiers: - source, 1..7 > mol_type, protein > organism, synthetic construct Residues: ADNRRPS 7 Sequence Number (ID): 176 Length: 10 Molecule Type: AAFeatures Location / Qualifiers: - source, 1..10 > mol_type, protein > organism, synthetic construct Residues: QSYDTRLRVV Sequence Number (ID): 177 Length: 22 Molecule Type: AA Features Location / Qualifiers: - source, 1..22 > mol_type, protein > organism, synthetic construct Residues: QAVLTQPSSI SGAPGQRVTI SC Sequence Number (ID): 178 Length: 15 Molecule Type: AA Features Location / Qualifiers: - source, 1..15 > mol_type, protein > organism, synthetic construct Residues: WYQQLPGTAP RLLIF Sequence Number (ID): 179 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: GVPDRFSASK SATSASLAIT GLQVDDEAEY YC Sequence Number (ID): 180 Length: 10 Molecule Type: AA Features Location / Qualifiers: - source, 1..10 > mol_type, protein > organism, synthetic construct Residues: FGGGTKVTVL Sequence Number (ID): 181 Length: 360Molecule Type: DNA Features Location / Qualifiers: - source, 1..360 > mol_type, other DNA > organism, synthetic construct Residues: gaggtgcagc tgcaggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caaaattacc cactatacta tgggctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggtag cacatactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagagggggt 300 gggactatat cagctcggtt cgacccctgg gggcaaggga ccacggtcac cgtctcgagt 360 Sequence Number (ID): 182 Length: 120 Molecule Type: AA Features Location / Qualifiers: - source, 1..120 > mol_type, protein > organism, synthetic construct Residues: EVQLQESGGG LVQPGGSLRL SCAASGFKIT HYTMGWVRQA PGKGLEWVSA ISGSGGSTYY 60 ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARGG GTISARFDPW GQGTTVTVSS 120 Sequence Number (ID): 183 Length: 5 Molecule Type: AA Features Location / Qualifiers: - source, 1..5 > mol_type, protein > organism, synthetic construct Residues: HYTMG 5 Sequence Number (ID): 184 Length: 17 Molecule Type: AA Features Location / Qualifiers: - source, 1..17 > mol_type, protein > organism, synthetic construct Residues: AISGSGGSTY YADSVKG 17Sequence Number (ID): 185 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: GGGTISARFD P Sequence Number (ID): 186 Length: 30 Molecule Type: AA Features Location / Qualifiers: - source, 1..30 > mol_type, protein > organism, synthetic construct Residues: EVQLQESGGG LVQPGGSLRL SCAASGFKIT Sequence Number (ID): 187 Length: 14 Molecule Type: AA Features Location / Qualifiers: - source, 1..14 > mol_type, protein > organism, synthetic construct Residues: WVRQAPGKGL EWVS Sequence Number (ID): 188 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: RFTISRDNSK NTLYLQMNSL RAEDTAVYYC AR Sequence Number (ID): 189 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: WGQGTTVTVS SSequence Number (ID): 190 Length: 324 Molecule Type: DNA Features Location / Qualifiers: - source, 1..324 > mol_type, other DNA > organism, synthetic construct Residues: tcttctgagc tgactcagga ccctgctgtg tctgtggcct tgggacagac agtcaggatc 60 acatgccaag gagacagcct cagaagctat tatgcaagct ggtaccagca gaagccagga 120 caggcccctg tacttgtcat ctatggtaaa aacaaccggc cctcagggat cccagaccga 180 ttctctggct ccagctcagg aaacacagct tccttgacca tcactggggc tcaggcggaa 240 gatgaggctg actattactg taactcccgg gacagcagtg gtaaccatgt ggtattcggc 300 ggagggacca agctgaccgt ccta 324 Sequence Number (ID): 191 Length: 108 Molecule Type: AA Features Location / Qualifiers: - source, 1..108 > mol_type, protein > organism, synthetic construct Residues: SSELTQDPAV SVALGQTVRI TCQGDSLRSY YASWYQQKPG QAPVLVIYGK NNRPSGIPDR 60 FSGSSSGNTA SLTITGAQAE DEADYYCNSR DSSGNHVVFG GGTKLTVL 108 Sequence Number (ID): 192 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: QGDSLRSYYA S 11 Sequence Number (ID): 193 Length: 7 Molecule Type: AA Features Location / Qualifiers: - source, 1..7 > mol_type, protein > organism, synthetic construct Residues:GKNNRPS Sequence Number (ID): 194 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: NSRDSSGNHV V Sequence Number (ID): 195 Length: 22 Molecule Type: AA Features Location / Qualifiers: - source, 1..22 > mol_type, protein > organism, synthetic construct Residues: SSELTQDPAV SVALGQTVRI TC Sequence Number (ID): 196 Length: 15 Molecule Type: AA Features Location / Qualifiers: - source, 1..15 > mol_type, protein > organism, synthetic construct Residues: WYQQKPGQAP VLVIY Sequence Number (ID): 197 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: GIPDRFSGSS SGNTASLTIT GAQAEDEADY YC Sequence Number (ID): 198 Length: 10 Molecule Type: AA Features Location / Qualifiers: - source, 1..10 > mol_type, protein > organism, synthetic constructResidues: FGGGTKLTVL 10 Sequence Number (ID): 199 Length: 366 Molecule Type: DNA Features Location / Qualifiers: - source, 1..366 > mol_type, other DNA > organism, synthetic construct Residues: gaagttcaac tgcaggcgtc cggcggtggc ctggtgcagg ctggcggctc tctgcgtctg 60 tcctgtgctg ccagcggctt taaaatcact cactatacta tgggctggtt ccgccaggca 120 ccgggcaaag agcgtgaatt cgtgagccgc atcacctggg gcggtgacaa caccttttac 180 tccaactccg ttaagggtcg ttttactatc tctcgtgata acgctaaaaa caccgtttac 240 ctgcagatga acagcctgaa accagaggac actgctgact actattgtgc tgcaggttcc 300 gcctctacgg ctgacccact gcgcgtcgac tattggggca aaggcaccca ggtgaccgtt 360 tcttcc 366 Sequence Number (ID): 200 Length: 122 Molecule Type: AA Features Location / Qualifiers: - source, 1..122 > mol_type, protein > organism, synthetic construct Residues: EVQLQASGGG LVQAGGSLRL SCAASGFKIT HYTMGWFRQA PGKEREFVSR ITWGGDNTFY 60 SNSVKGRFTI SRDNAKNTVY LQMNSLKPED TADYYCAAGS ASTADPLRVD YWGKGTQVTV 120 SS 122 Sequence Number (ID): 201 Length: 5 Molecule Type: AA Features Location / Qualifiers: - source, 1..5 > mol_type, protein > organism, synthetic construct Residues: HYTMG 5 Sequence Number (ID): 202Length: 17 Molecule Type: AA Features Location / Qualifiers: - source, 1..17 > mol_type, protein > organism, synthetic construct Residues: RITWGGDNTF YSNSVKG Sequence Number (ID): 203 Length: 13 Molecule Type: AA Features Location / Qualifiers: - source, 1..13 > mol_type, protein > organism, synthetic construct Residues: GSASTADPLR VDY Sequence Number (ID): 204 Length: 30 Molecule Type: AA Features Location / Qualifiers: - source, 1..30 > mol_type, protein > organism, synthetic construct Residues: EVQLQASGGG LVQAGGSLRL SCAASGFKIT Sequence Number (ID): 205 Length: 14 Molecule Type: AA Features Location / Qualifiers: - source, 1..14 > mol_type, protein > organism, synthetic construct Residues: WFRQAPGKER EFVS Sequence Number (ID): 206 Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: RFTISRDNAK NTVYLQMNSL KPEDTADYYC AASequence Number (ID): 207 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: WGKGTQVTVS S 11 Sequence Number (ID): 208 Length: 387 Molecule Type: DNA Features Location / Qualifiers: - source, 1..387 > mol_type, other DNA > organism, synthetic construct Residues: ggggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcagt agctatgcta tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagcaa taaatactac 180 gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagagatgat 300 attgtagtag taccagctgc taatgcgaac tactactact actacatgga cgtctggggc 360 caaggaacca cagtcaccgt ctcctca 387 Sequence Number (ID): 209 Length: 129 Molecule Type: AA Features Location / Qualifiers: - source, 1..129 > mol_type, protein > organism, synthetic construct Residues: GVQLVQSGGG VVQPGRSLRL SCAASGFTFS SYAMHWVRQA PGKGLEWVAV ISYDGSNKYY 60 ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARDD IVVVPAANAN YYYYYMDVWG 120 QGTTVTVSS 129 Sequence Number (ID): 210 Length: 5 Molecule Type: AA Features Location / Qualifiers: - source, 1..5> mol_type, protein > organism, synthetic construct Residues: SYAMH Sequence Number (ID): 211 Length: 17 Molecule Type: AA Features Location / Qualifiers: - source, 1..17 > mol_type, protein > organism, synthetic construct Residues: VISYDGSNKY YADSVKG Sequence Number (ID): 212 Length: 20 Molecule Type: AA Features Location / Qualifiers: - source, 1..20 > mol_type, protein > organism, synthetic construct Residues: DDIVVVPAAN ANYYYYYMDV Sequence Number (ID): 213 Length: 30 Molecule Type: AA Features Location / Qualifiers: - source, 1..30 > mol_type, protein > organism, synthetic construct Residues: GVQLVQSGGG VVQPGRSLRL SCAASGFTFS Sequence Number (ID): 214 Length: 14 Molecule Type: AA Features Location / Qualifiers: - source, 1..14 > mol_type, protein > organism, synthetic construct Residues: WVRQAPGKGL EWVA Sequence Number (ID): 215 Length: 32 Molecule Type: AA Features Location / Qualifiers:- source, 1..32 > mol_type, protein > organism, synthetic construct Residues: RFTISRDNSK NTLYLQMNSL RAEDTAVYYC AR 32 Sequence Number (ID): 216 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: WGQGTTVTVS S 11 Sequence Number (ID): 217 Length: 321 Molecule Type: DNA Features Location / Qualifiers: - source, 1..321 > mol_type, other DNA > organism, synthetic construct Residues: gacatccaga tgacccagtc tccatccttc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggccagtca gggcattaac aattatttag cctggtatca gcaaaaacca 120 gggagagccc ctaagctcct gatctacgct gcatccagtt tacaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tggcacagat ttcactctca ccatcagcag cctgcagcct 240 gaagattttg caacttatta ctgtctccaa gattccgatt atcccctcac tttcggcgga 300 gggaccaagc tggagatcaa a 321 Sequence Number (ID): 218 Length: 107 Molecule Type: AA Features Location / Qualifiers: - source, 1..107 > mol_type, protein > organism, synthetic construct Residues: DIQMTQSPSF LSASVGDRVT ITCRASQGIN NYLAWYQQKP GRAPKLLIYA ASSLQSGVPS 60 RFSGSGSGTD FTLTISSLQP EDFATYYCLQ DSDYPLTFGG GTKLEIK 107 Sequence Number (ID): 219 Length: 11Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: RASQGINNYL A Sequence Number (ID): 220 Length: 7 Molecule Type: AA Features Location / Qualifiers: - source, 1..7 > mol_type, protein > organism, synthetic construct Residues: AASSLQS Sequence Number (ID): 221 Length: 9 Molecule Type: AA Features Location / Qualifiers: - source, 1..9 > mol_type, protein > organism, synthetic construct Residues: LQDSDYPLT Sequence Number (ID): 222 Length: 23 Molecule Type: AA Features Location / Qualifiers: - source, 1..23 > mol_type, protein > organism, synthetic construct Residues: DIQMTQSPSF LSASVGDRVT ITC Sequence Number (ID): 223 Length: 15 Molecule Type: AA Features Location / Qualifiers: - source, 1..15 > mol_type, protein > organism, synthetic construct Residues: WYQQKPGRAP KLLIY Sequence Number (ID): 224Length: 32 Molecule Type: AA Features Location / Qualifiers: - source, 1..32 > mol_type, protein > organism, synthetic construct Residues: GVPSRFSGSG SGTDFTLTIS SLQPEDFATY YC 32 Sequence Number (ID): 225 Length: 10 Molecule Type: AA Features Location / Qualifiers: - source, 1..10 > mol_type, protein > organism, synthetic construct Residues: FGGGTKLEIK 10 Sequence Number (ID): 226 Length: 128 Molecule Type: AA Features Location / Qualifiers: - source, 1..128 > mol_type, protein > organism, synthetic construct Residues: EVHLLESGGG LVQPGGSLRL SCAASGFTFS SYAMSWVRQA PGKGLEWVSA ISGSGGSTYY 60 AHSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKNY YYDTSAYYYV GSDYFDYWGQ 120 GTMVTVSS 128 Sequence Number (ID): 227 Length: 110 Molecule Type: AA Features Location / Qualifiers: - source, 1..110 > mol_type, protein > organism, synthetic construct Residues: QSALTQPASV SGSPGQSITI SCTATSSNVG AYNFVSWYQQ HPGKAPKVLI YRVSNRPSGV 60 SNRFSGSKSG NTASLTISGL QADEEADYYC SSYTTDYIWV FGGGTKLTVL 110 Sequence Number (ID): 228 Length: 14 Molecule Type: AA Features Location / Qualifiers: - source, 1..14> mol_type, protein > organism, synthetic construct Residues: GGGGSGGGGS GGGG Sequence Number (ID): 229 Length: 17 Molecule Type: AA Features Location / Qualifiers: - source, 1..17 > mol_type, protein > organism, synthetic construct Residues: GGGGSGGGGS GGGGSAL Sequence Number (ID): 230 Length: 15 Molecule Type: AA Features Location / Qualifiers: - source, 1..15 > mol_type, protein > organism, synthetic construct Residues: GGGGSGGGGS GGGGS Sequence Number (ID): 231 Residues: 000 Sequence Number (ID): 232 Residues: 000 Sequence Number (ID): 233 Length: 16 Molecule Type: AA Features Location / Qualifiers: - source, 1..16 > mol_type, protein > organism, synthetic construct Residues: GGGGSGGGGS GGGGSA Sequence Number (ID): 234 Length: 117 Molecule Type: AA Features Location / Qualifiers: - source, 1..117> mol_type, protein > organism, Homo sapiens Residues: EVQLVQSGAE VKKPGESLKI SCKGSGYIFT NYWIAWVRQM PGKGLESMGI IYPGDSDIRY 60 SPSFQGQVTI SADKSITTAY LQWSSLKASD TAMYYCARHD IEGFDYWGRG TLVTVSS 117 Sequence Number (ID): 235 Length: 108 Molecule Type: AA Features Location / Qualifiers: - source, 1..108 > mol_type, protein > organism, Homo sapiens Residues: EIVLTQSPGT LSLSPGERAT LSCRASQSVS SSFFAWYQQK PGQAPRLLIY GASSRATGIP 60 DRLSGSGSGT DFTLTITRLE PEDFAVYYCQ QYDSSAITFG QGTRLEIK 108 Sequence Number (ID): 236 Length: 5 Molecule Type: AA Features Location / Qualifiers: - source, 1..5 > mol_type, protein > organism, synthetic construct Residues: NYWIA 5 Sequence Number (ID): 237 Length: 17 Molecule Type: AA Features Location / Qualifiers: - source, 1..17 > mol_type, protein > organism, synthetic construct Residues: IIYPGDSDIR YSPSFQG 17 Sequence Number (ID): 238 Length: 8 Molecule Type: AA Features Location / Qualifiers: - source, 1..8 > mol_type, protein > organism, synthetic construct Residues: HDIEGFDY 8Sequence Number (ID): 239 Length: 12 Molecule Type: AA Features Location / Qualifiers: - source, 1..12 > mol_type, protein > organism, synthetic construct Residues: RASQSVSSSF FA 12 Sequence Number (ID): 240 Length: 7 Molecule Type: AA Features Location / Qualifiers: - source, 1..7 > mol_type, protein > organism, synthetic construct Residues: GASSRAT 7 Sequence Number (ID): 241 Length: 9 Molecule Type: AA Features Location / Qualifiers: - source, 1..9 > mol_type, protein > organism, synthetic construct Residues: QQYDSSAIT 9 Sequence Number (ID): 242 Length: 107 Molecule Type: AA Features Location / Qualifiers: - source, 1..107 > mol_type, protein > organism, Homo sapiens Residues: RTVAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG NSQESVTEQD 60 SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC 107 Sequence Number (ID): 243 Length: 330 Molecule Type: AA Features Location / Qualifiers: - source, 1..330 > mol_type, protein > organism, Homo sapiens Residues:ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 60 GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPEFEGG 120 PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 180 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPASIEKTIS KAKGQPREPQ VYTLPPSREE 240 MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW 300 QQGNVFSCSV MHEALHNHYT QKSLSLSPGK 330 Sequence Number (ID): 244 Length: 440 Molecule Type: AA Features Location / Qualifiers: - source, 1..440 > mol_type, protein > organism, Homo sapiens Residues: EVQLVQSGAE VKKPGESLKI SCKGSGYIFT NYWIAWVRQM PGKGLESMGI IYPGDSDIRY 60 SPSFQGQVTI SADKSITTAY LQWSSLKASD TAMYYCARHD IEGFDYWGRG TLVTVSSAST 120 KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY 180 SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKRVEPKSC DKTHTCPPCP APEFEGGPSV 240 FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY 300 RVVSVLTVLH QDWLNGKEYK CKVSNKALPA SIEKTISKAK GQPREPQVYT LPPSREEMTK 360 NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG 420 NVFSCSVMHE ALHNHYTQKS 440 Sequence Number (ID): 245 Length: 215 Molecule Type: AA Features Location / Qualifiers: - source, 1..215 > mol_type, protein > organism, Homo sapiens Residues: EIVLTQSPGT LSLSPGERAT LSCRASQSVS SSFFAWYQQK PGQAPRLLIY GASSRATGIP 60 DRLSGSGSGT DFTLTITRLE PEDFAVYYCQ QYDSSAITFG QGTRLEIKRT VAAPSVFIFP 120 PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS QESVTEQDSK DSTYSLSSTL 180 TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC 215Sequence Number (ID): 246 Length: 80 Molecule Type: AA Features Location / Qualifiers: - source, 1..80 > mol_type, protein > organism, synthetic construct Residues: EVQLVQSGAE VKKPGESLRI SCKGSGYTFT NYWVAWVRQM PGKGLESMGI IYPGDSDTRY 60 SPSFQGHVTI SADKSISTAY 80 Sequence Number (ID): 247 Length: 108 Molecule Type: AA Features Location / Qualifiers: - source, 1..108 > mol_type, protein > organism, synthetic construct Residues: DIQMTQSPSS LSASLGDRVT ITCRASQNVG NYLNWYQQKP GKAPKLLIYR ASNLASGVPS 60 RFSGSGSGTD FTLTISSLQP EDFATYYCQQ MEHAPPTFGQ GTKVEIKR 108 Sequence Number (ID): 248 Length: 108 Molecule Type: AA Features Location / Qualifiers: - source, 1..108 > mol_type, protein > organism, synthetic construct Residues: EIVLTQSPGT LSLSPGERAT LSCRASQSVI GYYLAWYQQK PGQAPRLLIY SVSTLASGIP 60 DRFSGSGSGT DFTLTISRLE PEDFAVYYCQ QYYRFPITFG QGTKVEIK 108 Sequence Number (ID): 249 Length: 117 Molecule Type: AA Features Location / Qualifiers: - source, 1..117 > mol_type, protein > organism, synthetic construct Residues: EVQLVQSGAE VKKPGESLRI SCKGSGYTFT NYWMAWVRQM PGKGLESMGI IYPSDSDTRY 60 SPSFQGHVTI SADKSISTAY LQWSSLKASD TAMYYCARHD VEGYDYWGQG TLVTVSS 117 Sequence Number (ID): 250Length: 119 Molecule Type: AA Features Location / Qualifiers: - source, 1..119 > mol_type, protein > organism, synthetic construct Residues: EVQLVESGGG LVQPGGSLRL SCAASGFSLS SYYMTWVRQA PGKGLEWVSV INVYGGTYYA 60 SWAKGRFTIS RDNSKNTLYL QMNSLRAEDT AVYYCAREDV AVYMAIDLWG QGTLVTVSS 119 Sequence Number (ID): 251 Length: 111 Molecule Type: AA Features Location / Qualifiers: - source, 1..111 > mol_type, protein > organism, synthetic construct Residues: AIQMTQSPSS LSASVGDRVT ITCQASQSIS NQLSWYQQKP GKAPKLLIYD ASSLASGVPS 60 RFSGSRSGTK FTLTISSLQP EDFATYYCLG IYGDGADDGI AFGGGTKVEI K 111 Sequence Number (ID): 252 Length: 5 Molecule Type: AA Features Location / Qualifiers: - source, 1..5 > mol_type, protein > organism, synthetic construct Residues: SYYMT 5 Sequence Number (ID): 253 Length: 16 Molecule Type: AA Features Location / Qualifiers: - source, 1..16 > mol_type, protein > organism, synthetic construct Residues: VINVYGGTYY ASWAKG 16 Sequence Number (ID): 254 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic constructResidues: EDVAVYMAID L 11 Sequence Number (ID): 255 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: QASQSISNQL S 11 Sequence Number (ID): 256 Length: 7 Molecule Type: AA Features Location / Qualifiers: - source, 1..7 > mol_type, protein > organism, synthetic construct Residues: DASSLAS 7 Sequence Number (ID): 257 Length: 13 Molecule Type: AA Features Location / Qualifiers: - source, 1..13 > mol_type, protein > organism, synthetic construct Residues: LGIYGDGADD GIA 13 Sequence Number (ID): 258 Length: 123 Molecule Type: AA Features Location / Qualifiers: - source, 1..123 > mol_type, protein > organism, synthetic construct Residues: GVQLVQSGAE LKKPGSSVKV SCKASGGTFS SYAISWVRQA PGQGLEWMGR IIPILGTSNY 60 AQKFQGRVTI TADERTSTAY MELSSLRSED TAVYYCARRS SLAAADRGAF DIWGQGTMVT 120 VSS 123 Sequence Number (ID): 259 Length: 369Molecule Type: DNA Features Location / Qualifiers: - source, 1..369 > mol_type, other DNA > organism, synthetic construct Residues: caggtccagc tggtgcagtc tggggcagag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgtaagg cttctggagg caccttcagc agttatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta ttcttggtac atcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggacg aatctacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtat attactgtgc gagaaggagt 300 agtttagcag cagcggatag gggggctttt gatatctggg gccaggggac aatggtcacc 360 gtctcctca 369 Sequence Number (ID): 260 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct - VARIANT, 6 > note, T or R - VARIANT, 7 > note, S, R, or T - VARIANT, 10 > note, A or T - VARIANT, 11 > note, N or S Residues: QGDSLXXYYX X 11 Sequence Number (ID): 261 Length: 7 Molecule Type: AA Features Location / Qualifiers: - source, 1..7 > mol_type, protein > organism, synthetic construct - VARIANT, 2 > note, K or E - VARIANT, 3 > note, N or D Residues: GXXNRPS 7Sequence Number (ID): 262 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct - VARIANT, 5 > note, S or N - VARIANT, 6 > note, S or T - VARIANT, 8 > note, N, K, or H - VARIANT, 9 > note, H or P - VARIANT, 10 > note, V or W Residues: NSRDXXGXXX V Sequence Number (ID): 263 Length: 5 Molecule Type: AA Features Location / Qualifiers: - source, 1..5 > mol_type, protein > organism, synthetic construct Residues: GGGGS Sequence Number (ID): 264 Length: 10 Molecule Type: AA Features Location / Qualifiers: - source, 1..10 > mol_type, protein > organism, synthetic construct Residues: GGGGSGGGGS Sequence Number (ID): 265 Length: 15 Molecule Type: AA Features Location / Qualifiers: - source, 1..15 > mol_type, protein > organism, synthetic construct Residues: GGGGSGGGGS GGGGSSequence Number (ID): 266 Length: 20 Molecule Type: AA Features Location / Qualifiers: - source, 1..20 > mol_type, protein > organism, synthetic construct Residues: GGGGSGGGGS GGGGSGGGGS Sequence Number (ID): 267 Length: 25 Molecule Type: AA Features Location / Qualifiers: - source, 1..25 > mol_type, protein > organism, synthetic construct Residues: GGGGSGGGGS GGGGSGGGGS GGGGS Sequence Number (ID): 268 Length: 30 Molecule Type: AA Features Location / Qualifiers: - source, 1..30 > mol_type, protein > organism, synthetic construct Residues: GGGGSGGGGS GGGGSGGGGS GGGGSGGGGS Sequence Number (ID): 269 Length: 35 Molecule Type: AA Features Location / Qualifiers: - source, 1..35 > mol_type, protein > organism, synthetic construct Residues: GGGGSGGGGS GGGGSGGGGS GGGGSGGGGS GGGGS Sequence Number (ID): 270 Length: 40 Molecule Type: AA Features Location / Qualifiers: - source, 1..40 > mol_type, protein > organism, synthetic construct Residues:GGGGSGGGGS GGGGSGGGGS GGGGSGGGGS GGGGSGGGGS Sequence Number (ID): 271 Length: 45 Molecule Type: AA Features Location / Qualifiers: - source, 1..45 > mol_type, protein > organism, synthetic construct Residues: GGGGSGGGGS GGGGSGGGGS GGGGSGGGGS GGGGSGGGGS GGGGS Sequence Number (ID): 272 Length: 50 Molecule Type: AA Features Location / Qualifiers: - source, 1..50 > mol_type, protein > organism, synthetic construct Residues: GGGGSGGGGS GGGGSGGGGS GGGGSGGGGS GGGGSGGGGS GGGGSGGGGS Sequence Number (ID): 273 Length: 6 Molecule Type: AA Features Location / Qualifiers: - source, 1..6 > mol_type, protein > organism, synthetic construct Residues: SGGGGS Sequence Number (ID): 274 Length: 11 Molecule Type: AA Features Location / Qualifiers: - source, 1..11 > mol_type, protein > organism, synthetic construct Residues: SGGGGSGGGG S Sequence Number (ID): 275 Length: 16 Molecule Type: AA Features Location / Qualifiers: - source, 1..16 > mol_type, protein > organism, synthetic constructResidues: SGGGGSGGGG SGGGGS Sequence Number (ID): 276 Length: 21 Molecule Type: AA Features Location / Qualifiers: - source, 1..21 > mol_type, protein > organism, synthetic construct Residues: SGGGGSGGGG SGGGGSGGGG S Sequence Number (ID): 277 Length: 26 Molecule Type: AA Features Location / Qualifiers: - source, 1..26 > mol_type, protein > organism, synthetic construct Residues: SGGGGSGGGG SGGGGSGGGG SGGGGS Sequence Number (ID): 278 Length: 31 Molecule Type: AA Features Location / Qualifiers: - source, 1..31 > mol_type, protein > organism, synthetic construct Residues: SGGGGSGGGG SGGGGSGGGG SGGGGSGGGG S Sequence Number (ID): 279 Length: 36 Molecule Type: AA Features Location / Qualifiers: - source, 1..36 > mol_type, protein > organism, synthetic construct Residues: SGGGGSGGGG SGGGGSGGGG SGGGGSGGGG SGGGGS Sequence Number (ID): 280 Length: 41 Molecule Type: AA Features Location / Qualifiers: - source, 1..41 > mol_type, protein> organism, synthetic construct Residues: SGGGGSGGGG SGGGGSGGGG SGGGGSGGGG SGGGGSGGGG S Sequence Number (ID): 281 Length: 46 Molecule Type: AA Features Location / Qualifiers: - source, 1..46 > mol_type, protein > organism, synthetic construct Residues: SGGGGSGGGG SGGGGSGGGG SGGGGSGGGG SGGGGSGGGG SGGGGS Sequence Number (ID): 282 Length: 51 Molecule Type: AA Features Location / Qualifiers: - source, 1..51 > mol_type, protein > organism, synthetic construct Residues: SGGGGSGGGG SGGGGSGGGG SGGGGSGGGG SGGGGSGGGG SGGGGSGGGG S Sequence Number (ID): 283 Length: 108 Molecule Type: AA Features Location / Qualifiers: - source, 1..108 > mol_type, protein > organism, synthetic construct - VARIANT, 15 > note, R or G - VARIANT, 28 > note, T or R - VARIANT, 29 > note, S, R, or T - VARIANT, 32 > note, A or T - VARIANT, 33 > note, N or S - VARIANT, 37 > note, H or Q - VARIANT, 47 > note, M or I - VARIANT, 50 > note, K or E - VARIANT, 51 > note, N or D - VARIANT, 57 > note, V or I- VARIANT, 65 > note, S or R - VARIANT, 68 > note, N or T - VARIANT, 92 > note, S or N - VARIANT, 93 > note, S or T - VARIANT, 95 > note, N, K, or H - VARIANT, 96 > note, H or P - VARIANT, 97 > note, V or W Residues: SSELTQDPAV SVALXQTVRI TCQGDSLXXY YXXWYQXKPG QAPVLVXYGX XNRPSGXPDR 60 FSGSXSGXTA SLTITGAQAE DEADYYCNSR DXXGXXXVFG GGTKLTVL 108 END

Claims

CLAIMS 1. A method of treating or preventing a neurodegenerative disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an inhibitor of type I IFN signalling.

2. The method of the claim 1, wherein the inhibitor of type I IFN signalling is a type I IFN receptor (IFNAR1) inhibitor.

3. The method of claim 2, wherein the IFNAR1 inhibitor is a human monoclonal antibody specific for IFNAR1, optionally a modified IgG1 class human monoclonal antibody.

4. The method of claim 3, wherein the antibody comprises: (a) a heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 236; (b) a heavy chain variable region complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 237; (c) a heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 238; (d) a light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence SEQ ID NO: 239; (e) a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence SEQ ID NO: 240; and / or (f) a light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence SEQ ID NO:

241.

5. The method of claim 3 or 4, wherein the antibody comprises: (a) a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 234; and (b) a human light chain variable region comprising the amino acid sequence of SEQ ID NO:

235.

6. The method of any of claims 3 to 5, wherein the antibody comprises an Fc region comprising an amino acid substitution of L234F, as numbered by the EU index as set forth in Kabat, and wherein said antibody exhibits reduced affinity for at least one Fc ligand compared to an unmodified antibody, optionally wherein the antibody comprises in the Fc region an amino acid substitution of L235E and / or P331S, as numbered by the EU index as set forth in Kabat.

7. The method of any of claims 3 to 6, wherein the antibody comprises: (a) a human heavy chain comprising the amino acid sequence of SEQ ID NO: 244; and (b) a human light chain comprising the amino acid sequence of SEQ ID NO:

245.

8. The method of any of claims 3 to 7, wherein the antibody is Anifrolumab or a functional variant thereof.

9. The method of any of the preceding claims, wherein the inhibitor is capable of crossing the blood brain barrier.

10. The method of claim 9, wherein the inhibitor comprises a blood brain barrier transporter molecule.

11. The method of claim 10, wherein the blood brain barrier transporter molecule binds to brain microvascular endothelial cells (BMVECs).

12. The method of claim 11, wherein the BMVECs are brain capillary endothelial cells (BCECs).

13. The method of any of claims 10 to 12, wherein the blood brain barrier transporter molecule binds to antigen on the surface of brain capillary endothelial cells.

14. The method of any of claims 10 to 13, wherein the blood brain barrier transporter molecule is a humanised isolated antibody or antigen binding fragment thereof.

115. The method of claim 14, wherein the antibody or antigen binding fragment thereof comprises: (a) a heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 21; (b) a heavy chain variable region complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 22; (c) a heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 23; (d) a light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence SEQ ID NO: 30; (e) a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence SEQ ID NO: 31; and / or (f) a light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence SEQ ID NO:

32.

16. The method of claim 14 or claim 15, wherein the antibody or antigen binding fragment thereof comprises: (a) a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 20; and (b) a human light chain variable region comprising the amino acid sequence of SEQ ID NO:

29.

17. The method of any of claims 14 to 16, wherein the antibody or antigen binding fragment thereof comprises an IgG constant domain or fragment thereof comprising one or more amino acid substitutions relative to a wild-type IgG constant domain wherein the modified IgG has an increased half-life and / or increase binding affinity for FcRn compared to half-life of an IgG having the wild-type IgG constant domain.

18. The method of any preceding claim, wherein the inhibitor of type I IFN signalling comprises a linker sequence.

19. The method of claim 18, wherein the linker sequence comprises the sequence of SEQ ID NO:

228.

20. The method of any of claims 1 to 19, wherein the inhibitor of type I IFN signalling comprises a variable chain heavy region comprising SEQ ID NO: 234, a variable chain light region comprising SEQ ID: 235, and constant chain light region comprising SEQ ID: 242, a constant chain heavy region comprising SEQ ID: 243, a linker sequence comprising the sequence of SEQ ID NO: 228, a heavy chain variable region comprising SEQ ID NO: 20, a light chain variable region comprising SEQ ID NO:

29.

21. The method of any preceding claim, wherein the neurodegenerative disorder is Amyotrophic Lateral Sclerosis (ALS).

22. The method of any preceding claim, wherein the patient has high interferon gene signature expression compared to a healthy subject.

23. The method of claim 22, wherein the high interferon gene signature comprises elevated expression of the genes Interferon Alpha Inducible Protein 27 (IFI27), Interferon Induced Protein 44 (IFI44), Interferon Induced Protein 44 like (IFI44L), and Radical S-Adenosyl Methionine Domain Containing 2 (RSAD2) compared to a healthy subject.

24. The method of claim 22 or claim 23, wherein the high interferon gene signature expression is determined by an increased expression of IFI27, IFI44, IFI44L, and RSAD2 relative to expression of one or more control genes.

25. A pharmaceutical composition for use in any of the methods of claims 1 to 24, comprising an inhibitor of type I IFN signalling.

26. An injection device comprising the pharmaceutical composition of claim 25.

27. The injection device of claim 26, wherein the injection device is a pre-filled syringe (PFS).

228. The injection device of claim 27, wherein the injection device is an accessorized pre-filled syringe (AFPS).

29. The injection device of claim 26 wherein the injection device is an auto-injector.

30. A kit comprising the injection device of any of claims 26 to 29, and instructions for use.

31. The kit of claim 30, wherein the instructions for use comprise instructions for use according to the method of claims 1-24.

32. The kit of claim 30 or 31, wherein the instructions for use specify that the injection device and / or pharmaceutical composition are for use in the treatment of ALS.

33. The kit of any of claims 30 to 32, comprising packaging, wherein the packaging is adapted to hold the injection device and the instructions for use.

34. The kit of any of claims 30 to 33, wherein the instructions for use are attached to the injection device.

35. The method of claim 1, wherein the inhibitor is selected from the group consisting of: sifalimumab, PF-06823859, LABP-104, SAR443122, litifilimab, deucravacitinib, ABBV-599 and baricitinib. 3

Images