Transferrin receptor-targeting agents and GCN2 inhibitors

Abstract

The present application relates to complexes comprising a transferrin receptor (TfRl)- targeting agent covalently linked to a molecular payload (e.g., an oligonucleotide) for delivery to cells (e.g., muscle cells and / or cells of the CNS) and uses thereof in combination with GCN2 inhibitors, particularly uses relating to treatment of disease.

Description

TRANSFERRIN RECEPTOR-TARGETING AGENTS AND GCN2 INHIBITORS RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U. S. C § 119(e) of the filing date of U. S.Provisional Application No. 63 / 749,199, entitled “TRANSFERRIN RECEPTORTARGETING AGENTS AND GCN2 INHIBITORS”, filed January 24, 2025, the contents of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION

[0002] The present application relates to combinations of GCN2 inhibitors with transferrin receptor (TfRl)-targeting agents (e.g., TfRl -targeting complexes) for delivering molecular payloads to cells (e.g., muscle cells and / or cells of the central nervous system), formulations comprising such agents and inhibitors, and uses thereof, particularly uses relating to treatment of disease.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0003] The contents of the electronic sequence listing (D082470091WO00-SEQ-KGC.xml; Size: 3,642,097 bytes; and Date of Creation: January 14, 2026) are incorporated herein by reference in their entirety.BACKGROUND

[0004] Numerous diseases result from genetic mutations that may be amenable to exon skipping therapeutics. For example, multiple therapeutics that facilitate exon-skipping have been approved for Duchenne muscular dystrophy. These therapeutics generally facilitate skipping of exons containing premature stop codons, resulting in mature mRNA transcripts having functional reading frames.

[0005] Muscle disease and neurological diseases may be particularly promising targets for exon skipping therapeutics, and many have few or no treatment options. Therapeutic compounds in various muscle and / or neurological conditions often fail to achieve their intended effects or are limited in their efficacy because of limitations in their biodistribution, e.g., because of inability to enter muscle cells or inability to efficiently cross the blood-brain barrier.1 / 350#14837954v1SUMMARY

[0006] The present disclosure is based in part on the development of transferrin receptor (TfRl) targeting compounds that facilitate delivery of therapeutic cargoes to muscle cells and / or cells of the central nervous system (CNS). Some such therapeutic cargoes may be limited in their efficacy even after successful delivery because of poor expression of functional protein after transcription of disease-causing genes. The combination of TfRl -targeting compounds (e.g., anti-TfR1 antibody-molecular payload complexes) which can facilitate modulation of disease-causing genes, with inhibitors of GCN2, which can improve protein expression, can improve outcomes in treatment of diseases or disorders (e.g., muscle and / or CNS diseases or disorders).

[0007] According to some aspects, the present disclosure provides methods of treating a disease or disorder in a subject in need thereof. In some embodiments, a method of treating a disease or disorder in a subject in need thereof comprises administering to the subject:(i) a complex comprising an anti-TfR1 antibody covalently linked to a molecular payload, wherein the anti-TfR1 antibody comprises:(a) a heavy chain complementarity determining region 1 (CDR-H1) having the amino acid sequence of SEQ ID NO: 27, a heavy chain complementarity determining region 2 (CDR-H2) having the amino acid sequence of SEQ ID NO: 28, a heavy chain complementarity determining region 3 (CDR-H3) having the amino acid sequence of SEQ ID NO: 29, a light chain complementarity determining region 1 (CDR-L1) having the amino acid sequence of SEQ ID NO: 30, a light chain complementarity determining region 2 (CDR-L2) having the amino acid sequence of SEQ ID NO: 31, and a light chain complementarity determining region 3 (CDR-L3) having the amino acid sequence of SEQ ID NO: 32;(b) a CDR-H1 having the amino acid sequence of SEQ ID NO: 33, a CDR-H2 having the amino acid sequence of SEQ ID NO: 34, a CDR-H3 having the amino acid sequence of SEQ ID NO: 35, a CDR-L1 having the amino acid sequence of SEQ ID NO: 36, a CDR-L2 having the amino acid sequence of SEQ ID NO: 37, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 32; or(c) a CDR-H1 having the amino acid sequence of SEQ ID NO: 38, a CDR-H2 having the amino acid sequence of SEQ ID NO: 39, a CDR-H3 having the amino acid sequence of SEQ ID NO: 40, a CDR-L1 having the amino acid sequence of SEQ ID NO: 41, a CDR-L2 having the amino acid sequence of SEQ ID NO: 31, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 42; and2 / 350#14837954v1(ii) a GCN2 inhibitor.

[0008] In some embodiments, the anti-TfR1 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 76 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 75.

[0009] In some embodiments, the anti-TfR1 antibody comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 101 and a light chain comprising an amino acid sequence of SEQ ID NO: 90.

[0010] In some embodiments, the anti-TfR1 antibody is a Fab.

[0011] In some embodiments, the molecular payload is configured to modulate expression of a gene associated with the disease or disorder.

[0012] In some embodiments, the molecular payload is configured for inducing exon skipping.

[0013] In some embodiments, the molecular payload comprises an oligonucleotide. In some embodiments, the oligonucleotide comprises a region of complementarity to any one of SEQ ID NOs: 160-1460. In some embodiments, the region of complementarity is at least 15 nucleotides in length. In some embodiments, the oligonucleotide comprises at least 12 consecutive nucleotides of a sequence of any one of SEQ ID NOs: 1461-4062, wherein each thymine base (T) may independently and optionally be replaced with a uracil base (U), and each U may independently and optionally be replaced with a T. In some embodiments, the oligonucleotide comprises a sequence of any one of SEQ ID NOs: 1461-4062, wherein each thymine base (T) may independently and optionally be replaced with a uracil base (U), and each U may independently and optionally be replaced with a T.

[0014] In some embodiments, the complex comprises a structure of formula (J):wherein n is any number from 0-10, wherein m is any number from 0-10, optionally wherein n is 3 and / or m is 4, and wherein " represents an indirect or direct linkage.3 / 350#14837954v1

[0015] In some embodiments, the anti-TfR1 antibody is covalently linked to the molecular payload via a linker comprising a structure of formula (I):wherein n is any number from 0-10, and wherein m is any number from 0-10, optionally wherein n is 3 and / or m is 4.

[0016] In some embodiments, the complex comprises a structure of formula (E):wherein n is any number from 0-10, wherein m is any number from 0-10. In some embodiments, n is 3 and / or m is 4.

[0017] In some embodiments, LI is a spacer that is a substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -O-, -N(RA)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, -NRAC(=O)O-, -NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, -NRAS(O)2-, or a combination thereof, wherein each RAis independently hydrogen or substituted or unsubstituted alkyl.

[0018] In some embodiments, LI is4 / 350#14837954v1; wherein a labels the site directly linked to the carbamate moiety of formula (I) and b labels the site covalently linked to the molecular payload.

[0019] In some embodiments, the anti-TfR1 antibody is covalently linked to the molecular payload via a linker comprising a structure of:

[0020] In some embodiments, the complex comprises a structure formula (L): [R^ni-R2, in which each instance of R1independently comprises a structure of the formula (La):5 / 350#14837954v1Molecular payload(La), wherein R1is covalently linked to R2at attachment point A, wherein R2comprises the antibody, wherein the linker is linked to the antibody via an amine group.

[0021] In some embodiments, the complex comprises a structure formula (L): [R^ni-R2, in which each instance of R1independently comprises a structure of the formula (Lb):> molecular payload >n1(Lb),wherein R2comprises the antibody; wherein nl is an integer representing the number of instances of the group enclosed by square brackets, and wherein each instance of the group enclosed by square brackets is covalently linked to a different amino acid residue of the antibody, optionally wherein each different amino acid residue is a lysine.

[0022] In some embodiments, the complex comprises a structure of formula (L): [R^ni- R2, in which each instance of R1comprises a structure of the formula (Lb-1):6 / 350#14837954v1pC-pT-pC-pC-pA-pA-pC-pA-pT-pC-pA-pA-pG-pG-pA-pA-pG-pA-pT-pG-pG-pC-pA-pT-pT-pT-pC-pT-pA-pG-3'(Lb-1),in which -pN indicates a base position of a phosphorodiamidate morpholino oligomer (PMO); wherein R1is covalently linked to R2at attachment point A, wherein R2comprises the antibody, wherein -p reflects a phosphorodiamidate linkage, and wherein N corresponds to a nucleobase of adenine (A), cytosine (C), guanine (G), or thymine (T), such that the PMO comprises a base sequence of CTCCAACATCAAGGAAGATGGCATTTCTAG (SEQ ID NO: 2762).

[0023] In some embodiments, the complex comprises a structure of formula (L): [R^ni- R2, in which each instance of R1comprises a structure of the formula (Lc):(Lc),7 / 350#14837954v1wherein nl is an integer representing the number of instances of R1in each complex and each R1is covalently linked to R2at attachment point

[0024] In some embodiments, the complex comprises a structure of formula (L): [R^ni- R2, in which each instance of R1comprises a structure of the formula (Ld):> pC-pT-pC-pC-pA-pA-pC-pA-pT-pC-pA-pA-pG-pG-pA-pA-pG-pA-pT-pG-pG-pC-pA-pT-pT-pT-pC-pT-pA-pG-3' >(Ld), in which -pN indicates a base position of a phosphorodiamidate morpholino oligomer (PMO); wherein -p reflects a phosphorodiamidate linkage, and wherein N corresponds to a nucleobase of adenine (A), cytosine (C), guanine (G), or thymine (T), such that the PMO comprises a base sequence of CTCCAACATCAAGGAAGATGGCATTTCTAG (SEQ ID NO: 2762); wherein R2comprises the antibody; wherein nl is an integer representing the number of instances of the group enclosed by square brackets, and wherein each instance of the group enclosed by square brackets is covalently linked to a different amino acid residue of the antibody, optionally wherein each different amino acid residue is a lysine.

[0025] In some embodiments, LI is:wherein a labels; wherein a labels the site directly linked to the carbamate moiety of formula (I) and b labels the site covalently linked to the molecular payload.

[0026] In some embodiments,LI is8 / 350#14837954v1

[0027] In some embodiments, the GCN2 inhibitor is selected from the group consisting of: N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-2,5-dichlorobenzene-l-sulfonamide;N-{3-[(2-aminopyrimidin-5-yl)ethynyl]-2,4-difluorophenyl}-5-chl oro-2-methoxypyridine-3 -carboxamide;N-{3-[6-(2-aminopyrimidin-5-yl)pyridin-3-yl]-2,4-difluorophenyl}-5-chl oro-2-methoxypyridine-3 -sulfonamide;N-[3-(2-aminoquinazolin-7-yl)-2,4-difluorophenyl]-2,5-dichlorobenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-7-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;5-({3-[5-(5-chloro-2-methoxypyridin-3-yl)-l,3,4-oxadiazol-2-yl]-2,6-difluorophenyl}ethynyl)pyrimidin-2-amine;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-2,5-difluorobenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-3,4-dichlorobenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxybenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2-methylphenyl]-2,5-dichlorobenzene-1-sulfonamide; N-[3-(2-aminoquinazolin-6-yl)-2,6-difluorophenyl]-2,5-dichlorobenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2-fluorophenyl]-2,5-dichlorobenzene-l-sulfonamide; N-[3-(2-aminoquinazolin-6-yl)-5-fluorophenyl]-2,5-dichlorobenzene-l-sulfonamide; N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-2,4-dichlorobenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-4-methylphenyl]-2,5-dichlorobenzene-1-sulfonamide; N-[3-(4-aminoquinazolin-6-yl)-2,4-difluorophenyl]-2,5-dichlorobenzene-l-sulfonamide;2,5-dichloro-N-[2,4-difluoro-3-(7-fluoro-lH-benzimidazol-5-yl)phenyl]benzene-l-sulfonamide;9 / 350#14837954v1N-[3-(2-aminoquinazolin-6-yl)-4-fluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-aminoquinolin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(3-aminoisoquinolin-7-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-aminopyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3 -sulfonamide;N-[3-(2-aminopyrido[3,2-d]pyrimidin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3 -sulfonamide;N-[3-(6-aminopyrido[2,3-b]pyrazin-2-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3 -sulfonamide;N-[3-(7-aminopyrido[3,4-b]pyrazin-3-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3 -sulfonamide;N-[3-(2-aminopteridin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-aminoquinoxalin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(6-amino-9H-purin-8-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-amino-9H-purin-8-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(6-amino-9H-purin-2-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(8-amino-9H-purin-2-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;5-chloro-N-[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-2-methoxypyridine-3 -sulfonamide;5-chloro-N-[2,4-difluoro-3-(7H-pyrrolo[3,2-d]pyrimidin-2-yl)phenyl]-2-methoxypyridine-3 -sulfonamide;N-[3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3 -sulfonamide;N-[3-(2-amino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3 -sulfonamide;10 / 350#14837954v1N-[3-(4-amino-7H-pyrrolo[3,2-d]pyrimidin-2-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3 -sulfonamide;N-[3-(6-amino-7H-pyrrolo[3,2-d]pyrimidin-2-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3 -sulfonamide;5-chloro-N-[2,4-difluoro-3-(lH-indazol-6-yl)phenyl]-2-methoxypyridine-3-sulfonamide;5-chloro-N-[2,4-difluoro-3-(lH-pyrrolo[2,3-b]pyridin-6-yl)phenyl]-2-methoxypyridine-3 -sulfonamide;N-[3-(2-amino-lH-pyrrolo[2,3-b]pyridin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3 -sulfonamide;N-[3-(4-aminoquinazolin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(3-amino-lH-indazol-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;5-chloro-N-[3-(2,4-diaminoquinolin-6-yl)-2,4-difluorophenyl]-2-methoxypyridine-3-sulfonamide;N-[3-(2-aminoquinazolin-8-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-aminoquinazolin-5-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;5-chloro-N-(2,4-difluoro-3-{2-[(2-hydroxyethyl)amino]quinazolin-6-yl}phenyl)-2-methoxypyridine-3 -sulfonamide;5-chloro-N-{2,4-difluoro-3-[2-(methylamino)quinazolin-6-yl]phenyl}-2-methoxypyridine-3 -sulfonamide;N-[3-(lH-benzimidazol-5-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-amino-1H-benzimidazol-5-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;5-chloro-N-[2,4-difluoro-3-(7-fluoro-lH-benzimidazol-5-yl)phenyl]-2-methoxypyridine-3 -sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2-methylphenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2-fluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;11 / 350#14837954v1N-[3-(2-aminoquinazolin-6-yl)-5-fluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,6-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-5-chloro-2,4-difluorobenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]sulfuric diamide;N-[3-(2-aminoquinazolin-6-yl)-4-fluorophenyl]-2,5-dichlorobenzene-l-sulfonamide; N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-5-chloro-2-(trifluoromethyl)benzene-l -sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-3,5-dichlorobenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-2-chloro-5-methylbenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methylbenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-2,3-dichlorobenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-3-chloro-5-(trifluoromethyl)benzene-l -sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]isoquinoline-5-sulfonamide;5-chloro-N-[2,4-difluoro-3-(2-{[(lr,4r)-4-hydroxycyclohexyl]amino}quinazolin-6-yl)phenyl]-2-methoxypyridine-3-sulfonamide;5-chloro-N-[2,4-difluoro-3-(2-{[(2R)-l-hydroxypropan-2-yl]amino}quinazolin-6-yl)phenyl]-2-methoxypyridine-3-sulfonamide;2.5-dichloro-N-[2,4-difluoro-3-(2-{[(lr,4r)-4-hydroxycyclohexyl]amino}quinazolin-6-yl)phenyl]benzene- 1 -sulfonamide;2.5-dichloro-N-[2,4-difluoro-3-(2-{[(2R)-l-hydroxypropan-2-yl]amino}quinazolin-6-yl)phenyl]benzene- 1 -sulfonamide;2.5-dichloro-N-[2,4-difluoro-3-(2-{[(lr,4r)-4-hydroxycyclohexyl]amino}quinazolin-6-yl)phenyl]-3-(hydroxymethyl)benzene-l -sulfonamide;2.5-dichloro-N-[2,4-difluoro-3-(2-{[(2R)-l-hydroxypropan-2-yl]amino}quinazolin-6-yl)phenyl]-3-(hydroxymethyl)benzene-l -sulfonamide;12 / 350#14837954v16-[l-(5-chloro-2-methoxypyridine-3-sulfonyl)-5-fluoro-lH-indol-4-yl]quinazolin-2-amine;6-[l-(5-chloro-2-methoxypyridine-3-sulfonyl)-lH-indol-4-yl]quinazolin-2-amine; 6-[l-(5-chloro-2-methoxypyridine-3-sulfonyl)-5-fluoro-2,3-dihydro-lH-indol-4-yl]quinazolin-2-amine;6-[l-(5-chloro-2-methoxypyridine-3-sulfonyl)-2,3-dihydro-lH-indol-4-yl]quinazolin-2-amine;6-[l-(2,5-dichlorobenzene-l-sulfonyl)-5-fluoro-lH-indol-4-yl]quinazolin-2-amine; 6-[1-(2,5-dichlorobenzene-1-sulfonyl)-1H-indol-4-yl]quinazolin-2-amine;{3-[4-(2-aminoquinazolin-6-yl)-5-fluoro-1H-indole-1-sulfonyl]-2,5-dichlorophenyl}methanol;6-[l-(2,5-dichlorobenzene-l-sulfonyl)-5-fluoro-2,3-dihydro-lH-indol-4-yl]quinazolin-2-amine;6-[l-(2,5-dichlorobenzene-l-sulfonyl)-2,3-dihydro-lH-indol-4-yl]quinazolin-2-amine; {3-[4-(2-aminoquinazolin-6-yl)-5-fluoro-2,3-dihydro-1H-indole-1-sulfonyl]-2,5-dichlorophenyl}methanol;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]cyclohexanesulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]piperidine-4-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-l-methylpiperidine-4-sulfonamide; N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]piperidine-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]piperazine-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-methylpiperazine-l-sulfonamide; N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]oxane-4-sulfonamide;(lr,4r)-N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-hydroxycyclohexane-l-sulfonamide;(ls,4s)-N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-hydroxycyclohexane-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]thiane-4-sulfonamide;(1r,4r)-N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-methoxycyclohexane-1-sulfonamide;(ls,4s)-N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-methoxycyclohexane-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]morpholine-4-sulfonamide;13 / 350#14837954v1N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-hydroxypiperidine-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-(hydroxymethyl)piperidine-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]thiomorpholine-4-sulfonamide; (lr,4r)-N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-(hydroxymethyl)cyclohexane- 1 -sulfonamide;(ls,4s)-N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-(hydroxymethyl)cyclohexane- 1 -sulfonamide;3 - { [3 -(2-aminoquinazolin-6-yl)-2,4-difluoropheny 1] sulfamoyl } cyclohexane- 1 -carboxamide;3 - { [3 -(2-aminoquinazolin-6-yl)-2,4-difluoropheny 1] sulfamoyl } cyclohexane- 1 -carboxylic acid;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]piperidine-3-sulfonamide;3-{[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]sulfamoyl}-N-methylcyclohexane- 1 -carboxamide;methyl 3 - { [3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl] sulfamoyl } cyclohexane- 1 -carboxylate;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-6-methylpiperidine-3-sulfonamide; N-(6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2,6-difluorophenyl)quinazolin- 2-yl)pival amide;N-(6-(3((2,5-dichlorophenyl)sulfonamido)2,6-difluorophenyl)quinazolin-2-yl)acetamide;N-(3-(2-aminoquinolin-6-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide; N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2, 5-dichl oro-3 -(hydroxymethyl)benzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-chloro-2,5-dimethylbenzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-fluoro-2-methoxybenzenesulfonamide;N-(3-(2-aminoquinazolin-5-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide; N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,5-difluorobenzenesulfonamide; N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,5-dimethylbenzenesulfonamide;14 / 350#14837954v1N-(5-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pival amide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,4-dimethoxybenzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-fluorobenzenesulfonamide; N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-m ethoxy-3 -methylbenzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2-methoxy-5-methylbenzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-dimethoxybenzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-ethyl-2-methoxybenzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-bis(trifluoromethyl)benzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)benzofuran-5-sulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-fluoro-5-(trifluoromethyl)benzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,3-difluorobenzenesulfonamide; N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-methylbenzenesulfonamide; 2.5-dichloro-N-(3,5-difluoro-4-(2-((2-hydroxyethyl)amino)quinazolin-6-yl)pyridin-2-yl)benzenesulfonamide;5-chloro-N-(2,4-difluoro-3-(2-(((ls,4s)-4-hydroxycyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)pyridine-3-sulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-dichlorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,4-difluorobenzenesulfonamide; N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-fluoro-2-methylbenzenesulfonamide;2.5-dichloro-N-(2,4-difluoro-3-(2-((2-hydroxyethyl)amino)quinazolin-6-yl)phenyl)-3-(hydroxymethyl)benzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2-fluoro-5-(trifluoromethyl)benzenesulfonamide;15 / 350#14837954v1N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-fluoro-3 -(trifluoromethyl)benzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-chloro-2-(trifluoromethyl)benzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)quinoxaline-5-sulfonamide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3 -(trifluoromethoxy )benzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)thiophene-3-sulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-isopropylbenzenesulfonamide; N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)thiophene-2-sulfonamide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-fluoro-3 -methoxybenzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,5-bis(trifluoromethyl)benzenesulfonamide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3 -(trifluoromethyl)benzenesulfonamide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-chl oro-3 -fluorobenzenesulfonamide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3 -chloro-4-methylbenzenesulfonamide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3 -chloro-4-methoxybenzenesulfonamide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-chl oro-3 -(trifluoromethyl)benzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,4,5-trichlorobenzenesulfonamide; 5-chloro-N-(3-(2-((l,3-dihydroxypropan-2-yl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide;(R)-5-chloro-N-(2,4-difluoro-3-(2-((2-hydroxy-l-phenylethyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide;5-chloro-N-(3-(2-(dimethylamino)quinazolin-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3 -sulfonamide;5-chloro-N-(2,4-difluoro-3-(2-(piperidin-l-yl)quinazolin-6-yl)phenyl)-2-methoxypyridine-3 -sulfonamide;16 / 350#14837954v1(S)-5-chloro-N-(2,4-difluoro-3-(2-((l-hydroxypropan-2-yl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3 -chloro-4-fluorobenzenesulfonamide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3 -fluoro-4-methylbenzenesulfonamide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-fluoro-3 -methylbenzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,3-dihydro-lH-indene-5-sulfonamide;2.5-dichloro-N-(2,4-difluoro-3-(2-(methylamino)quinazolin-6-yl)phenyl)-3-(hydroxymethyl)benzenesulfonamide;(S)-5-chloro-N-(2,4-difluoro-3-(2-((2-hydroxy-l-phenylethyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide;5-chloro-N-(2,4-difluoro-3-(2-(((lr,4r)-4-hydroxycyclohexyl)amino)quinazolin-6-yl)phenyl)-2-(trifluoromethyl)benzenesulfonamide;5-chloro-N-(2,4-difluoro-3-(2-(((ls,4s)-4-hydroxycyclohexyl)amino)quinazolin-6-yl)phenyl)-2-(trifluoromethyl)benzenesulfonamide;(S)-5-chloro-N-(2,4-difluoro-3-(2-((2-hydroxy-l-phenylethyl)amino)quinazolin-6-yl)phenyl)-2-(trifluoromethyl)benzenesulfonamide;(R)-5-chloro-N-(2,4-difluoro-3-(2-((2-hydroxy-l-phenylethyl)amino)quinazolin-6-yl)phenyl)-2-(trifluoromethyl)benzenesulfonamide;2.5-dichloro-N-(2,4-difluoro-3-(2-((tetrahydrofuran-3-yl)amino)quinazolin-6-yl)phenyl)benzenesulfonamide;and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

[0028] In some embodiments, the GCN2 inhibitor is selected from the compounds listed in Table 9 and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

[0029] In some embodiments, the GCN2 inhibitor is selected from the compounds listed in Table 10 and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

[0030] In some embodiments, the GCN2 inhibitor is selected from the compounds listed in Table 11 and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

[0031] In some embodiments, the GCN2 inhibitor is selected from the group consisting of:N-(3-((2-aminopyrimidin-5-yl)ethynyl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3 -sulfonamide;17 / 350#14837954v15-chloro-N-(2,4-difluoro-3-((2-((trans-4-hydroxycyclohexyl)amino)pyrimidin-5-yl)ethynyl)phenyl)-2-methoxypyridine-3-sulfonamide;2,5-dichloro-N-(2,4-difluoro-3-((2-(((2R)-l-hydroxypropan-2-yl)amino)pyrimidin-5-yl)ethynyl)phenyl)-3-(hydroxymethyl)benzenesulfonamide;and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

[0032] In some embodiments, the GCN2 inhibitor isor a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0033] In some embodiments, the GCN2 inhibitor is or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0034] In some embodiments, the GCN2 inhibitor is selected from the group consisting of:6-(3-benzenesulfonamido-2,6-difluorophenyl)-7-fluoro-N-methyl-lH-indazole-3-carboxamide;6-[2,6-difluoro-3-[3-(hydroxymethyl)benzenesulfonamido]phenyl]-7-fluoro-N-methyl- lH-indazole-3-carboxamide;6- [2, 6-difluoro-3 - [3 -fluoro-5 -(hy droxymethyl)benzenesulfonamido]phenyl] -7 -fluoro-N-methyl-lH-indazole-3-carboxamide;6-(3-amino-2-fluorophenyl)-7-fluoro-N-methyl-l-[[2-(trimethylsilyl)ethoxy]methyl]indazole-3-carboxamide;N-(6-(3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl)-7-fluoro- lH-indazol-3-yl)acetamide;6-[3-[5-chloro-2-(difluoromethoxy)pyridine-3-sulfonamido]-2,6-difluorophenyl]-7-fluoro-N -methyl - 1 H-indazol e-3 -carb oxami de;18 / 350#14837954v16-[3-[5-cyano-2-(difluoromethoxy)pyridine-3-sulfonamido]-2,6-difluorophenyl]-7-fluoro-N-methyl-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N,4-dimethyl-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(2-methylpropyl)-lH-indazole-3-carboxamide;6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2,6-difluorophenyl)-N-ethyl-7-fluoro- lH-indazole-3 -carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(l-methyl-6-oxopiperidin-3-yl)-lH-indazole-3-carboxamide;N-(l-acetylpyrrolidin-3-yl)-6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(2-hydroxypropyl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(l-hydroxypropan-2-yl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(2-oxopyrrolidin-3-yl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(oxan-3-yl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(sec-butyl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(pyrrolidin-3-yl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-propyl-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(pentan-2-yl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(4-hydroxybutan-2-yl)-lH-indazole-3-carboxamide;6-[3-(l-benzofuran-4-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-methyl-lH-indazole-3 -carboxamide;6-[3-(lH-l,3-benzodiazole-4-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-methyl-lH-indazole-3 -carboxamide;19 / 350#14837954v16-[2,6-difluoro-3-(3-methyl-l,3-benzodiazole-4-sulfonamido)phenyl]-7-fluoro-N-methyl-lH-indazole-3-carboxamide;5-chloro-N-[2,4-difluoro-3-[7-fluoro-3-(l,3-oxazol-2-yl)-lH-indazol-6-yl]phenyl]-2-methoxypyridine-3 -sulfonamide;6-[2,6-difluoro-3-(5-fluoro-2-methylpyridine-3-sulfonamido)phenyl]-7-fluoro-N-methyl- lH-indazole-3-carboxamide;6-[2,6-difluoro-3-(5-fluoro-2-methylpyridine-3-sulfonamido)phenyl]-7-fluoro-N-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide;N-[2,4-difluoro-3-[7-fluoro-3-(hydrazinecarbonyl)-lH-indazol-6-yl]phenyl]-l-benzofuran-6-sulfonamide;6-[2,6-difluoro-3-(l-methyl-l,3-benzodiazole-4-sulfonamido)phenyl]-7-fluoro-N-methyl- lH-indazole-3-carboxamide;6-[2,6-difluoro-3-(5-fluoro-2-methoxypyridine-3-sulfonamido)phenyl]-7-fluoro-N-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[3-(5-cyano-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[3-(5-chloro-2-methylpyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide;5-chloro-N-[2,4-difluoro-3-(7-fluoro-lH-indazol-6-yl)phenyl]-2-methoxypyridine-3-sulfonamide;6-[3-(cyclopentylmethanesulfonamido)-2,6-difluorophenyl]-7-fluoro-N-methyl-lH-indazole-3 -carboxamide;6-[2,6-difluoro-3-(oxane-4-sulfonamido)phenyl]-7-fluoro-N-methyl-lH-indazole-3-carboxamide;6-[2,6-difluoro-3-(6-fluoro-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamido)phenyl]-7-fluoro-N-methy 1 - 1 H-indazol e-3 -carb oxami de;6-[2,6-difluoro-3-(1-methylpiperidine-3-sulfonamido)phenyl]-7-fluoro-N-methyl-1H-indazole-3-carboxamide;6-[2,6-difluoro-3-[(3-hydroxycyclopentyl)methanesulfonamido]phenyl]-7-fluoro-N-methyl-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-cyclopentyl- 7-fluoro-lH-indazole-3-carboxamide;20 / 350#14837954v16-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(3-hydroxycyclohexyl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-cyclopropyl-7-fluoro-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-ethoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(morpholin-4-ylmethyl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-[2-(pyrrolidin-l-yl)ethyl]-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(2-methanesulfonylethyl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-(cyclopropylmethyl)-7-fluoro-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-[2-(morpholin-4-yl)ethyl]-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(2-hydroxycyclopentyl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(2-hydroxycyclohexyl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(2-methylbut-3-yn-2-yl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(2,2,2-trifluoroethyl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-[cyano(cyclopropyl)methyl]-7-fluoro-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N- (prop-2-yn- 1 -yl)- lH-indazole-3 -carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(piperidin-3-ylmethyl)-lH-indazole-3-carboxamide;N-(2-aminocyclohexyl)-6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-lH-indazole-3-carboxamide;N-(l-aminopropan-2-yl)-6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(4-oxocyclohexyl)-lH-indazole-3-carboxamide;21 / 350#14837954v16-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(3-hydroxycyclopentyl)-lH-indazole-3-carboxamide;N-(3-aminocyclohexyl)-6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-[2-(2-oxopyrrolidin-l-yl)ethyl]-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-[(l-methylpyrrolidin-3-yl)methyl]-lH-indazole-3-carboxamide;6-[3-(l,3-dihydro-2-benzofuran-4-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-methyl-lH-indazole-3-carboxamide;6-[3-(2,3-dihydro-l-benzofuran-6-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-methyl-lH-indazole-3-carboxamide;6-[3-(2,3-dihydro-l-benzofuran-6-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-methyl-l-[[2-(trimethylsilyl)ethoxy]methyl]indazole-3-carboxamide;6-[3-(6-cyano-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-methyl-lH-indazole-3-carboxamide;6-[2,6-difluoro-3-(6-fluoro-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamido)phenyl]-7-fluoro-N-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide;and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

[0035] In some embodiments, the GCN2 inhibitor is, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0036] In some embodiments, the GCN2 inhibitor is HCI-1046.

[0037] In some embodiments, the GCN2 inhibitor is selected from the group consisting of:6-chloro-N-(2,4-difluoro-3 -(8-methoxy-2-((l-(pyri din-2 -yl)piperidin-4-y 1 )amino)quinazolin-6-yl)pheny 1 )- 1 -hydroxy-2,3 -dihydro- lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((l-(pyridin-3-yl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;22 / 350#14837954v16-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((l-(pyridin-4-yl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(pyridin-2-yl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)- 1 -hydroxy-2 -dihydro- lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(pyridin-3-yl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)- 1 -hydroxy-2 -dihydro- lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(pyridin-4-yl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)- 1 -hydroxy-23 -dihydro- lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxypropyl)piperidin-4-yl)amino)quinazolin- 6-yl)phenyl)- 1 -hydroxy-23 -dihydro- lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxycyclopentyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-23-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(l-methoxypropan-2-yl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-23-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-hydroxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)- 1 -hydroxy-23 -dihydro- lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(tetrahydrofuran-3-yl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-23-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-propylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-23-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((3- ((methylamino)methyl)cyclopentyl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-23-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(3-(2-((3-(dimethylamino)propyl)amino)-8-methoxyquinazolin-6-yl)-2,4-difluorophenyl)- 1 -hydroxy-23 -dihydro- lH-indene-4-sulfonamide;6-chloro-N-(3-(2-((2-(dimethylamino)ethyl)amino)-8-methoxyquinazolin-6-yl)-2,4-difluorophenyl)- 1 -hydroxy-23 -dihydro- lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)- 1 -hydroxy- 1 -methyl-23 -dihydro- lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)- 1 -oxo-23 -dihydro- lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)- 1 -hydroxy-23 -dihydro- lH-indene-4-sulfonamide- 1 -d;23 / 350#14837954v16-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((3-(((2-methoxyethyl)(methyl)amino)methyl)cyclopentyl)amino)quinazolin-6-yl)phenyl)-l -hydroxy- 2,3 -dihydro- 1 H-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((l-methylpiperidin-4-yl)amino)quinazolin- 6-yl)phenyl)- 1 -hydroxy-2,3 -dihydro- lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-2,3-dihydrobenzofuran-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((3-(((2-methoxyethyl)amino)methyl)cyclopentyl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxy-2-methylpropyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)benzo[D][l,3]dioxole-4-sulfonamide;5-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-2,3-dihydrobenzofuran-7-sulfonamide;6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-((tetrahydrofuran-2-yl)methyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin-3-yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-isopropylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(3-(2-((l-ethylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-l-hydroxy -2, 3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;24 / 350#14837954v1N-(3-(8-ethyl-2-((4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-6-fluoro-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;N-(2,4-difluoro-3-(2-((4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)phenyl)-6-fluoro-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;N-(2,4-difluoro-3-(2-((l-methylpiperi din-3 -yl)amino)quinazolin-6-yl)phenyl)-6-fluoro-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;1 -amino-N-(3-(2-aminoquinazolin-6-yl)-2, 4-difluorophenyl)-6-chl oro-2, 3-dihy dro-lH-indene-4-sulfonamide;N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-6-fluoro- 1 -hydroxy -2, 3 -dihydro- 1 H-indene-4-sulfonamide;N-(2,4-difluoro-3-(2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-6-fluoro-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;N-(2,4-difluoro-3 -(2-(piperidin-4-ylamino)quinazolin-6-yl)phenyl)-6-fluoro- 1 -hydroxy -2, 3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-(piperidin-4-ylamino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(3-(8-ethyl-2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4-difluorophenyl)- 1 -hydroxy-2,3 -dihydro- lH-indene-4-sulfonamide;3-chloro-N-(3-(8-ethyl-2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-l-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-hydroxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l,5-dihydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-hydroxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l,7-dihydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-(piperidin-4-ylamino)quinazolin-6-yl)phenyl)-l-hydroxy-5 -methoxy -2, 3-dihy dro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-(piperidin-4-ylamino)quinazolin-6-yl)phenyl)-l-hy droxy-7-methoxy -2, 3-dihy dro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-hydroxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)- 1, 2-dihydroxy-2, 3 -dihydro- lH-indene-4-sulfonamide;3-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-l-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-3,3-dimethyl-2,3-dihydro-lH-indene-4-sulfonamide;25 / 350#14837954v15-chloro-N-(2,4-difluoro-3-(2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((4-((2-methoxyethyl)(methyl)amino)cy cl ohexyl)amino)quinazolin-6-yl)phenyl)-l -hydroxy -2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-4-hydroxychromane-8-sulfonamide;N-(3-(2-((4-aminocy cl ohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-6-chl oro-1-hydroxy -2, 3-dihydro-lH-indene-4-sulfonamide;N-(3-(2-((4-(bis(2-methoxyethyl)amino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-6-chloro-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;5-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((4-morpholinocyclohexyl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(3,3,3-trifluoropropyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2, 4-difluoro-3-(2-(pyridin-4-ylamino)quinazolin-6-yl)phenyl)-l -hydroxy- 2,3 -dihydro- 1 H-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-(trifluoromethoxy)ethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(8-fluoro-2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(5-fluoro-2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(5-fluoro-2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;5-chloro-N-(3-(8-ethyl-2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;26 / 350#14837954v15-chloro-N-(2,4-difluoro-3-(5-fluoro-2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(3-(2-((l-ethylpiperidin-4-yl)amino)-5-fluoroquinazolin-6-yl)-2,4-difluorophenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(2,4-difluoro-3-(5-fluoro-2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(2,4-difluoro-3-(2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(2,4-difluoro-3-(5-fluoro-2-((l-isopropylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(3-(8-ethyl-2-((l-isopropylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(3-(2-((l-ethylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-3-hydroxy -2, 3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(3-(8-ethyl-2-((l-ethylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(3-(8-ethyl-2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(2,4-difluoro-3-(8-fluoro-2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(3-(2-((l-ethylpiperidin-4-yl)amino)-8-fluoroquinazolin-6-yl)-2,4-difluorophenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(2,4-difluoro-3-(8-fluoro-2-((l-isopropylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(2,4-difluoro-3-(8-fluoro-2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(3-(2-((l-cyclopropylpiperidin-4-yl)amino)-5-fluoroquinazolin-6-yl)-2,4-difluorophenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;N-(3-(2-((4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;N-(3-(2-amino-8-ethylquinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;N-(3-(2-amino-8-ethylquinazolin-6-yl)-2,4-difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;27 / 350#14837954v1N-(3-(2-amino-8-fluoroquinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;N-(3-(2-amino-8-fluoroquinazolin-6-yl)-2, 4-difluorophenyl)-6-chl oro-1 -hydroxy-2, 3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(7-fluoro-2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)-7-methylquinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;N-[3-(2-amino-5-fluoroquinazolin-6-yl)-2,4-difluorophenyl]-5-chloro-3-hydroxy-2,3-dihydro-l-benzofuran-7-sulfonamide;5-chloro-N-(3-{8-ethyl-5-fluoro-2-[(l-methylpiperidin-4-yl)amino]quinazolin-6-yl}-2,4-difluorophenyl)-3-hydroxy-2,3-dihydro-l-benzofuran-7-sulfonamide;N-[3-(2-amino-5-fluoroquinazolin-6-yl)-2, 4-difluorophenyl]-6-chl oro-1 -hydroxy-2, 3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-[2,4-difluoro-3-(2-{ [l-(2 -methoxy ethyl)piperidin-4-yl]amino}-7-methylquinazolin-6-yl)phenyl]-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide, formic acid;6-chloro-N-[2,4-difluoro-3-(7-fluoro-2-{[l-(2-methoxyethyl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2-fluoro-3-{2-[(l-methylpiperidin-4-yl)amino]quinazolin-6-yl}phenyl)-l-hydroxy -2, 3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(4-fluoro-3-(2-((1-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;6-chloro-N-{2,4-difluoro-3-[2-(oxan-4-ylamino)quinazolin-6-yl]phenyl}-l -hydroxy- 2,3 -dihydro- 1 H-indene-4-sulfonamide;5-chloro-N-{3-[8-ethyl-2-(piperidin-4-ylamino)quinazolin-6-yl]-2,4-difluorophenyl}-3-hydroxy-2,3-dihydro-l-benzofuran-7-sulfonamide;5-chloro-N-(3-{8-ethyl-2-[(l-ethylpiperidin-4-yl)amino]quinazolin-6-yl}-2-fluorophenyl)-3-hydroxy-2,3-dihydro-l-benzofuran-7-sulfonamide;5-chloro-N-[2-fluoro-3-(5-fluoro-2-{[l-(2-methoxyethyl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-3-hydroxy-2,3-dihydro-l-benzofuran-7-sulfonamide;5-chloro-N-(2-fluoro-3-{5-fluoro-2-[(l-methylpiperidin-4-yl)amino]quinazolin-6-yl}phenyl)-3-hydroxy-2,3-dihydro-l-benzofuran-7-sulfonamide;5-chloro-N-{3-[8-ethyl-2-(oxan-4-ylamino)quinazolin-6-yl]-2,4-difluorophenyl}-3-hydroxy-2,3-dihydro-l-benzofuran-7-sulfonamide; and28 / 350#14837954v15-chloro-N-{2,4-difluoro-3-[5-fluoro-2-(piperidin-4-ylamino)quinazolin-6-yl]phenyl}-3-hydroxy-2,3-dihydro-l-benzofuran-7-sulfonamide;and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

[0038] In some embodiments, the GCN2 inhibitor is selected from the compounds listed in Table 13, and pharmaceutically acceptable salts, stereoisomers, and tautomer thereof.

[0039] In some embodiments, the GCN2 inhibitor is selected from the group consisting of:29 / 350#14837954v1#14837954v1#14837954v1#14837954v1#14837954v1stereoisomers, and tautomers thereof.

[0040] In some embodiments, the GCN2 inhibitor is selected from the compounds listed in Table 12, and pharmaceutically acceptable salts, stereoisomers, and tautomer thereof.

[0041] In some embodiments, the complex delivers the molecular payload to a muscle cell. In some embodiments, the muscle cell is a skeletal muscle cell, a smooth muscle cell, or a cardiac muscle cell.

[0042] In some embodiments, the complex delivers the molecular payload to a cell of the CNS.

[0043] In some embodiments, the payload comprises an oligonucleotide.

[0044] In some embodiments, the molecular payload comprises an oligonucleotide comprising a region of complementarity to a target sequence of an oligonucleotide listed in Table 8. In some embodiments, the oligonucleotide comprises a sequence listed in Table 8.

[0045] In some embodiments, the complex is administered to the subject intravenously. In some embodiments, the administration is by intravenous infusion.

[0046] In some embodiments, the GCN2 inhibitor is administered to the subject orally.

[0047] In some embodiments, the subject has been diagnosed with or is suspected of having a muscular dystrophy. In some embodiments, the muscular dystrophy is Duchenne muscular dystrophy.

[0048] In some embodiments, the subject has a mutation amenable to exon skipping. In some embodiments, the mutation amenable to exon skipping is in a dystrophin allele.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0049] Aspects of the disclosure relate to a recognition that while certain molecular payloads (e.g., oligonucleotides, such as exon-skipping oligonucleotides) can have beneficial effects in muscle cells and / or cells of the central nervous system (CNS), it has proven challenging for 34 / 350#14837954v1such molecular payloads to achieve their intended effects because of limitations in their biodistribution, including inability to efficiently enter muscle cells and / or cross the blood-brain barrier. Furthermore, exon-skipping oligonucleotides may be limited in their efficacy even after successful delivery if the transcript in which they facilitate exon skipping is not efficiently translated into protein. Accordingly, the present disclosure, in some aspects, provides complexes comprising transferrin receptor (TfRl)-targeting agents covalently linked to molecular payloads used in combination with GCN2 inhibitors in order to overcome such challenges. The TfR1-targeting agent of the present disclosure comprises an anti -transferrin receptor 1 (TfRl) antibody that is demonstrated to be able to transport molecular payloads to muscle cells and / or cells of the CNS. GCN2 inhibitors of the present disclosure comprise compounds having structures disclosed herein, which can inhibit GCN2 and thereby facilitate increased protein expression, such as protein expression from transcripts in which exons have been skipped.

[0050] In some embodiments, complexes provided herein may comprise molecular payloads that modulate (e.g., increase or reduce) expression and / or activity of genes associated with diseases and disorders (e.g., muscle and / or CNS diseases or disorders), such as by modulating transcription, translation, post-transcriptional modification (e.g., splicing), mRNA stability, and / or protein stability. In some embodiments, complexes provided herein may comprise molecular payloads that are synthetic nucleic acids (e.g., DNA or RNA) that may be used to express one or more proteins that modulate expression and activity of genes associated with diseases and disorders. In some embodiments, complexes provided herein may comprise molecular payloads that modulate transcripts (e.g., by facilitating exon skipping) of genes associated with a disease or disorder, but may or may have limited activity in said disease or disorder due to low expression of protein from the modulated transcript. In some embodiments, GCN2 inhibitors provided herein increase expression of protein, e.g., from a modulated transcript.

[0051] Further aspects of the disclosure, including a description of defined terms, are provided below.I. Definitions

[0052] Administering: As used herein, the terms “administering” or “administration” means to provide a composition (e.g., a composition comprising a complex or a composition comprising a GCN2 inhibitor) to a subject in a manner that is physiologically and / or (e.g., and) pharmacologically useful (e.g., to treat a condition in the subject).35 / 350#14837954v1

[0053] Antibody: As used herein, the term “antibody” refers to a polypeptide that includes at least one immunoglobulin variable domain or at least one antigenic determinant, e.g., paratope that specifically binds to an antigen. In some embodiments, an antibody is a full-length antibody. In some embodiments, an antibody is a chimeric antibody. In some embodiments, an antibody is a humanized antibody. However, in some embodiments, an antibody is a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a Fv fragment or a scFv fragment. In some embodiments, an antibody is a nanobody derived from a camelid antibody or a nanobody derived from shark antibody. In some embodiments, an antibody is a diabody. In some embodiments, an antibody comprises a framework having a human germline sequence. In another embodiment, an antibody comprises a heavy chain constant domain selected from the group consisting of IgG, IgGl, IgG2, IgG2A, IgG2B, IgG2C, IgG3, IgG4, IgAl, IgA2, IgD, IgM, and IgE constant domains. In some embodiments, an antibody comprises a heavy (H) chain variable region (abbreviated herein as VH), and / or (e.g., and) a light (L) chain variable region (abbreviated herein as VL). In some embodiments, an antibody comprises a constant domain, e.g., an Fc region. An immunoglobulin constant domain refers to a heavy or light chain constant domain. Human IgG heavy chain and light chain constant domain amino acid sequences and their functional variations are known. With respect to the heavy chain, in some embodiments, the heavy chain of an antibody described herein can be an alpha (a), delta (A), epsilon (e), gamma (y) or mu (p) heavy chain. In some embodiments, the heavy chain of an antibody described herein can comprise a human alpha (a), delta (A), epsilon (e), gamma (y) or mu (p) heavy chain. In a particular embodiment, an antibody described herein comprises a human gamma 1 CHI, CH2, and / or (e.g., and) CH3 domain. In some embodiments, the amino acid sequence of the VH domain comprises the amino acid sequence of a human gamma (y) heavy chain constant region, such as any known in the art. Non-limiting examples of human constant region sequences have been described in the art, e.g., see U. S. Pat. No. 5,693,780 and Kabat E A et al., (1991) supra. In some embodiments, the VH domain comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or at least 99% identical to any of the variable chain constant regions provided herein. In some embodiments, an antibody is modified, e.g., modified via glycosylation, phosphorylation, sumoylation, and / or (e.g., and) methylation. In some embodiments, an antibody is a glycosylated antibody, which is conjugated to one or more sugar or carbohydrate molecules. In some embodiments, the one or more sugar or carbohydrate molecule are conjugated to the antibody via N-glycosylation, O-glycosylation, C-glycosylation, glypiation (GPI anchor attachment), and / or (e.g., and)36 / 350#14837954v1phosphoglycosylation. In some embodiments, the one or more sugar or carbohydrate molecule are monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, the one or more sugar or carbohydrate molecule is a branched oligosaccharide or a branched glycan. In some embodiments, the one or more sugar or carbohydrate molecule includes a mannose unit, a glucose unit, an N-acetylglucosamine unit, an N-acetylgalactosamine unit, a galactose unit, a fucose unit, or a phospholipid unit. In some embodiments, an antibody is a construct that comprises a polypeptide comprising one or more antigen binding fragments of the disclosure linked to a linker polypeptide or an immunoglobulin constant domain. Linker polypeptides comprise two or more amino acid residues joined by peptide bonds and are used to link one or more antigen binding portions. Examples of linker polypeptides have been reported (see e.g., Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R. J., et al. (1994) Structure 2:1121-1123). Still further, an antibody may be part of a larger immunoadhesion molecule, formed by covalent or noncovalent association of the antibody or antibody portion with one or more other proteins or peptides. Examples of such immunoadhesion molecules include use of the streptavidin core region to make a tetrameric scFv molecule (Kipriyanov, S. M., et al. (1995) Human Antibodies and Hybridomas 6:93-101) and use of a cysteine residue, a marker peptide and a C-terminal polyhistidine tag to make bivalent and biotinylated scFv molecules (Kipriyanov, S. M., et al. (1994) Mol. Immunol. 31:1047-1058).

[0054] Approximately: As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0055] CDR: As used herein, the term " CDR" refers to the complementarity determining region within antibody variable sequences. A typical antibody molecule comprises a heavy chain variable region (VH) and a light chain variable region (VL), which are usually involved in antigen binding. The VH and VL regions can be further subdivided into regions of hypervariability, also known as “complementarity determining regions” (“CDR”), interspersed with regions that are more conserved, which are known as “framework regions” (“FR”). Each VH and VL is typically composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The 37 / 350#14837954v1extent of the framework region and CDRs can be precisely identified using methodology known in the art, for example, by the Kabat definition, the IMGT definition, the Chothia definition, the AbM definition, and / or (e.g., and) the contact definition, all of which are well known in the art. See, e.g., Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U. S. Department of Health and Human Services, NIH Publication No.91-3242; IMGT®, the international ImMunoGeneTics information system® imgt.org, Lefranc, M.-P. et al., Nucleic Acids Res., 27:209-212 (1999); Ruiz, M. et al., Nucleic Acids Res., 28:219-221 (2000); Lefranc, M.-P, Nucleic Acids Res., 29:207-209 (2001); Lefranc, M.-P., Nucleic Acids Res., 31:307-310 (2003); Lefranc, M.-P. et al., In Silico Biol., 5, 0006 (2004) [Epub], 5:45-60 (2005); Lefranc, M.-P. et al., Nucleic Acids Res., 33: D593-597 (2005);Lefranc, M.-P. et al., Nucleic Acids Res., 37: D1006-1012 (2009); Lefranc, M.-P. et al., Nucleic Acids Res., 43: D413-422 (2015); Chothia et al., (1989) Nature 342:877; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917, Al-lazikani et al (1997) J. Molec. Biol. 273:927-948; and Almagro, J. Mol. Recognit. 17:132-143 (2004). See also hgmp.mrc.ac.uk and bioinf.org.uk / abs. As used herein, a CDR may refer to the CDR defined by any method known in the art. Two antibodies having the same CDR means that the two antibodies have the same amino acid sequence of that CDR as determined by the same method, for example, the IMGT definition.

[0056] There are three CDRs in each of the variable regions of the heavy chain and the light chain, which are designated CDR1, CDR2 and CDR3, for each of the variable regions. The term " CDR set" as used herein refers to a group of three CDRs that occur in a single variable region capable of binding the antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries defining the three CDRs. These CDRs may be referred to as Kabat CDRs. Sub-portions of CDRs may be designated as LI, L2 and L3 or Hl, H2 and H3 where the " L" and the " H" designates the light chain and the heavy chains regions, respectively. These regions may be referred to as Chothia CDRs, which have boundaries that overlap with Kabat CDRs. Other boundaries defining CDRs overlapping with the Kabat CDRs have been described by Padlan (FASEB J. 9:133-139 (1995)) and MacCallum (J Mol Biol 262(5):732-45 (1996)). Still other CDR boundary definitions may not strictly follow one of the above systems, but will nonetheless overlap with the Kabat CDRs, although they may be shortened or lengthened in light of prediction or 38 / 350#14837954v1experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. The methods used herein may utilize CDRs defined according to any of these systems. Examples of CDR definition systems are provided in Table 1.Table 1. CDR DefinitionsIMGT1Kabat2Chothia3CDR-H1 27-38 31-35 26-32CDR-H2 56-65 50-65 53-55CDR-H3 105-116 / 117 95-102 96-101CDR-L1 27-38 24-34 26-32CDR-L2 56-65 50-56 50-52CDR-L3 105-116 / 117 89-97 91-961IMGT®, the international ImMunoGeneTics information system®, imgt.org, Lefranc, M.-P. et al., Nucleic Acids Res., 27:209-212 (1999)2Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U. S. Department of Health and Human Services, NIH Publication No. 91-32423Chothia et al., J. Mol. Biol. 196:901-917 (1987))

[0057] CDR-grafted antibody: The term " CDR-grafted antibody" refers to antibodies which comprise heavy and light chain variable region sequences from one species but in which the sequences of one or more of the CDR regions of VH and / or (e.g., and) VL are replaced with CDR sequences of another species, such as antibodies having murine heavy and light chain variable regions in which one or more of the murine CDRs (e.g., CDR3) has been replaced with human CDR sequences.

[0058] Central nervous system (CNS): as used herein, the term “central nervous system” (CNS) refers to the brain and spinal cord, and includes neurons and non-nervous supporting cells (e.g., glia) as well as the blood-brain barrier cells. The blood-brain barrier prevents various molecules from non-selectively crossing into the extracellular fluid of the CNS from the circulation. The CNS also includes cells of the blood-cerebrospinal fluid barrier, such as the cells of the choroid plexus.

[0059] CNS disease or disorder: as used herein, a “CNS disease or disorder” refers to a disease or disorder which affects the CNS (e.g., CNS structure or function) and / or which has an etiology in the CNS. CNS diseases and disorders are also known as neurological disease or disorders. Examples of CNS diseases or disorders include, but are not limited to, neuromuscular diseases and disorders (e.g., muscular dystrophy, myotonic dystrophy, spinal muscular atrophy, and Friedreich’s ataxia), amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, epilepsy, and pain disorders, amongst others. Certain lysosomal storage disorders are also examples of CNS diseases or disorders.39 / 350#14837954v1

[0060] Chimeric antibody: The term "chimeric antibody" refers to antibodies which comprise heavy and light chain variable region sequences from one species and constant region sequences from another species, such as antibodies having murine heavy and light chain variable regions linked to human constant regions.

[0061] Complementary: As used herein, the term “complementary” refers to the capacity for precise pairing between two nucleosides or two sets of nucleosides. In particular, complementary is a term that characterizes an extent of hydrogen bond pairing that brings about binding between two nucleosides or two sets of nucleosides. For example, if a base at one position of an oligonucleotide is capable of hydrogen bonding with a base at the corresponding position of a target nucleic acid (e.g., an mRNA), then the bases are considered to be complementary to each other at that position. Base pairings may include both canonical Watson-Crick base pairing and non-Watson-Crick base pairing (e.g., Wobble base pairing and Hoogsteen base pairing). For example, in some embodiments, for complementary base pairings, adenosine-type bases (A) are complementary to thymidine-type bases (T) or uracil-type bases (U), that cytosine-type bases (C) are complementary to guanosine-type bases (G), and that universal bases such as 3 -nitropyrrole or 5-nitroindole can hybridize to and are considered complementary to any A, C, U, or T. Inosine (I) has also been considered in the art to be a universal base and is considered complementary to any A, C, U or T.

[0062] Conservative amino acid substitution: As used herein, a “conservative amino acid substitution” refers to an amino acid substitution that does not alter the relative charge or size characteristics of the protein in which the amino acid substitution is made. Variants can be prepared according to methods for altering polypeptide sequence known to one of ordinary skill in the art such as are found in references which compile such methods, e.g. Molecular Cloning: A Laboratory Manual, J. Sambrook, et al., eds., Fourth Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2012, or Current Protocols in Molecular Biology, F. M. Ausubel, et al., eds., John Wiley & Sons, Inc., New York. Conservative substitutions of amino acids include substitutions made amongst amino acids within the following groups: (a) M, I, L, V; (b) F, Y, W; (c) K, R, H; (d) A, G; (e) S, T; (f) Q, N; and (g) E, D.

[0063] Covalently linked: As used herein, the term “covalently linked” refers to a characteristic of two or more molecules being linked together via at least one covalent bond. In some embodiments, two molecules can be covalently linked together by a single bond, e.g., a disulfide bond or disulfide bridge, that serves as a linker between the molecules. However, in some embodiments, two or more molecules can be covalently linked together via a molecule 40 / 350#14837954v1that serves as a linker that joins the two or more molecules together through multiple covalent bonds. In some embodiments, a linker may be a cleavable linker. However, in some embodiments, a linker may be a non-cleavable linker.

[0064] Cross-reactive: As used herein and in the context of a targeting agent (e.g., a TfRl-targeting agent, such as an antibody), the term “cross-reactive,” refers to a property of the agent being capable of specifically binding to more than one antigen of a similar type or class (e.g., antigens of multiple homologs, paralogs, or orthologs) with similar affinity or avidity. For example, in some embodiments, an antibody that is cross-reactive against human and nonhuman primate antigens of a similar type or class (e.g., a human transferrin receptor and nonhuman primate transferrin receptor) is capable of binding to the human antigen and nonhuman primate antigens with a similar affinity or avidity. In some embodiments, an antibody is cross-reactive against a human antigen and a rodent antigen of a similar type or class. In some embodiments, an antibody is cross-reactive against a rodent antigen and a non-human primate antigen of a similar type or class. In some embodiments, an antibody is cross-reactive against a human antigen, a non-human primate antigen, and a rodent antigen of a similar type or class.

[0065] Dystrophin: As used herein, the term “dystrophin” refers to a gene that encodes dystrophin protein, a key component of the dystrophin-glycoprotein complex, which bridges the inner cytoskeleton and the extracellular matrix in muscle cells, particularly muscle fibers. Deletions, duplications, and point mutations in dystrophin may cause dystrophinopathies, such as Duchenne muscular dystrophy, Becker muscular dystrophy, or cardiomyopathy. Alternative promoter usage and alternative splicing result in numerous distinct transcript variants and protein isoforms for this gene. Dystrophin has been implicated in the central nervous system, e.g., in the organization of GABA receptors at the post-synapse in the hippocampus (See Knuesel et al., “Short communication: Altered synaptic clustering of GABAA receptors in mice lacking dystrophin (mdx mice)” Eur. J. Neurosci. 11(12):4457-4462 (1999); doi:10.1046 / j.1460-9568.1999.00887.x.). In some embodiments, a dystrophin gene may be a human (Gene ID: 1756), non-human primate (e.g., Gene ID: 465559), or rodent gene (e.g., Gene ID: 13405; Gene ID: 24907). In addition, multiple human transcript variants (e.g., as annotated under GenBank RefSeq Accession Numbers: NM_000109.3, NM_004006.2, NM_004009.3, NM_004010.3 and NM_004011.3) have been characterized that encode different protein isoforms. “Dystrophin” is sometimes referred to as “DMD”.

[0066] Dystrophin allele: As used herein, the term “dystrophin allele” refers to any one of alternative forms (e.g., wild-type or mutant forms) of a dystrophin gene. In some41 / 350#14837954v1embodiments, a dystrophin allele may encode for dystrophin that retains its normal and typical functions. In some embodiments, a dystrophin allele may comprise one or more mutations that results in muscular dystrophy. Common mutations that lead to Duchenne muscular dystrophy involve frameshift, deletion, substitution, and duplicative mutations of one or more of 79 exons present in a dystrophin allele, e.g., exon 8, exon 23, exon 41, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53, or exon 55. Further examples of dystrophin mutations are disclosed, for example, in Flanigan KM, et al., Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort. Hum Mutat. 2009 Dec; 30 (12): 1657-66, the contents of which are incorporated herein by reference in its entirety.

[0067] Dystrophinopathy: As used herein, the term “dystrophinopathy” refers to a muscle or neurological disease results from one or more mutated dystrophin alleles. Dystrophinopathies include a spectrum of conditions (ranging from mild to severe) that includes Duchenne muscular dystrophy, Becker muscular dystrophy, and dystrophin-associated dilated cardiomyopathy (DCM). In some embodiments, at one end of the spectrum, dystrophinopathy is phenotypically associated with an asymptomatic increase in serum concentration of creatine phosphokinase (CK) and / or (e.g., and) muscle cramps with myoglobinuria. In some embodiments, at the other end of the spectrum, dystrophinopathy is phenotypically associated with progressive muscle diseases that are generally classified as Duchenne or Becker muscular dystrophy when skeletal muscle is primarily affected and as dystrophin-associated dilated cardiomyopathy (DCM) when the heart is primarily affected. Symptoms of Duchenne muscular dystrophy include muscle loss or degeneration, diminished muscle function, pseudohypertrophy of the tongue and calf muscles, higher risk of neurological abnormalities, and a shortened lifespan. Duchenne muscular dystrophy is associated with Online Mendelian Inheritance in Man (OMIM) Entry # 310200. Becker muscular dystrophy is associated with OMIM Entry # 300376. Dilated cardiomyopathy is associated with OMIM Entry X# 302045.

[0068] Exonic splicing enhancer (ESE): As used herein, the term “exonic splicing enhancer” or “ESE” refers to a nucleic acid sequence motif within an exon of a gene, pre-mRNA, or mRNA that directs or enhances splicing of pre-mRNA into mRNA, e.g., as described in Blencowe et al., Trends Biochem Sci 25, 106-10. (2000), incorporated herein by reference. ESEs can be referred to as splicing features. ESEs may direct or enhance splicing, for example, to remove one or more introns and / or one or more exons from a gene transcript. ESE motifs are typically 6-8 nucleobases in length. SR proteins (e.g., proteins encoded by the gene SRSF1, SRSF2, SRSF3, SRSF4, SRSF5, SRSF6, SRSF7, SRSF8, SRSF9, SRSF10, SRSF11, SRSF12,42 / 350#14837954v1TRA2A or TRA2B) bind to ESEs through their RNA recognition motif region to facilitate splicing. ESE motifs can be identified through a number of methods, including those described in Cartegni et al., Nucleic Acids Research, 2003, Vol. 31, No. 13, 3568–3571, incorporated herein by reference.

[0069] Framework: As used herein, the term "framework" or "framework sequence" refers to the remaining sequences of a variable region minus the CDRs. Because the exact definition of a CDR sequence can be determined by different systems, the meaning of a framework sequence is subject to correspondingly different interpretations. The six CDRs (CDR-L1, CDR-L2, and CDR-L3 of light chain and CDR-H1, CDR-H2, and CDR-H3 of heavy chain) also divide the framework regions on the light chain and the heavy chain into four sub-regions (FR1, FR2, FR3 and FR4) on each chain, in which CDR1 is positioned between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4. Without specifying the particular sub-regions as FR1, FR2, FR3 or FR4, a framework region, as referred by others, represents the combined FRs within the variable region of a single, naturally occurring immunoglobulin chain. As used herein, a FR represents one of the four sub-regions, and FRs represents two or more of the four sub-regions constituting a framework region. Human heavy chain and light chain acceptor sequences are known in the art. In one embodiment, the acceptor sequences known in the art may be used in the antibodies disclosed herein.

[0070] GCN2: The term “GCN2”, as used herein, refers to a gene that encodes general control nonderepressible 2 protein, a serine / threonine-protein kinase, or the GCN2 protein itself.GCN2 is one of four stress kinases of the integrated stress response (ISR) pathway that senses amino acid availability and controls gene expression in response to amino acid deprivation, UV irradiation, viral infection, proteasome inhibition, hypoxia, glucose deprivation, and oxidative stress. In mammals, GCN2 is also called EIF2AK4 (eukaryotic translation initiation factor 2 alpha kinase 4).

[0071] GCN2 inhibitor: The term “GCN2 inhibitor”, as used herein, refers to a compound that suppresses the expression and / or activity of GCN2. A GCN2 inhibitory may be a compound of any type, such as a small molecule, an oligonucleotide, or a protein, but is preferably a small molecule provided herein.

[0072] Human antibody: The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs 43 / 350#14837954v1and in particular CDR3. However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0073] Humanized antibody: The term "humanized antibody" refers to antibodies which comprise heavy and light chain variable region sequences from a non-human species (e.g., a mouse) but in which at least a portion of the VH and / or (e.g., and) VL sequence has been altered to be more "human-like", i.e., more similar to human germline variable sequences. One type of humanized antibody is a CDR-grafted antibody, in which human CDR sequences are introduced into non-human VH and VL sequences to replace the corresponding non-human CDR sequences. In one embodiment, humanized anti-TfRl antibodies and antigen binding portions are provided. Such antibodies may be generated by obtaining murine anti-TfRl monoclonal antibodies using traditional hybridoma technology followed by humanization using in vitro genetic engineering, such as those disclosed in Kasaian et al PCT publication No. WO 2005 / 123126 A2.

[0074] Internalizing cell surface receptor: As used herein, the term, “internalizing cell surface receptor” refers to a cell surface receptor that is internalized by cells, e.g., upon external stimulation, e.g., ligand binding to the receptor. In some embodiments, an internalizing cell surface receptor is internalized by endocytosis. In some embodiments, an internalizing cell surface receptor is internalized by clathrin-mediated endocytosis. However, in some embodiments, an internalizing cell surface receptor is internalized by a clathrin-independent pathway, such as, for example, phagocytosis, macropinocytosis, caveolae- and raft-mediated uptake or constitutive clathrin-independent endocytosis. In some embodiments, the internalizing cell surface receptor comprises an intracellular domain, a transmembrane domain, and / or (e.g., and) an extracellular domain, which may optionally further comprise a ligand-binding domain. In some embodiments, a cell surface receptor becomes internalized by a cell after ligand binding. In some embodiments, a ligand may be a TfR1-targeting agent or a TfRl -targeting antibody. In some embodiments, an internalizing cell surface receptor is a transferrin receptor.

[0075] Isolated antibody: An "isolated antibody", as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds transferrin receptor is substantially free of antibodies that specifically bind antigens other than transferrin receptor). An isolated antibody that specifically binds transferrin receptor complex may, however, have cross-reactivity to44 / 350#14837954v1other antigens, such as transferrin receptor molecules from other species. Moreover, an isolated antibody may be substantially free of other cellular material and / or (e.g., and) chemicals.

[0076] Kabat numbering: The terms " Kabat numbering", " Kabat definitions and " Kabat labeling" are used interchangeably herein. These terms, which are recognized in the art, refer to a system of numbering amino acid residues which are more variable (i.e. hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody, or an antigen binding portion thereof (Kabat et al. (1971) Ann. NY Acad. Sci. 190:382-391 and, Kabat, E. A., etal. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U. S. Department of Health and Human Services, NIH Publication No. 91-3242). For the heavy chain variable region, the hypervariable region ranges from amino acid positions 31 to 35 for CDR1, amino acid positions 50 to 65 for CDR2, and amino acid positions 95 to 102 for CDR3. For the light chain variable region, the hypervariable region ranges from amino acid positions 24 to 34 for CDR1, amino acid positions 50 to 56 for CDR2, and amino acid positions 89 to 97 for CDR3.

[0077] Molecular payload: As used herein, the term “molecular payload” refers to a molecule or species that functions to modulate a biological outcome. In some embodiments, a molecular payload is linked (e.g., covalently linked) to, or otherwise associated with a TfR1-targeting agent. In some embodiments, the molecular payload comprises a small molecule, a protein, a peptide, a nucleic acid, or an oligonucleotide. In some embodiments, the molecular payload comprises an oligonucleotide. In some embodiments, the molecular payload functions to modulate the processing of an RNA transcript (e.g., a pre-mRNA transcript), to modulate the transcription of a DNA sequence, to modulate the expression of a protein, or to modulate the activity of a protein. In some embodiments, the molecular payload comprises an oligonucleotide that comprises a strand having a region of complementarity to a target gene. In some embodiments, the molecular payload comprises an oligonucleotide with biological activity in a particular disease context (e.g., a muscle disease or disorder or a CNS disease or disorder).

[0078] Oligonucleotide: As used herein, the term “oligonucleotide” refers to an oligomeric nucleic acid compound of up to 200 nucleotides in length. Examples of oligonucleotides include, but are not limited to, RNAi oligonucleotides (e.g., siRNAs, shRNAs), microRNAs, gapmers, mixmers, phosphorodiamidate morpholino oligomers, peptide nucleic acids, aptamers, guide nucleic acids (e.g., Cas9 guide RNAs), etc. Oligonucleotides may be singlestranded or double-stranded. In some embodiments, an oligonucleotide may comprise one or more modified nucleosides (e.g., 2'-O-methyl sugar modifications, purine or pyrimidine 45 / 350#14837954v1modifications). In some embodiments, an oligonucleotide may comprise one or more modified internucleoside linkages. In some embodiments, an oligonucleotide may comprise one or more phosphorothioate linkages, which may be in the Rp or Sp stereochemical conformation.

[0079] Recombinant antibody: The term "recombinant human antibody", as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described in more details in this disclosure), antibodies isolated from a recombinant, combinatorial human antibody library (Hoogenboom H. R., (1997) TIB Tech. 15:62-70; Azzazy H., and Highsmith W. E., (2002) Clin. Biochem. 35:425-445;Gavilondo J. V., and Larrick J. W. (2002) BioTechniques 29:128-145; Hoogenboom H., and Chames P. (2000) Immunology Today 21:371-378), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor, L. D., et al.(1992) Nucl. Acids Res. 20:6287-6295; Kellermann S-A., and Green L. L. (2002) Current Opinion in Biotechnology 13:593-597; Little M. et al (2000) Immunology Today 21:364-370) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo. One embodiment of the disclosure provides fully human antibodies capable of binding human transferrin receptor which can be generated using techniques well known in the art, such as, but not limited to, using human Ig phage libraries such as those disclosed in Jermutus et al., PCT publication No. WO 2005 / 007699 A2.

[0080] Region of complementarity: As used herein, the term “region of complementarity” refers to a nucleotide sequence, e.g., of an oligonucleotide, that is sufficiently complementary to a cognate nucleotide sequence, e.g., of a target nucleic acid, such that the two nucleotide sequences are capable of annealing to one another under physiological conditions (e.g., in a cell). In some embodiments, a region of complementarity is fully complementary to a cognate nucleotide sequence of target nucleic acid. However, in some embodiments, a region of complementarity is partially complementary to a cognate nucleotide sequence of target nucleic acid (e.g., at least 80%, 90%, 95% or 99% complementarity). In some embodiments, a region 46 / 350#14837954v1of complementarity contains 1, 2, 3, or 4 mismatches compared with a cognate nucleotide sequence of a target nucleic acid.

[0081] Specifically binds: As used herein, the term “specifically binds” refers to the ability of a molecule to bind to a binding partner with a degree of affinity or avidity that enables the molecule to be used to distinguish the binding partner from an appropriate control in a binding assay or other binding context. With respect to an antibody, the term, “specifically binds”, refers to the ability of the antibody to bind to a specific antigen with a degree of affinity or avidity, compared with an appropriate reference antigen or antigens, that enables the antibody to be used to distinguish the specific antigen from others, e.g., to an extent that permits preferential targeting to certain cells, e.g., CNS cells, through binding to the antigen, as described herein. In some embodiments, an antibody specifically binds to a target if the antibody has a KD for binding the target of at least about IO’4M, 10'5M, 10'6M, 10'7M, 10'8M, 10'9M, IO'10M, IO'11M, IO’12M, 10'13M, or less. In some embodiments, an antibody specifically binds to the transferrin receptor, e.g., an epitope of the apical domain of transferrin receptor.

[0082] Splice acceptor site: As used herein, the term “splice acceptor site” or “splice acceptor” refers to a nucleic acid sequence motif at the 3’ end of an intron or across an intron / exon junction of a gene or pre-mRNA that is involved in splicing of pre-mRNA into mRNA (z.e., removing introns from the pre-mRNA), and can be referred to as a splicing feature. A splice acceptor site includes a terminal AG sequence at the 3’ end of an intron, which is typically preceded (5’-ward) by a region high in pyrimidines (C / U). Upstream from the splice acceptor site is the branch point. Formation of a lariat loop intermediate structure by a transesterification reaction between the branch point and the splice donor site releases a 3’-OH of the 5’ exon, which subsequently reacts with the first nucleotide of the 3’ exon, thereby joining the exons and releasing the intron lariat. The AG sequence at the 3’ end of the intron in the splice acceptor site is known to be critical for proper splicing, as changing one of these nucleotides results in inhibition of splicing. Rarely, alternative splice acceptor sites have an AC at the 3’ end of the intron, instead of the more common AG. A common splice acceptor site motif has a sequence of or similar to [Y-rich region]-NCAGG or YxNYAGG (SEQ ID NO: 4086), in which Y represents a pyrimidine, N represents any nucleotide, and x is a number from 4 to 20. The cut site follows the AG, which represent the 3 ’-terminal nucleotides of the excised intron.

[0083] Splice donor site: As used herein, the term “splice donor site” or “splice donor” refers to a nucleic acid sequence motif at the 5’ end of an intron or across an exon / intron junction of a 47 / 350#14837954v1gene or pre-mRNA that is involved in splicing of pre-mRNA into mRNA ( / .<?., removing introns from the pre-mRNA), and can be referred to as a splicing feature. A splice donor site includes a terminal GU sequence at the 5’ end of the intron, within a larger and fairly unconstrained sequence. During splicing, the 2’ -OH of a nucleotide within the branch point initiates a transesterification reaction via a nucleophilic attack on the 5’ G of the intron within the splice donor site. The G is thereby cleaved from the pre-mRNA and bonds instead to the branch point nucleotide, forming a loop lariat structure. The 3’ nucleotide of the upstream exon subsequently binds the splice acceptor sitejoining the exons and excising the intron. A typical splice donor site has a sequence of or similar to GGGURAGU or AGGURNG, in which R represents a purine and N represents any nucleotide. The cut site precedes the first GU ( / .<?., GG / GURAGU or AG / GURNG), which represent the 5’-terminal nucleotides of the excised intron.

[0084] Subject: As used herein, the term “subject” refers to a mammal. In some embodiments, a subject is non-human primate, or rodent. In some embodiments, a subject is a human. In some embodiments, a subject is a patient, e.g., a human patient that has or is suspected of having a disease. In some embodiments, the subject is a human patient who has or is suspected of having a muscle disease or disorder. In some embodiments, the subject is a human patient who has or is suspected of having a CNS disease or disorder. In some embodiments, the subject is a human patient who has one or more symptoms associated with a muscle disease or disorder and / or a CNS disease or disorder, such as one or more symptoms disclosed herein.

[0085] Transferrin receptor: As used herein, the term, “transferrin receptor” (also known as TFRC, CD71, p90, TFR, or TFR1) refers to an internalizing cell surface receptor that binds transferrin to facilitate iron uptake by endocytosis. In some embodiments, a transferrin receptor may be of human (NCBI Gene ID 7037), non-human primate (e.g., NCBI Gene ID 711568 or NCBI Gene ID 102136007), or rodent (e.g., NCBI Gene ID 22042) origin. In addition, multiple human transcript variants have been characterized that encoded different isoforms of the receptor (e.g., as annotated under GenBank RefSeq Accession Numbers:NP_001121620.1, NP_003225.2, NP_001300894.1, and NP_001300895.1).

[0086] 2’-modified nucleoside: As used herein, the terms “2’-modified nucleoside” and “2’-modified ribonucleoside” are used interchangeably and refer to a nucleoside having a sugar moiety modified at the 2’ position. In some embodiments, the 2’-modified nucleoside is a 2’-4’ bicyclic nucleoside, where the 2’ and 4’ positions of the sugar are bridged (e.g., via a methylene, an ethylene, or a (S)-constrained ethyl bridge). In some embodiments, the 2’- 48 / 350#14837954v1modified nucleoside is a non-bicyclic 2’ -modified nucleoside, e.g., where the 2’ position of the sugar moiety is substituted. Non-limiting examples of 2’ -modified nucleosides include: 2’-deoxy, 2’-fluoro (2’-F), 2’-O-methyl (2’-0-Me), 2’-O-methoxyethyl (2’-M0E), 2’-O-aminopropyl (2’-O-AP), 2’-O-dimethylaminoethyl (2’-0-DMA0E), 2’-O-dimethylaminopropyl (2’-0-DMAP), 2’-O-dimethylaminoethyloxyethyl (2’-0-DMAE0E), 2’- O-N-methylacetamido (2’-0-NMA), locked nucleic acid (LNA, methylene-bridged nucleic acid), ethylene-bridged nucleic acid (ENA), and (S)-constrained ethyl-bridged nucleic acid (cEt). In some embodiments, the 2’-modified nucleosides described herein are high-affinity modified nucleosides and oligonucleotides comprising the 2’ -modified nucleosides have increased affinity to a target sequences, relative to an unmodified oligonucleotide. Examples of structures of 2’ -modified nucleosides are provided below:2'-O-methoxyethyl2'-O-methyl(MOE)locked nucleic acid ethylene-bridged (S)-constrained(LNA) nucleic acid (ENA) ethyl (cEt)These examples are shown with phosphate groups, but any internucleoside linkages are contemplated between 2’-modified nucleosides.

[0087] Ranges: All ranges provided in the present disclosure are inclusive of the end points.II. Complexes

[0088] Provided herein are complexes that comprise a targeting agent, e.g. an antibody, covalently linked to a molecular payload. In some embodiments, a complex comprises a transferrin receptor (TfRl)-targeting antibody covalently linked to an oligonucleotide. A complex may comprise an antibody that specifically binds a single antigenic site or that binds to at least two antigenic sites that may exist on the same or different antigens.49 / 350#14837954v1

[0089] A complex may be used to modulate the activity or function of at least one gene, protein, and / or (e.g., and) nucleic acid in cells (e.g., muscle cells and / or cells of the CNS), or to alleviate the symptoms of a disease or disorder. In some embodiments, the molecular payload present with a complex is responsible for the modulation of a gene, protein, and / or (e.g., and) nucleic acid. A molecular payload may be a small molecule, protein, nucleic acid, oligonucleotide, or any molecular entity capable of modulating the activity or function of a gene, protein, and / or (e.g., and) nucleic acid in a cell. In particular embodiments, a molecular payload is an oligonucleotide capable of inducing exon skipping in a gene of interest.

[0090] In some embodiments, a TfR1-targeting agent of the complexes described herein comprises an anti -transferrin receptor 1 (TfRl) antibody, covalently linked to a molecular payload, e.g., an exon-skipping oligonucleotide.Antibodies

[0091] Some aspects of the disclosure are based on the recognition that agents binding to transferrin receptor, e.g., anti-transferrin-receptor antibodies, are capable of targeting muscle cells and / or (e.g., and) cells of the CNS. Transferrin receptors are internalizing cell surface receptors that transport transferrin across the cellular membrane and participate in the regulation and homeostasis of intracellular iron levels. Transferrin receptors also play a role in transport into the CNS from the circulatory system, e.g., across the blood-brain barrier. Some aspects of the disclosure provide transferrin receptor binding proteins, which are capable of binding to transferrin receptor. Accordingly, aspects of the disclosure provide binding proteins (e.g., antibodies) that bind to transferrin receptor. In some embodiments, binding proteins that bind to transferrin receptor are internalized, along with any bound molecular payload, into a muscle cell and / or a cell of the CNS. As used herein, an antibody that binds to a transferrin receptor may be referred to interchangeably as an, transferrin receptor antibody, an antitransferrin receptor antibody, or an anti-TfR1 antibody. Antibodies that bind, e.g. specifically bind, to a transferrin receptor may be internalized into the cell, e.g. through receptor-mediated endocytosis, upon binding to a transferrin receptor.

[0092] It should be appreciated that anti-TfRl antibodies may be produced, synthesized, and / or (e.g., and) derivatized using several known methodologies, e.g. library design using phage display. Exemplary methodologies have been characterized in the art and are incorporated by reference (Diez, P. et al. “High-throughput phage-display screening in array format”, Enzyme and microbial technology, 2015, 79, 34-41.; Christoph M. H. and Stanley, J. R. “Antibody Phage Display: Technique and Applications” J Invest Dermatol. 2014, 134:2.;50 / 350#14837954v1Engleman, Edgar (Ed.) “Human Hybridomas and Monoclonal Antibodies.” 1985, Springer.). In other embodiments, an anti-TfR1 antibody has been previously characterized or disclosed. Antibodies that specifically bind to transferrin receptor are known in the art (see, e.g. US Patent. No. 4,364,934, filed 12 / 4 / 1979, “Monoclonal antibody to a human early thymocyte antigen and methods for preparing same”; US Patent No. 8,409,573, filed 6 / 14 / 2006, “Anti-CD71 monoclonal antibodies and uses thereof for treating malignant tumor cells”; US Patent No. 9,708,406, filed 5 / 20 / 2014, “Anti-transferrin receptor antibodies and methods of use”; US 9,611,323, filed 12 / 19 / 2014, “Low affinity blood brain barrier receptor antibodies and uses therefor”; WO 2015 / 098989, filed 12 / 24 / 2014, “Novel anti-Transferrin receptor antibody that passes through blood-brain barrier”; Schneider C. et al. “Structural features of the cell surface receptor for transferrin that is recognized by the monoclonal antibody OKT9.” J Biol Chem.1982, 257:14, 8516-8522.; Lee et al. “Targeting Rat Anti-Mouse Transferrin Receptor Monoclonal Antibodies through Blood-Brain Barrier in Mouse” 2000, J Pharmacol. Exp. T er., 292: 1048-1052.).

[0093] In some embodiments, the anti-TfR1 antibody described herein binds to transferrin receptor with high specificity and affinity. In some embodiments, the anti-TfR1 antibody described herein specifically binds to any extracellular epitope of a transferrin receptor or an epitope that becomes exposed to an antibody. In some embodiments, anti-TfRl antibodies provided herein bind specifically to transferrin receptor from human, non-human primates, mouse, rat, etc. In some embodiments, anti-TfRl antibodies provided herein bind to human transferrin receptor. In some embodiments, the anti-TfR1 antibody described herein binds to an amino acid segment of a human or non-human primate transferrin receptor, as provided in SEQ ID NOs: 105-108. In some embodiments, the anti-TfR1 antibody described herein binds to an amino acid segment corresponding to amino acids 90-96 of a human transferrin receptor as set forth in SEQ ID NO: 105, which is not in the apical domain of the transferrin receptor.

[0094] In some embodiments, the anti-TfRl antibodies described herein (e.g., Anti-TfR clone 8 in Table 2 below) bind an epitope in TfRl, wherein the epitope comprises residues in amino acids 214-241 and / or amino acids 354-381 of SEQ ID NO: 105. In some embodiments, the anti-TfRl antibodies described herein bind an epitope comprising residues in amino acids 214-241 and amino acids 354-381 of SEQ ID NO: 105. In some embodiments, the anti-TfRl antibodies described herein bind an epitope comprising one or more of residues Y222, T227, K231, H234, T367, S368, S370, T376, and S378 of human TfRl as set forth in SEQ ID NO: 105. In some embodiments, the anti-TfRl antibodies described herein bind an epitope51 / 350#14837954v1comprising residues Y222, T227, K231, H234, T367, S368, S370, T376, and S378 of human TfRl as set forth in SEQ ID NO: 105.

[0095] In some embodiments, the anti-TfR1 antibody described herein (e.g., 3M12 in Table 2 below and its variants) bind an epitope in TfRl, wherein the epitope comprises residues in amino acids 258-291 and / or amino acids 358-381 of SEQ ID NO: 105. In some embodiments, the anti-TfRl antibodies (e.g., 3M12 in Table 2 below and its variants) described herein bind an epitope comprising residues in amino acids amino acids 258-291 and amino acids 358-381 of SEQ ID NO: 105. In some embodiments, the anti-TfRl antibodies described herein (e.g., 3M12 in Table 2 below and its variants) bind an epitope comprising one or more of residues K261, S273, Y282, T362, S368, S370, and K371 of human TfRl as set forth in SEQ ID NO: 105. In some embodiments, the anti-TfRl antibodies described herein (e.g., 3M12 in Table 2 below and its variants) bind an epitope comprising residues K261, S273, Y282, T362, S368, S370, and K371 of human TfRl as set forth in SEQ ID NO: 105.

[0096] An example human transferrin receptor amino acid sequence, corresponding to NCBI sequence NP_003225.2 (transferrin receptor protein 1 isoform 1, homo sapiens) is as follows: MM DQ A RS AF SNLFGGEPLS YTRF SLARQ VDGDNSHVEMKL AVDEEENADNNTKANV TKPKRCSGSICYGTIAVIVFFLIGFMIGYLGYCKGVEPKTECERLAGTESPVREEPGEDF PAARRLYWDDLKRKLSEKLDSTDFTGTIKLLNENSYVPREAGSQKDENLALYVENQF REFKLSKVWRDQHFVKIQVKDSAQNSVIIVDKNGRLVYLVENPGGYVAYSKAATVTG KLVHANFGTKKDFEDLYTPVNGSIVIVRAGKITFAEKVANAESLNAIGVLIYMDQTKF PIVNAELSFFGHAHLGTGDPYTPGFPSFNHTQFPPSRSSGLPNIPVQTISRAAAEKLFGN MEGDCPSDWKTDSTCRMVTSESKNVKLTVSNVLKEIKILNIFGVIKGFVEPDHYVVVG AQRDAWGPGAAKSGVGTALLLKLAQMFSDMVLKDGFQPSRSIIFASWSAGDFGSVG ATEWLEGYLSSLHLKAFTYINLDKAVLGTSNFKVSASPLLYTLIEKTMQNVKHPVTGQ FL YQD SNW ASKVEKLTLDN AAFPFL A YSGIPAVSFCFCEDTDYPYLGTTMD TYKELIE RIPELNKVARAAAEVAGQFVIKLTHDVELNLDYERYNSQLLSFVRDLNQYRADIKEM GLSLQWLYSARGDFFRATSRLTTDFGNAEKTDRFVMKKLNDRVMRVEYHFLSPYVSP KESPFRHVFWGSGSHTLPALLENLKLRKQNNGAFNETLFRNQLALATWTIQGAANAL SGDVWDIDNEF (SEQ ID NO: 105).

[0097] An example non-human primate transferrin receptor amino acid sequence, corresponding to NCBI sequence NP_001244232.1 (transferrin receptor protein 1, Macaca mulatto is as follows:MM DQ ARS AF SNLFGGEPLS YTRF SLARQ VDGDNSHVEMKLGVDEEENTDNNTKPNG TKPKRCGGNICYGTIAVIIFFLIGFMIGYLGYCKGVEPKTECERLAGTESPAREEPEEDFP52 / 350#14837954v1AAPRLYWDDLKRKLSEKLDTTDFTSTIKLLNENLYVPREAGSQKDENLALYIENQFRE FKLSKVWRDQHFVKIQVKDSAQNSVIIVDKNGGLVYLVENPGGYVAYSKAATVTGK LVHANFGTKKDFEDLDSPVNGSIVIVRAGKITFAEKVANAESLNAIGVLIYMDQTKFPI VKADLSFFGHAHLGTGDPYTPGFPSFNHTQFPPSQSSGLPNIPVQTISRAAAEKLFGNM EGDCPSDWKTDSTCKMVTSENKSVKLTVSNVLKETKILNIFGVIKGFVEPDHYVVVGA QRDAWGPGAAKSSVGTALLLKLAQMFSDMVLKDGFQPSRSIIFASWSAGDFGSVGAT EWLEGYLSSLHLKAFTYINLDKAVLGTSNFKVSASPLLYTLIEKTMQDVKHPVTGRSL YQDSNWASKVEKLTLDNAAFPFLAYSGIPAVSFCFCEDTDYPYLGTTMDTYKELVERI PELNKVARAAAEVAGQFVIKLTHDTELNLDYERYNSQLLLFLRDLNQYRADVKEMGL SLQWLYSARGDFFRATSRLTTDFRNAEKRDKFVMKKLNDRVMRVEYYFLSPYVSPKE SPFRHVFWGSGSHTLSALLESLKLRRQNNSAFNETLFRNQLALATWTIQGAANALSGD VWDIDNEF (SEQ ID NO: 106)

[0098] An example non-human primate transferrin receptor amino acid sequence, corresponding to NCBI sequence XP_005545315.1 (transferrin receptor protein 1, Macaca fascicularis) is as follows:MM DQ ARS AF SNLFGGEPLS YTRF SLARQ VDGDNSHVEMKLGVDEEENTDNNTKANG TKPKRCGGNICYGTIAVIIFFLIGFMIGYLGYCKGVEPKTECERLAGTESPAREEPEEDFP AAPRLYWDDLKRKLSEKLDTTDFTSTIKLLNENLYVPREAGSQKDENLALYIENQFRE FKLSKVWRDQHFVKIQVKDSAQNSVIIVDKNGGLVYLVENPGGYVAYSKAATVTGK LVHANFGTKKDFEDLDSPVNGSIVIVRAGKITFAEKVANAESLNAIGVLIYMDQTKFPI VKADLSFFGHAHLGTGDPYTPGFPSFNHTQFPPSQSSGLPNIPVQTISRAAAEKLFGNM EGDCPSDWKTDSTCKMVTSENKSVKLTVSNVLKETKILNIFGVIKGFVEPDHYVVVGA QRDAWGPGAAKSSVGTALLLKLAQMFSDMVLKDGFQPSRSIIFASWSAGDFGSVGAT EWLEGYLSSLHLKAFTYINLDKAVLGTSNFKVSASPLLYTLIEKTMQDVKHPVTGRSL YQDSNWASKVEKLTLDNAAFPFLAYSGIPAVSFCFCEDTDYPYLGTTMDTYKELVERI PELNKVARAAAEVAGQFVIKLTHDTELNLDYERYNSQLLLFLRDLNQYRADVKEMGL SLQWLYSARGDFFRATSRLTTDFRNAEKRDKFVMKKLNDRVMRVEYYFLSPYVSPKE SPFRHVFWGSGSHTLSALLESLKLRRQNNSAFNETLFRNQLALATWTIQGAANALSGD VWDIDNEF (SEQ ID NO: 107).

[0099] An example mouse transferrin receptor amino acid sequence, corresponding to NCBI sequence NP_001344227.1 (transferrin receptor protein 1, mus musculus) is as follows:MM DQ ARS AF SNLFGGEPLS YTRF SLARQ VDGDNSHVEMKL AADEEENADNNMKAS V RKPKRFNGRLCFAAIALVIFFLIGFMSGYLGYCKRVEQKEECVKLAETEETDKSETMET EDVPTSSRLYWADLKTLLSEKLNSIEFADTIKQLSQNTYTPREAGSQKDESLAYYIENQ53 / 350#14837954v1FHEFKFSKVWRDEHYVKIQVKSSIGQNMVTIVQSNGNLDPVESPEGYVAFSKPTEVSG KLVHANFGTKKDFEELSYSVNGSLVIVRAGEITFAEKVANAQSFNAIGVLIYMDKNKF PVVEADLALFGHAHLGTGDPYTPGFPSFNHTQFPPSQSSGLPNIPVQTISRAAAEKLFG KMEGSCPARWNIDSSCKLELSQNQNVKLIVKNVLKERRILNIFGVIKGYEEPDRYVVV GAQRDALGAGVAAKSSVGTGLLLKLAQVFSDMISKDGFRPSRSIIFASWTAGDFGAVG ATEWLEGYLSSLHLKAFTYINLDKVVLGTSNFKVSASPLLYTLMGKIMQDVKHPVDG KSLYRDSNWISKVEKLSFDNAAYPFLAYSGIPAVSFCFCEDADYPYLGTRLDTYEALT QKVPQLNQMVRTAAEVAGQLIIKLTHDVELNLDYEMYNSKLLSFMKDLNQFKTDIRD MGLSLQWLYSARGDYFRATSRLTTDFHNAEKTNRFVMREINDRIMKVEYHFLSPYVS PRESPFRHIFWGSGSHTLSALVENLKLRQKNITAFNETLFRNQLALATWTIQGVANALS GDIWNIDNEF (SEQ ID NO: 108)

[0100] In some embodiments, an anti-TfR1 antibody binds to an amino acid segment of the receptor as follows:FVKIQVKDSAQNSVIIVDKNGRLVYLVENPGGYVAYSKAATVTGKLVHANFGTKKDF EDLYTPVNGSIVIVRAGKITFAEKVANAESLNAIGVLIYMDQTKFPIVNAELSFFGHAH LGTGDPYTPGFPSFNHTQFPPSRSSGLPNIPVQTISRAAAEKLFGNMEGDCPSDWKTDS TCRMVTSESKNVKLTVSNVLKE (SEQ ID NO: 109) and does not inhibit the binding interactions between transferrin receptors and transferrin and / or (e.g., and) human hemochromatosis protein (also known as HFE). In some embodiments, the anti-TfR1 antibody described herein does not bind an epitope in SEQ ID NO: 109.

[0101] Appropriate methodologies may be used to obtain and / or (e.g., and) produce antibodies, antibody fragments, or antigen-binding agents, e.g., through the use of recombinant DNA protocols. In some embodiments, an antibody may also be produced through the generation of hybridomas (see, e.g., Kohler, G and Milstein, C. “Continuous cultures of fused cells secreting antibody of predefined specificity” Nature, 1975, 256: 495-497). The antigen-of-interest may be used as the immunogen in any form or entity, e.g., recombinant or a naturally occurring form or entity. Hybridomas are screened using standard methods, e.g. ELISA screening, to find at least one hybridoma that produces an antibody that targets a particular antigen.Antibodies may also be produced through screening of protein expression libraries that express antibodies, e.g., phage display libraries. Phage display library design may also be used, in some embodiments, (see, e.g. U. S. Patent No 5,223,409, filed 3 / 1 / 1991, “Directed evolution of novel binding proteins”; WO 1992 / 18619, filed 4 / 10 / 1992, “Heterodimeric receptor libraries using phagemids”; WO 1991 / 17271, filed 5 / 1 / 1991, “Recombinant library screening methods”; WO 1992 / 20791, filed 5 / 15 / 1992, “Methods for producing members of specific binding pairs”;54 / 350#14837954v1WO 1992 / 15679, filed 2 / 28 / 1992, and “Improved epitope displaying phage”). In some embodiments, an antigen-of-interest may be used to immunize a non-human animal, e.g., a rodent or a goat. In some embodiments, an antibody is then obtained from the non-human animal, and may be optionally modified using a number of methodologies, e.g., using recombinant DNA techniques. Additional examples of antibody production and methodologies are known in the art (see, e.g. Harlow et al. “Antibodies: A Laboratory Manual”, Cold Spring Harbor Laboratory, 1988.).

[0102] In some embodiments, an antibody is modified, e.g., modified via glycosylation, phosphorylation, sumoylation, and / or (e.g., and) methylation. In some embodiments, an antibody is a glycosylated antibody, which is conjugated to one or more sugar or carbohydrate molecules. In some embodiments, the one or more sugar or carbohydrate molecule are conjugated to the antibody via N-glycosylation, O-glycosylation, C-glycosylation, glypiation (GPI anchor attachment), and / or (e.g., and) phosphoglycosylation. In some embodiments, the one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, the one or more sugar or carbohydrate molecule is a branched oligosaccharide or a branched glycan. In some embodiments, the one or more sugar or carbohydrate molecule includes a mannose unit, a glucose unit, an N-acetylglucosamine unit, an N-acetylgalactosamine unit, a galactose unit, a fucose unit, or a phospholipid unit. In some embodiments, there are about 1-10, about 1-5, about 5-10, about 1-4, about 1-3, or about 2 sugar molecules. In some embodiments, a glycosylated antibody is fully or partially glycosylated. In some embodiments, an antibody is glycosylated by chemical reactions or by enzymatic means. In some embodiments, an antibody is glycosylated in vitro or inside a cell, which may optionally be deficient in an enzyme in the N- or O- glycosylation pathway, e.g. a glycosyltransferase. In some embodiments, an antibody is functionalized with sugar or carbohydrate molecules as described in International Patent Application Publication WO2014065661, published on May 1, 2014, entitled, “Modified antibody, antibody-conjugate and process for the preparation thereof’.

[0103] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VL domain and / or (e.g., and) a VH domain of any one of the anti-TfRl antibodies selected from any one of Tables 2-7, and comprises a constant region comprising the amino acid sequences of the constant regions of an IgG, IgE, IgM, IgD, IgA or IgY immunoglobulin molecule, any class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2), or any subclass (e.g., IgG2a and IgG2b) of immunoglobulin molecule. Non-limiting examples of human constant regions are described in the art, e.g., see Kabat E A et al., (1991) supra.55 / 350#14837954v1

[0104] In some embodiments, agents binding to transferrin receptor, e.g., anti-TfRl antibodies, are capable of targeting muscle cell and / or (e.g., and) mediate the transportation of an agent across the blood brain barrier. Transferrin receptors are internalizing cell surface receptors that transport transferrin across the cellular membrane and participate in the regulation and homeostasis of intracellular iron levels. Some aspects of the disclosure provide transferrin receptor binding proteins, which are capable of binding to transferrin receptor. Antibodies that bind, e.g. specifically bind, to a transferrin receptor may be internalized into the cell, e.g. through receptor-mediated endocytosis, upon binding to a transferrin receptor.

[0105] Provided herein, in some aspects, are humanized antibodies that bind to transferrin receptor with high specificity and affinity. In some embodiments, the humanized anti-TfR1 antibody described herein specifically binds to any extracellular epitope of a transferrin receptor or an epitope that becomes exposed to an antibody. In some embodiments, the humanized anti-TfRl antibodies provided herein bind specifically to transferrin receptor from human, non-human primates, mouse, rat, etc. In some embodiments, the humanized anti-TfRl antibodies provided herein bind to human transferrin receptor. In some embodiments, the humanized anti-TfR1 antibody described herein binds to an amino acid segment of a human or non-human primate transferrin receptor, as provided in SEQ ID NOs: 105-108. In some embodiments, the humanized anti-TfR1 antibody described herein binds to an amino acid segment corresponding to amino acids 90-96 of a human transferrin receptor as set forth in SEQ ID NO: 105, which is not in the apical domain of the transferrin receptor. In some embodiments, the humanized anti-TfRl antibodies described herein binds to TfRl but does not bind to TfR2.

[0106] In some embodiments, an anti-TFRl antibody specifically binds a TfRl (e.g., a human or non-human primate TfRl) with binding affinity (e.g., as indicated by Kd) of at least about IO’4M, 10’5M, IO’6M, IO’7M, IO’8M, IO’9M, IO’10M, 10’11M, IO’12M, IO’13M, or less. In some embodiments, the anti-TfRl antibodies described herein bind to TfRl with a KD of sub-nanomolar range. In some embodiments, the anti-TfRl antibodies described herein selectively bind to transferrin receptor 1 (TfRl) but do not bind to transferrin receptor 2 (TfR2). In some embodiments, the anti-TfRl antibodies described herein bind to human TfRl and cyno TfRl (e.g., with a Kd of IO’7M, IO’8M, IO’9M, IO’10M, 10’11M, IO’12M, IO’13M, or less), but do not bind to a mouse TfRl. The affinity and binding kinetics of the anti-TfR1 antibody can be tested using any suitable method including but not limited to biosensor technology (e.g., OCTET or BIACORE). In some embodiments, binding of any one of the anti-TfRl antibodies described herein does not complete with or inhibit transferrin binding to the TfRl.56 / 350#14837954v1In some embodiments, binding of any one of the anti-TfRl antibodies described herein does not complete with or inhibit HFE-beta-2-microglobulin binding to the TfRl.

[0107] Non-limiting examples of anti-TfRl antibodies are provided in Table 2.Table 2. Examples of Anti-TfRl AntibodiesNumbering SystemAb Feature IMGT Kabat Chothia CDR- GFNIKDDY (SEQ ID GFNIKDD (SEQ ID NO: H1 NO: 1) DDYMY (SEQ ID NO: 7)12)CDR- IDPENGDT (SEQ ID WIDPENGDTEYASKFQDH2 ENG (SEQ ID NO: 13)NO: 2) (SEQ ID NO: 8)CDR- TLWLRRGLDY (SEQ WLRRGLDY (SEQ ID NO: LRRGLD (SEQ ID NO: 14) H3 ID NO: 3) 9)CDR- KSLLHSNGYTY RSSKSLLHSNGYTYLF SKSLLHSNGYTY (SEQ L1 (SEQ ID NO: 4) (SEQ ID NO: 10) ID NO: 15) CDR- 3-A4 RMS (SEQ ID NO: 5) RMS (SEQ ID NO: 5) RMSNLAS (SEQ ID NO: 11) L2CDR- MQHLEYPFT (SEQ MQHLEYPFT (SEQ ID NO: HLEYPF (SEQ ID NO: 16) L3 ID NO: 6) 6) EVQLQQSGAELVRPGASVKLSCTASGFNIKDDYMYWVKQRPEQGLEWIGWIDP VH ENGDTEYASKFQDKATVTADTSSNTAYLQLSSLTSEDTAVYYCTL WLRRGLDY WGQGTSVTVSS (SEQ ID NO: 17) DIVMTQAAPSVPVTPGESVSISCRSSKSLLHSNGYTYLFWFLQRPGQSPQLLIYR VL MSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPFTFGGGTKL EIK (SEQ ID NO: 18)CDR- GFNIKDDY (SEQ ID GFNIKDD (SEQ ID NO: DDYMY (SEQ ID NO: 7) H1 NO: 1) 12) CDR- IDPETGDT (SEQ ID WIDPETGDTEYASKFQD ETG (SEQ ID NO: 21) H2 (SEQ ID NO: 20) NO: 19)CDR- TLWLRRGLDY (SEQ WLRRGLDY (SEQ ID NO: LRRGLD (SEQ ID NO: 14) H3 ID NO: 3) 9)CDR- KSLLHSNGYTY RSSKSLLHSNGYTYLF SKSLLHSNGYTY (SEQ L1 (SEQ ID NO: 4) (SEQ ID NO: 10) ID NO: 15) 3-A4 CDR- RMS (SEQ ID NO: 5) RMS(SEQ ID NO: 5) RMSNLAS (SEQ ID NO: 11) N54T* L2CDR- MQHLEYPFT (SEQ MQHLEYPFT (SEQ ID NO: HLEYPF (SEQ ID NO: 16) L3 ID NO: 6) 6) EVQLQQSGAELVRPGASVKLSCTASGFNIKDDYMYWVKQRPEQGLEWIGWIDP VH ETGDTEYASKFQDKATVTADTSSNTAYLQLSSLTSEDTAVYYCTL WLRRGLDY WGQGTSVTVSS (SEQ ID NO: 22) DIVMTQAAPSVPVTPGESVSISCRSSKSLLHSNGYTYLFWFLQRPGQSPQLLIYR VL MSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPFTFGGGTKL EIK (SEQ ID NO: 18)CDR- GFNIKDDY (SEQ ID GFNIKDD (SEQ ID NO: DDYMY (SEQ ID NO: 7) H1 NO: 1) 12) CDR- IDPESGDT (SEQ ID WIDPESGDTEYASKFQD ESG (SEQ ID NO: 25) H2 (SEQ ID NO: 24) NO: 23)CDR- TLWLRRGLDY (SEQ WLRRGLDY (SEQ ID NO: LRRGLD (SEQ ID NO: 14) H3 ID NO: 3) 3-A4 9)N54S* CDR- KSLLHSNGYTY RSSKSLLHSNGYTYLF SKSLLHSNGYTY (SEQ L1 (SEQ ID NO: 4) (SEQ ID NO: 10) ID NO: 15) CDR- RMS (SEQ ID NO: 5) RMS (SEQ ID NO: 5) RMSNLAS (SEQ ID NO: 11) L2CDR- MQHLEYPFT (SEQ MQHLEYPFT (SEQ ID NO: HLEYPF (SEQ ID NO: 16) L3 ID NO: 6) 6)57 / 350#14837954v1Numbering SystemAb Feature IMGT Kabat Chothia EVQLQQSGAELVRPGASVKLSCTASGFNIKDDYMYWVKQRPEQGLEWIGWIDP VH ESGDTEYASKFQDKATVTADTSSNTAYLQLSSLTSEDTAVYYCTLWLRRGLDY WGQGTSVTVSS (SEQ ID NO: 26) DIVMTQAAPSVPVTPGESVSISCRSSKSLLHSNGYTYLFWFLQRPGQSPQLLIYR VL MSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPFTFGGGTKL EIK (SEQ ID NO: 18)CDR- GYSITSGYY (SEQ ID GYSITSGY (SEQ ID NO:SGYYWN (SEQ ID NO: 33)H1 NO: 27) 38)CDR- ITFDGAN (SEQ ID YITFDGANNYNPSLKNFDG (SEQ ID NO: 39) H2 NO: 28) (SEQ ID NO: 34)CDR- TRSSYDYDVLDY SSYDYDVLDY (SEQ ID SYDYDVLD (SEQ ID NO: H3 (SEQ ID NO: 29) NO: 35) 40)CDR- QDISNF (SEQ ID NO: RASQDISNFLN (SEQ IDSQDISNF (SEQ ID NO: 41) L1 30) NO: 36)3-M12 CDR- L2 YTS (SEQ ID NO: 31) YTSRLHS (SEQ ID NO: 37) YTS (SEQ ID NO: 31) CDR- QQGHTLPYT (SEQ QQGHTLPYT (SEQ ID NO:GHTLPY (SEQ ID NO: 42) L3 ID NO: 32) 32) DVQLQESGPGLVKPSQSLSLTCSVTGYSITSGYYWNWIRQFPGNKLEWMGYITF VH DGANNYNPSLKNRISITRDTSKNQFFLKLTSVTTEDTATYYCTRSSYDYDVLDY WGQGTTLTVSS (SEQ ID NO: 43) DIQMTQTTSSLSASLGDRVTISCRASQDISNFLNWYQQRPDGTVKLLIYYTSRLH VL SGVPSRFSGSGSGTDFSLTVSNLEQEDIATYFCQQGHTLPYTFGGGTKLEIK (SEQ ID NO: 44)CDR- GYSFTDYC (SEQ ID GYSFTDY (SEQ ID NO:DYCIN (SEQ ID NO: 51)H1 NO: 45) 56)CDR- IYPGSGNT (SEQ ID WIYPGSGNTRYSERFKG GSG (SEQ ID NO: 57) H2 NO: 46) (SEQ ID NO: 52)CDR- AREDYYPYHGMDY EDYYPYHGMDY (SEQ ID DYYPYHGMD (SEQ ID H3 (SEQ ID NO: 47) NO: 53) NO: 58) CDR- ESVDGYDNSF (SEQ RASESVDGYDNSFMH SESVDGYDNSF (SEQ ID L1 ID NO: 48) (SEQ ID NO: 54) NO: 59) 5-H12 CDR- RAS (SEQ ID NO: 49) RASNLES (SEQ ID NO: 55) RAS (SEQ ID NO: 49) L2CDR- QQSSEDPWT (SEQ QQSSEDPWT (SEQ ID NO:L3 ID NO: 50) 50) SSEDPW (SEQ ID NO: 60) QIQLQQSGPELVRPGASVKISCKASGYSFTDYCINWVNQRPGQGLEWIGWIYPG VH SGNTRYSERFKGKATLTVDTSSNTAYMQLSSLTSEDSAVYFCAREDYYPYHGM DYWGQGTSVTVSS (SEQ ID NO: 61) DIVLTQSPTSLAVSLGQRATISCRASESVDGYDNSFMHWYQQKPGQPPKLLIFRA VL SNLESGIPARFSGSGSRTDFTLTINPVEAADVATYYCQQSSEDPWTFGGGTKLEIK (SEQ ID NO: 62)CDR- GYSFTDYY (SEQ ID GYSFTDY (SEQ ID NO:DYYIN (SEQ ID NO: 64)H1 NO: 63) 56)CDR- IYPGSGNT (SEQ ID WIYPGSGNTRYSERFKG GSG (SEQ ID NO: 57) H2 NO: 46) (SEQ ID NO: 52)CDR- AREDYYPYHGMDY EDYYPYHGMDY (SEQ ID DYYPYHGMD (SEQ ID H3 (SEQ ID NO: 47) NO: 53) NO: 58) CDR- ESVDGYDNSF (SEQ RASESVDGYDNSFMH SESVDGYDNSF (SEQ ID 5-H12L1 ID NO: 48) (SEQ ID NO: 54)C33Y* NO: 59)CDR- RAS (SEQ ID NO: 49) RASNLES (SEQ ID NO: 55) RAS (SEQ ID NO: 49) L2CDR- QQSSEDPWT (SEQ QQSSEDPWT (SEQ ID NO:L3 ID NO: 50) 50) SSEDPW (SEQ ID NO: 60) QIQLQQSGPELVRPGASVKISCKASGYSFTDYYINWVNQRPGQGLEWIGWIYPG VH SGNTRYSERFKGKATLTVDTSSNTAYMQLSSLTSEDSAVYFCAREDYYPYHGMDYWGQGTSVTVSS (SEQ ID NO: 65)58 / 350#14837954v1Numbering SystemAb FeatureIMGT Kabat Chothia DIVLTQSPTSLAVSLGQRATISCRASESVDGYDNSFMHWYQQKPGQPPKLLIFRA VL SNLESGIPARFSGSGSRTDFTLTINPVEAADVATYYCQQSSEDPWTFGGGTKLEIK (SEQ ID NO: 62)CDR- GYSFTDYD (SEQ ID GYSFTDY (SEQ ID NO:DYDIN (SEQ ID NO: 67)H1 NO: 66) 56)CDR- IYPGSGNT (SEQ ID WIYPGSGNTRYSERFKG GSG (SEQ ID NO: 57) H2 NO: 46) (SEQ ID NO: 52)CDR- AREDYYPYHGMDY EDYYPYHGMDY (SEQ ID DYYPYHGMD (SEQ ID H3 (SEQ ID NO: 47) NO: 53) NO: 58) CDR- ESVDGYDNSF (SEQ RASESVDGYDNSFMH SESVDGYDNSF (SEQ ID L1 ID NO: 48) (SEQ ID NO: 54) NO: 59) 5-H12 CDR- C33D* RAS (SEQ ID NO: 49)L2 RASNLES (SEQ ID NO: 55) RAS (SEQ ID NO: 49) CDR- QQSSEDPWT (SEQ QQSSEDPWT (SEQ ID NO:L3 ID NO: 50) 50) SSEDPW (SEQ ID NO: 60) QIQLQQSGPELVRPGASVKISCKASGYSFTDYDINWVNQRPGQGLEWIGWIYPGS VH GNTRYSERFKGKATLTVDTSSNTAYMQLSSLTSEDSAVYFCAREDYYPYHGMDY WGQGTSVTVSS (SEQ ID NO: 68) DIVLTQSPTSLAVSLGQRATISCRASESVDGYDNSFMHWYQQKPGQPPKLLIFRA VL SNLESGIPARFSGSGSRTDFTLTINPVEAADVATYYCQQSSEDPWTFGGGTKLEIK (SEQ ID NO: 62)CDR- GYSFTSYW (SEQ ID GYSFTSY (SEQ ID NO:SYWIG (SEQ ID NO: 144)H1 NO: 138) 149)CDR- IYPGDSDT (SEQ ID IIYPGDSDTRYSPSFQGQ GDS (SEQ ID NO: 150) H2 NO: 139) (SEQ ID NO: 145)CDR- ARFPYDSSGYYSFD FPYDSSGYYSFDY (SEQ ID PYDSSGYYSFD (SEQ ID Anti- H3 Y (SEQ ID NO: 140) NO: 146) NO: 151)TfRclone 8 CDR- QSISSY (SEQ ID NO: RASQSISSYLN (SEQ ID SQSISSY (SEQ ID NO:L1 141) NO: 147) 152)CDR- AAS (SEQ ID NO:AASSLQS (SEQ ID NO: 148) AAS (SEQ ID NO: 142) L2 142)CDR- QQSYSTPLT (SEQ ID QQSYSTPLT (SEQ ID NO:SYSTPL (SEQ ID NO: 153)L3 NO: 143) 143)* mutation positions are according to Kabat numbering of the respective VH sequences containing the mutations

[0108] In some embodiments, the anti-TfR1 antibody of the present disclosure is a humanized variant of any one of the anti-TfRl antibodies provided in Table 2. In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 that are the same as the CDR-H1, CDR-H2, and CDR-H3 in any one of the anti-TfRl antibodies provided in Table 2, and comprises a humanized heavy chain variable region and / or (e.g., and) a humanized light chain variable region.

[0109] Examples of amino acid sequences of anti-TfRl antibodies described herein are provided in Table 3.Table 3. Variable Regions of Anti-TfRl AntibodiesAntibody Variable Region Amino Acid Sequence**3A4 VH:EVQLVQSGSELKKPGASVKVSCTASGFNIKDDYMYWVRQPPGKGLEWIGWID VH3 (N54T*) / VK4PETGDTEYASKFQDRVTVTADTSTNTAYMELSSLRSEDTAVYYCTLWLRRGLDYWGQGTLVTVSS (SEQ ID NO: 69)59 / 350#14837954v1Antibody Variable Region Amino Acid Sequence**VL:DIVMTQSPLSLPVTPGEPASISCRSSKSLLHSNGYTYLFWFQQRPGQSPRLLIYR MSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQHLEYPFTFGGGT KVEIK (SEQ ID NO: 70)VH:EVQLVQSGSELKKPGASVKVSCTASGFNIKDDYMYWVRQPPGKGLEWIGWID PESGDTEYASKFQDRVTVTADTSTNTAYMELSSLRSEDTAVYYCTLWLRRGL3A4VH3 (N54S*) / VK4 DYWGQGTLVTVSS (SEQ ID NO: 71)VL:DIVMTQSPLSLPVTPGEPASISCRSSKSLLHSNGYTYLFWFQQRPGQSPRLLIYR MSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQHLEYPFTFGGGT KVEIK (SEQ ID NO: 70)VH:EVQLVQSGSELKKPGASVKVSCTASGFNIKDDYMYWVRQPPGKGLEWIGWID PENGDTEYASKFQDRVTVTADTSTNTAYMELSSLRSEDTAVYYCTLWLRRGL3A4 DYWGQGTLVTVSS (SEQ ID NO: 72)VH3 / VK4 VL:DIVMTQSPLSLPVTPGEPASISCRSSKSLLHSNGYTYLFWFQQRPGQSPRLLIYR MSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQHLEYPFTFGGGT KVEIK (SEQ ID NO: 70)VH:QVQLQESGPGLVKPSQTLSLTCSVTGYSITSGYYWNWIRQPPGKGLEWMGYIT FDGANNYNPSLKNRVSISRDTSKNQFSLKLSSVTAEDTATYYCTRSSYDYDVL3M12 DYWGQGTTVTVSS (SEQ ID NO: 73)VH3 / VK2 VL:DIQMTQSPSSLSASVGDRVTITCRASQDISNFLNWYQQKPGQPVKLLIYYTSRL HSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQGHTLPYTFGQGTKLEIK(SEQ ID NO: 74)VH:QVQLQESGPGLVKPSQTLSLTCSVTGYSITSGYYWNWIRQPPGKGLEWMGYIT FDGANNYNPSLKNRVSISRDTSKNQFSLKLSSVTAEDTATYYCTRSSYDYDVL3M12 DYWGQGTTVTVSS (SEQ ID NO: 73)VH3 / VK3 VL:DIQMTQSPSSLSASVGDRVTITCRASQDISNFLNWYQQKPGQPVKLLIYYTSRL HSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGHTLPYTFGQGTKLEIK(SEQ ID NO: 75)VH:QVQLQESGPGLVKPSQTLSLTCTVTGYSITSGYYWNWIRQPPGKGLEWIGYITF DGANNYNPSLKNRVSISRDTSKNQFSLKLSSVTAEDTATYYCTRSSYDYDVLD3M12 YWGQGTTVTVSS (SEQ ID NO: 76)VH4 / VK2 VL:DIQMTQSPSSLSASVGDRVTITCRASQDISNFLNWYQQKPGQPVKLLIYYTSRL HSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQGHTLPYTFGQGTKLEIK(SEQ ID NO: 74)VH:QVQLQESGPGLVKPSQTLSLTCTVTGYSITSGYYWNWIRQPPGKGLEWIGYITF DGANNYNPSLKNRVSISRDTSKNQFSLKLSSVTAEDTATYYCTRSSYDYDVLD3M12 YWGQGTTVTVSS (SEQ ID NO: 76)VH4 / VK3 VL:DIQMTQSPSSLSASVGDRVTITCRASQDISNFLNWYQQKPGQPVKLLIYYTSRL HSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGHTLPYTFGQGTKLEIK(SEQ ID NO: 75)VH:5H12 QVQLVQSGAEVKKPGASVKVSCKASGYSFTDYYINWVRQAPGQGLEWMGWI VH5 (C33Y*) / VK3 YPGSGNTRYSERFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCAREDYYPYHGMD YWGQGTTVTVSS (SEQ ID NO: 77)60 / 350#14837954v1Antibody Variable Region Amino Acid Sequence**VL:DIVLTQSPDSLAVSLGERATINCRASESVDGYDNSFMHWYQQKPGQPPKLLIFR ASNLESGVPDRFSGSGSRTDFTLTISSLQAEDVAVYYCQQSSEDPWTFGQGTK LEIK (SEQ ID NO: 78)VH:QVQLVQSGAEVKKPGASVKVSCKASGYSFTDYDINWVRQAPGQGLEWMGWI YPGSGNTRYSERFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCAREDYYPY5H12 HGMDYWGQGTLVTVSS (SEQ ID NO: 79)VH5 (C33D*) / VK4 VL:DIVMTQSPDSLAVSLGERATINCRASESVDGYDNSFMHWYQQKPGQPPKLLIF RASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSSEDPWTFGQGT KLEIK (SEQ ID NO: 80)VH:QVQLVQSGAEVKKPGASVKVSCKASGYSFTDYYINWVRQAPGQGLEWMGWI YPGSGNTRYSERFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCAREDYYPY5H12 HGMDYWGQGTLVTVSS (SEQ ID NO: 77)VH5 (C33Y*) / VK4 VL:DIVMTQSPDSLAVSLGERATINCRASESVDGYDNSFMHWYQQKPGQPPKLLIF RASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSSEDPWTFGQGT KLEIK (SEQ ID NO: 80)VH:QVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIY PGDSDTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARFPYDSSGAnti-TfR clone 8 YYSFDYWGQGTLVTVSS (SEQ ID NO: 154)VL:DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSL QSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK(SEQ ID NO: 155)* mutation positions are according to Kabat numbering of the respective VH sequences containing the mutations ** CDRs according to the Kabat numbering system are bolded

[0110] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VH comprising the CDR-H1, CDR-H2, and CDR-H3 of any one of the anti-TfRl antibodies provided in Table 3 and comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid variations in the framework regions as compared with the respective VH provided in Table 3. Alternatively or in addition (e.g., in addition), the anti-TfR1 antibody of the present disclosure comprises a VL comprising the CDR-L1, CDR-L2, and CDR-L3 of any one of the anti-TfRl antibodies provided in Table 3 and comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid variations in the framework regions as compared with the respective VL provided in Table 3. In some embodiments, the VH of the anti-TfR1 antibody is a humanized VH, and / or the VL of the anti-TfR1 antibody is a humanized VL.

[0111] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VH comprising the CDR-H1, CDR-H2, and CDR-H3 of any one of the anti-TfRl antibodies provided in Table 3 and comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical in the framework regions as compared with the respective VH provided in Table 3.Alternatively or in addition (e.g., in addition), the anti-TfR1 antibody of the present disclosure 61 / 350#14837954v1comprises a VL comprising the CDR-L1, CDR-L2, and CDR-L3 of any one of the anti-TfRl antibodies provided in Table 3 and comprising an amino acid sequence that is at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%) identical in the framework regions as compared with the respective VL provided in Table 3. In some embodiments, the VH of the anti-TfR1 antibody is a humanized VH, and / or the VL of the anti-TfR1 antibody is a humanized VL.

[0112] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 69 and a VL comprising the amino acid sequence of SEQ ID NO: 70.

[0113] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 71 and a VL comprising the amino acid sequence of SEQ ID NO: 70.

[0114] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 72 and a VL comprising the amino acid sequence of SEQ ID NO: 70.

[0115] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 73 and a VL comprising the amino acid sequence of SEQ ID NO: 74.

[0116] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 73 and a VL comprising the amino acid sequence of SEQ ID NO: 75.

[0117] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 76 and a VL comprising the amino acid sequence of SEQ ID NO: 74.

[0118] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 76 and a VL comprising the amino acid sequence of SEQ ID NO: 75.

[0119] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 77 and a VL comprising the amino acid sequence of SEQ ID NO: 78.

[0120] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 79 and a VL comprising the amino acid sequence of SEQ ID NO: 80.62 / 350#14837954v1

[0121] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 77 and a VL comprising the amino acid sequence of SEQ ID NO: 80.

[0122] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 154 and a VL comprising the amino acid sequence of SEQ ID NO: 155.

[0123] In some embodiments, the anti-TfR1 antibody described herein is a full-length IgG, which can include a heavy constant region and a light constant region from a human antibody. In some embodiments, the heavy chain of any of the anti-TfRl antibodies as described herein may comprise a heavy chain constant region (CH) or a portion thereof (e.g., CHI, CH2, CH3, or a combination thereof). The heavy chain constant region can be of any suitable origin, e.g., human, mouse, rat, or rabbit. In one specific example, the heavy chain constant region is from a human IgG (a gamma heavy chain), e.g., IgGl, IgG2, or IgG4. An example of a human IgGl constant region is given below:

[0124] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 81)

[0125] In some embodiments, the heavy chain of any of the anti-TfRl antibodies described herein comprises a mutant human IgGl constant region. For example, the introduction of LALA mutations (a mutant derived from mAb bl2 that has been mutated to replace the lower hinge residues Leu234 Leu235 with Ala234 and Ala235) in the CH2 domain of human IgGl is known to reduce Fey receptor binding (Bruhns, P., et al. (2009) and Xu, D. et al. (2000)). The mutant human IgGl constant region is provided below (mutations bolded and underlined):

[0126] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 82)

[0127] In some embodiments, the light chain of any of the anti-TfRl antibodies described herein may further comprise a light chain constant region (CL), which can be any CL known in 63 / 350#14837954v1the art. In some examples, the CL is a kappa light chain. In other examples, the CL is a lambda light chain. In some embodiments, the CL is a kappa light chain, the sequence of which is provided below:

[0128] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 83)

[0129] Other antibody heavy and light chain constant regions are well known in the art, e.g., those provided in the IMGT database (imgt.org) or at vbase2.org / vbstat.php, both of which are incorporated by reference herein.

[0130] In some embodiments, the anti-TfR1 antibody described herein comprises a heavy chain comprising any one of the VH as listed in Table 3 or any variants thereof and a heavy chain constant region that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 81 or SEQ ID NO: 82. In some embodiments, the anti-TfR1 antibody described herein comprises a heavy chain comprising any one of the VH as listed in Table 3 or any variants thereof and a heavy chain constant region that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with SEQ ID NO: 81 or SEQ ID NO: 82. In some embodiments, the anti-TfR1 antibody described herein comprises a heavy chain comprising any one of the VH as listed in Table 3 or any variants thereof and a heavy chain constant region as set forth in SEQ ID NO: 81. In some embodiments, the anti-TfR1 antibody described herein comprises heavy chain comprising any one of the VH as listed in Table 3 or any variants thereof and a heavy chain constant region as set forth in SEQ ID NO: 82.

[0131] In some embodiments, the anti-TfR1 antibody described herein comprises a light chain comprising any one of the VL as listed in Table 3 or any variants thereof and a light chain constant region that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 83. In some embodiments, the anti-TfR1 antibody described herein comprises a light chain comprising any one of the VL as listed in Table 3 or any variants thereof and a light chain constant region contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with SEQ ID NO: 83. In some embodiments, the anti-TfR1 antibody described herein comprises a light chain comprising any one of the VL as listed in Table 3 or any variants thereof and a light chain constant region set forth in SEQ ID NO: 83.64 / 350#14837954v1

[0132] Examples of IgG heavy chain and light chain amino acid sequences of the anti-TfRl antibodies described are provided in Table 4 below.Table 4. Heavy chain and light chain sequences of examples of anti-TfRl IgGs Antibody IgG Heavy Chain / Light Chain Sequences**Heavy Chain (with wild type human IgGl constant region) EVQLVQSGSELKKPGASVKVSCTASGFNIKDDYMYWVRQPPGKGLEWIGWIDPETGDTEYASKFQDRVTVTADTSTNTAYMELSSLRSEDTAVYYCTLWLRRGLDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD3A4 VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK VH3 (N54T*) / VK4 GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 84)Light Chain (with kappa light chain constant region) DIVMTQSPLSLPVTPGEPASISCR SSKSLLHSNGYTYLFWFQQRPGQSPRLLIY RMSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQHLEYPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 85)Heavy Chain (with wild type human IgGl constant region) EVQLVQSGSELKKPGASVKVSCTASGFNIKDDYMYWVRQPPGKGLEWIGWIDPESGDTEYASKFQDRVTVTADTSTNTAYMELSSLRSEDTAVYYCTLWLRRGLDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD3A4 VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG VH3 (N54S*) / VK4 KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 86)Light Chain (with kappa light chain constant region) DIVMTQSPLSLPVTPGEPASISCR SSKSLLHSNGYTYLFWFQQRPGQSPRLLIY RMSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQHLEYPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 85)Heavy Chain (with wild type human IgGl constant region) EVOLVOSGSELKKPGASVKVSCTASGFNIKDDYMYWVROPPGKGLEWIGWID PENGDTEYASKFODRVTVTADTSTNTAYMELSSLRSEDTAVYYCTLWLRRG LDYWGOGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKV DKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG3A4 KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK VH3 / VK4 GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 87)Light Chain (with kappa light chain constant region) DIVMTQSPLSLPVTPGEPASISCRSSKSLLHSNGYTYLFWFQQRPGQSPRLLIYR MSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQHLEYPFTFGGGT KVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 85)65 / 350#14837954v1Antibody IgG Heavy Chain / Light Chain Sequences**Heavy Chain (with wild type human IgGl constant region) QVQLQESGPGLVKPSQTLSLTCSVTGYSITSGYYWNWIRQPPGKGLEWMGYIT FDGANNYNPSLKNRVSISRDTSKNQFSLKLSSVTAEDTATYYCTRSSYDYDVL DYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKV DKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG3M12 KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK VH3 / VK2 GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 88)Light Chain (with kappa light chain constant region) DIQMTQSPSSLSASVGDRVTITCRASQDISNFLNWYQQKPGQPVKLLIYYTSRL HSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQGHTLPYTFGQGTKLEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO: 89)Heavy Chain (with wild type human IgGl constant region) QVQLQESGPGLVKPSQTLSLTCSVTGYSITSGYYWNWIRQPPGKGLEWMGYIT FDGANNYNPSLKNRVSISRDTSKNQFSLKLSSVTAEDTATYYCTRSSYDYDVL DYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKV DKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG3M12 KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK VH3 / VK3 GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 88)Light Chain (with kappa light chain constant region) DIQMTQSPSSLSASVGDRVTITCRASQDISNFLNWYQQKPGQPVKLLIYYTSRL HSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGHTLPYTFGQGTKLEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO: 90)Heavy Chain (with wild type human IgGl constant region) QVQLQESGPGLVKPSQTLSLTCTVTGYSITSGYYWNWIRQPPGKGLEWIGYITFDGANNYNPSLKNRVSISRDTSKNQFSLKLSSVTAEDTATYYCTRSSYDYDVLDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE3M12 YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF VH4 / VK2 YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 91)Light Chain (with kappa light chain constant region) DIQMTQSPSSLSASVGDRVTITCRASQDISNFLNWYQQKPGQPVKLLIYYTSRL HSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQGHTLPYTFGQGTKLEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO: 89)Heavy Chain (with wild type human IgGl constant region) QVQLQESGPGLVKPSQTLSLTCTVTGYSITSGYYWNWIRQPPGKGLEWIGYITFDGANNYNPSLKNRVSISRDTSKNQFSLKLSSVTAEDTATYYCTRSSYDYDVLDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW3M12 NSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVD VH4 / VK3 KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 91)66 / 350#14837954v1Antibody IgG Heavy Chain / Light Chain Sequences**Light Chain (with kappa light chain constant region) DIQMTQSPSSLSASVGDRVTITCRASQDISNFLNWYQQKPGQPVKLLIYYTSRL HSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGHTLPYTFGQGTKLEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO: 90)Heavy Chain (with wild type human IgGl constant region) QVQLVQSGAEVKKPGASVKVSCKASGYSFTDYYINWVRQAPGQGLEWMGWIYPGSGNTRYSERFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCAREDYYPYHGMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW5H12 LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTC VH5 (C33Y*) / VK3 LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 92) Light Chain (with kappa light chain constant region) DIVLTQSPDSLAVSLGERATINCRASESVDGYDNSFMHWYQQKPGQPPKLLIFRASNLESGVPDRFSGSGSRTDFTLTISSLQAEDVAVYYCQQSSEDPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 93)Heavy Chain (with wild type human IgGl constant region) QVQLVQSGAEVKKPGASVKVSCKASGYSFTDYDINWVRQAPGQGLEWMGWIYPGSGNTRYSERFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCAREDYYPYHGMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW5H12 LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTC VH5 (C33D*) / VK4 LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 94) Light Chain (with kappa light chain constant region) DIVMTQSPDSLAVSLGERATINCRASESVDGYDNSFMHWYQQKPGQPPKLLIFRASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSSEDPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 95)Heavy Chain (with wild type human IgGl constant region) QVQLVQSGAEVKKPGASVKVSCKASGYSFTDYYINWVRQAPGQGLEWMGWIYPGSGNTRYSERFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCAREDYYPYHGMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW5H12 LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTC VH5 (C33Y*) / VK4 LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 92) Light Chain (with kappa light chain constant region) DIVMTQSPDSLAVSLGERATINCRASESVDGYDNSFMHWYQQKPGQPPKLLIFRASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSSEDPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 95)67 / 350#14837954v1Antibody IgG Heavy Chain / Light Chain Sequences**VH:QVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARFPYDSSGYYSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLAnti-TfR clone 8 VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 156)VL:DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO: 157)* mutation positions are according to Kabat numbering of the respective VH sequences containing the mutations ** CDRs according to the Kabat numbering system are bolded; VH / VL sequences underlined

[0133] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain containing no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with the heavy chain as set forth in any one of SEQ ID NOs: 84, 86, 87, 88, 91, 92, 94, and 156. Alternatively or in addition (e.g., in addition), the anti-TfR1 antibody of the present disclosure comprises a light chain containing no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with the light chain as set forth in any one of SEQ ID NOs: 85, 89, 90, 93, 95, and 157.

[0134] In some embodiments, the anti-TfR1 antibody described herein comprises a heavy chain comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to any one of SEQ ID NOs: 84, 86, 87, 88, 91, 92, 94, and 156. Alternatively or in addition (e.g., in addition), the anti-TfR1 antibody described herein comprises a light chain comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to any one of SEQ ID NOs: 85, 89, 90, 93, 95, and 157. In some embodiments, the anti-TfR1 antibody described herein comprises a heavy chain comprising the amino acid sequence of any one of SEQ ID NOs: 84, 86, 87, 88, 91, 92, 94, and 156. Alternatively or in addition (e.g., in addition), the anti-TfR1 antibody described herein comprises a light chain comprising the amino acid sequence of any one of SEQ ID NOs: 85, 89, 90, 93, 95 and 157.68 / 350#14837954v1

[0135] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 84 and a light chain comprising the amino acid sequence of SEQ ID NO: 85.

[0136] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 86 and a light chain comprising the amino acid sequence of SEQ ID NO: 85.

[0137] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 87 and a light chain comprising the amino acid sequence of SEQ ID NO: 85.

[0138] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 88 and a light chain comprising the amino acid sequence of SEQ ID NO: 89.

[0139] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 88 and a light chain comprising the amino acid sequence of SEQ ID NO: 90.

[0140] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 89.

[0141] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 90.

[0142] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 92 and a light chain comprising the amino acid sequence of SEQ ID NO: 93.

[0143] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 94 and a light chain comprising the amino acid sequence of SEQ ID NO: 95.

[0144] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 92 and a light chain comprising the amino acid sequence of SEQ ID NO: 95.

[0145] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 156 and a light chain comprising the amino acid sequence of SEQ ID NO: 157.69 / 350#14837954v1

[0146] In some embodiments, the anti-TfR1 antibody is a Fab fragment, Fab' fragment, or F(ab')2 fragment of an intact antibody (full-length antibody). Antigen binding fragment of an intact antibody (full-length antibody) can be prepared via routine methods (e.g., recombinantly or by digesting the heavy chain constant region of a full-length IgG using an enzyme such as papain). For example, F(ab')2 fragments can be produced by pepsin or papain digestion of an antibody molecule, and Fab fragments that can be generated by reducing the disulfide bridges of F(ab')2 fragments. In some embodiments, a heavy chain constant region in a Fab fragment of the anti-TfR1 antibody described herein comprises the amino acid sequence of:ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 96)

[0147] In some embodiments, the anti-TfR1 antibody described herein comprises a heavy chain comprising any one of the VH as listed in Table 3 or any variants thereof and a heavy chain constant region that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 96. In some embodiments, the anti-TfR1 antibody described herein comprises a heavy chain comprising any one of the VH as listed in Table 3 or any variants thereof and a heavy chain constant region that contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with SEQ ID NO: 96. In some embodiments, the anti-TfR1 antibody described herein comprises a heavy chain comprising any one of the VH as listed in Table 3 or any variants thereof and a heavy chain constant region as set forth in SEQ ID NO: 96.

[0148] In some embodiments, the anti-TfR1 antibody described herein comprises a light chain comprising any one of the VL as listed in Table 3 or any variants thereof and a light chain constant region that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 83. In some embodiments, the anti-TfR1 antibody described herein comprises a light chain comprising any one of the VL as listed in Table 3 or any variants thereof and a light chain constant region contains no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with SEQ ID NO: 83. In some embodiments, the anti-TfR1 antibody described herein comprises a light chain comprising any one of the VL as listed in Table 3 or any variants thereof and a light chain constant region set forth in SEQ ID NO: 83.

[0149] Examples of Fab heavy chain and light chain amino acid sequences of the anti-TfRl antibodies described are provided in Table 5 below.70 / 350#14837954v1Table 5. Heavy chain and light chain sequences of examples of anti-TfRl Tabs Antibody Fab Heavy Chain / Light Chain Sequences**Heavy Chain (with partial human IgGl constant region) EVQLVQSGSELKKPGASVKVSCTASGFNIKDDYMYWVRQPPGKGLEWIGWID PETGDTEYASKFQDRVTVTADTSTNTAYMELSSLRSEDTAVYYCTLWLRRG LDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKV3A4 DKKVEPKSCDKTHT (SEQ ID NO: 97)VH3 (N54T*) / VK4Light Chain (with kappa light chain constant region) DIVMTQSPLSLPVTPGEPASISCR SSKSLLHSNGYTYLFWFQQRPGQSPRLLIY RMSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQHLEYPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 85)Heavy Chain (with partial human IgGl constant region) EVQLVQSGSELKKPGASVKVSCTASGFNIKDDYMYWVRQPPGKGLEWIGWID PESGDTEYASKFQDRVTVTADTSTNTAYMELSSLRSEDTAVYYCTLWLRRGL DYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKV3A4 DKKVEPKSCDKTHT (SEQ ID NO: 98)VH3 (N54S*) / VK4Light Chain (with kappa light chain constant region) DIVMTQSPLSLPVTPGEPASISCR SSKSLLHSNGYTYLFWFQQRPGQSPRLLIY RMSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQHLEYPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 85)Heavy Chain (with partial human IgGl constant region) EVQLVQSGSELKKPGASVKVSCTASGFNIKDDYMYWVRQPPGKGLEWIGWID PENGDTEYASKFQDRVTVTADTSTNTAYMELSSLRSEDTAVYYCTLWLRRG LDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKV3A4 DKKVEPKSCDKTHT (SEQ ID NO: 99)VH3 / VK4 Light Chain (with kappa light chain constant region)DIVMTQSPLSLPVTPGEPASISCR SSKSLLHSNGYTYLFWFQQRPGQSPRLLIY RMSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQHLEYPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 85)Heavy Chain (with partial human IgGl constant region) QVQLQESGPGLVKPSQTLSLTCSVTGYSITSGYYWNWIRQPPGKGLEWMGYIT FDGANNYNPSLKNRVSISRDTSKNQFSLKLSSVTAEDTATYYCTRSSYDYDVL DYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKV3M12 DKKVEPKSCDKTHT (SEQ ID NO: 100)VH3 / VK2 Light Chain (with kappa light chain constant region)DIQMTQSPSSLSASVGDRVTITCRASQDISNFLNWYQQKPGQPVKLLIYYTSRL HSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQGHTLPYTFGQGTKLEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO: 89)Heavy Chain (with partial human IgGl constant region) OVOLOESGPGLVKPSOTLSLTCSVTGYSITSGYYWNWIROPPGKGLEWMGYIT3M12 FDGANNYNPSLKNRVSISRDTSKNOFSLKLSSVTAEDTATYYCTRSSYDYDVL VH3 / VK3 DYWGOGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 100)71 / 350#14837954v1Antibody Fab Heavy Chain / Light Chain Sequences**Light Chain (with kappa light chain constant region) DIQMTQSPSSLSASVGDRVTITCRASQDISNFLNWYQQKPGQPVKLLIYYTSRL HSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGHTLPYTFGQGTKLEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO: 90)Heavy Chain (with partial human IgGl constant region) QVQLQESGPGLVKPSQTLSLTCTVTGYSITSGYYWNWIRQPPGKGLEWIGYITFDGANNYNPSLKNRVSISRDTSKNQFSLKLSSVTAEDTATYYCTRSSYDYDVLDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVD3M12 KKVEPKSCDKTHT (SEQ ID NO: 101)VH4 / VK2 Light Chain (with kappa light chain constant region)DIQMTQSPSSLSASVGDRVTITCRASQDISNFLNWYQQKPGQPVKLLIYYTSRL HSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQGHTLPYTFGQGTKLEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO: 89)Heavy Chain (with partial human IgGl constant region) QVQLQESGPGLVKPSQTLSLTCTVTGYSITSGYYWNWIRQPPGKGLEWIGYITFDGANNYNPSLKNRVSISRDTSKNQFSLKLSSVTAEDTATYYCTRSSYDYDVLDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVD3M12 KKVEPKSCDKTHT (SEQ ID NO: 101)VH4 / VK3 Light Chain (with kappa light chain constant region)DIQMTQSPSSLSASVGDRVTITCRASQDISNFLNWYQQKPGQPVKLLIYYTSRL HSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGHTLPYTFGQGTKLEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO: 90)Heavy Chain (with partial human IgGl constant region) QVQLVQSGAEVKKPGASVKVSCKASGYSFTDYYINWVRQAPGQGLEWMGWI YPGSGNTRYSERFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCAREDYYP YHGMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPS5H12 NTKVDKKVEPKSCDKTHT (SEQ ID NO: 102)VH5 (C33Y*) / VK3 Light Chain (with kappa light chain constant region)DIVLTQSPDSLAVSLGERATINCRASESVDGYDNSFMHWYQQKPGQPPKLLIFRASNLESGVPDRFSGSGSRTDFTLTISSLQAEDVAVYYCQQSSEDPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 93)Heavy Chain (with partial human IgGl constant region) QVQLVQSGAEVKKPGASVKVSCKASGYSFTDYDINWVRQAPGQGLEWMGWI YPGSGNTRYSERFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCAREDYYP YHGMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPS5H12 NTKVDKKVEPKSCDKTHT (SEQ ID NO: 103)VH5 (C33D*) / VK4 Light Chain (with kappa light chain constant region)DIVMTQSPDSLAVSLGERATINCRASESVDGYDNSFMHWYQQKPGQPPKLLIFRASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSSEDPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 95)72 / 350#14837954v1Antibody Fab Heavy Chain / Light Chain Sequences**Heavy Chain (with partial human IgGl constant region) QVQLVQSGAEVKKPGASVKVSCKASGYSFTDYYINWVRQAPGQGLEWMGWI YPGSGNTRYSERFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCAREDYYP YHGMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPS5H12 NTKVDKKVEPKSCDKTHT (SEQ ID NO: 102)VH5 (C33Y*) / VK4 Light Chain (with kappa light chain constant region)DIVMTQSPDSLAVSLGERATINCRASESVDGYDNSFMHWYQQKPGQPPKLLIFRASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSSEDPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 95)VH:QVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIY PGDSDTRYSPSF QGQVTISADKSISTAYLQWSSLKASDTAMYYCARFPYDSSG YYSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNAnti-TfR clone 8 TKVDKKVEPKSCDKTHTCP (SEQ ID NO: 158)Version 1 VL:DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO: 157)VH:QVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIY PGDSDTRYSPSF QGQVTISADKSISTAYLQWSSLKASDTAMYYCARFPYDSSG YYSFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNAnti-TfR clone 8 TKVDKKVEPKSCDKTHT (SEQ ID NO: 159)Version 2 VL:DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO: 157)* mutation positions are according to Kabat numbering of the respective VH sequences containing the mutations ** CDRs according to the Kabat numbering system are bolded; VH / VL sequences underlined

[0150] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain containing no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with the heavy chain as set forth in any one of SEQ ID NOs: 97-103, 158 and 159. Alternatively or in addition (e.g., in addition), the anti-TfR1 antibody of the present disclosure comprises a light chain containing no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with the light chain as set forth in any one of SEQ ID NOs: 85, 89, 90, 93, 95, and 157.

[0151] In some embodiments, the anti-TfR1 antibody described herein comprises a heavy chain comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%,73 / 350#14837954v195%, 98%, or 99%) identical to any one of SEQ ID NOs: 97-103, 158 and 159. Alternatively or in addition (e.g., in addition), the anti-TfR1 antibody described herein comprises a light chain comprising an amino acid sequence that is at least 75% (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) identical to any one of SEQ ID NOs: 85, 89, 90, 93, 95, and 157. In some embodiments, the anti-TfR1 antibody described herein comprises a heavy chain comprising the amino acid sequence of any one of SEQ ID NOs: 97-103, 158 and 159. Alternatively or in addition (e.g., in addition), the anti-TfR1 antibody described herein comprises a light chain comprising the amino acid sequence of any one of SEQ ID NOs: 85, 89, 90, 93, 95, and 157.

[0152] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 97 and a light chain comprising the amino acid sequence of SEQ ID NO: 85.

[0153] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 98 and a light chain comprising the amino acid sequence of SEQ ID NO: 85.

[0154] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 99 and a light chain comprising the amino acid sequence of SEQ ID NO: 85.

[0155] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 100 and a light chain comprising the amino acid sequence of SEQ ID NO: 89.

[0156] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 100 and a light chain comprising the amino acid sequence of SEQ ID NO: 90.

[0157] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 101 and a light chain comprising the amino acid sequence of SEQ ID NO: 89.

[0158] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 101 and a light chain comprising the amino acid sequence of SEQ ID NO: 90.

[0159] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 102 and a light chain comprising the amino acid sequence of SEQ ID NO: 93.74 / 350#14837954v1

[0160] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 103 and a light chain comprising the amino acid sequence of SEQ ID NO: 95.

[0161] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 102 and a light chain comprising the amino acid sequence of SEQ ID NO: 95.

[0162] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 158 and a light chain comprising the amino acid sequence of SEQ ID NO: 157.

[0163] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 159 and a light chain comprising the amino acid sequence of SEQ ID NO: 157.Other known anti-TfRl antibodies

[0164] Any other appropriate anti-TfRl antibodies known in the art may be used as the TfRl-targeting agent in the complexes disclosed herein. Examples of known anti-TfRl antibodies, including associated references and binding epitopes, are listed in Table 6. In some embodiments, the anti-TfR1 antibody comprises the complementarity determining regions (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3) of any of the anti-TfRl antibodies provided herein, e.g., anti-TfRl antibodies listed in Table 6.Table 6 - List of anti-TfR1 antibody clones, including associated references and binding epitope information.Antibody Clone Reference(s) Epitope / Notes NameOKT9 US Patent. No. 4,364,934, filed 12 / 4 / 1979, Apical domain of TfRl entitled “MONOCLONAL ANTIBODY TO (residues 305-366 of A HUMAN EARLY THYMOCYTE human TfRl sequence ANTIGEN AND METHODS FOR XM_052730.3, available PREPARING SAME” in GenBank) Schneider C. et al. “Structural features of thecell surface receptor for transferrin that isrecognized by the monoclonal antibodyOKT9.” J Biol Chem. 1982, 257:14, 8516-8522.75 / 350#14837954v1Antibody Clone Reference(s) Epitope / Notes Name(From JCR) • WO 2015 / 098989, filed 12 / 24 / 2014, Apical domain (residues “Novel anti-Transferrin receptor antibody 230-244 and 326-347 of Clone Ml 1 that passes through blood-brain barrier” TfRl) and protease-like Clone M23 • US Patent No. 9,994,641, filed domain (residues 461- Clone M27 12 / 24 / 2014, “Novel anti-Transferrin 473)Clone B84 receptor antibody that passes throughblood-brain barrier”(From • WO 2016 / 081643, filed 5 / 26 / 2016, Apical domain and non- Genentech) entitled “ANTI-TRANSFERRIN apical regions RECEPTOR ANTIBODIES AND7A4, 8A2, 15D2, METHODS OF USE”10D11, 7B10, • US Patent No. 9,708,406, filed15G11, 16G5, 5 / 20 / 2014, “Anti -transferrin receptor13C3, 16G4, antibodies and methods of use”16F6, 7G7, 4C2,1B12, and 13D4(From Armagen) • Lee et al. “Targeting Rat Anti-MouseTransferrin Receptor Monoclonal8D3 Antibodies through Blood-Brain Barrierin Mouse” 2000, J Pharmacol. Exp.Then, 292: 1048-1052.• US Patent App. 2010 / 077498, filed9 / 11 / 2008, entitled “COMPOSITIONSAND METHODS FOR BLOOD-BRAINBARRIER DELIVERY IN THE MOUSE”0X26 • Haobam, B. et al. 2014. Rabl7-mediatedrecycling endosomes contribute toautophagosome formation in response toGroup A Streptococcus invasion. Cellularmicrobiology. 16: 1806-21.DF1513 • Ortiz-Zapater E et al. Trafficking of thehuman transferrin receptor in plant cells:effects of tyrphostin A23 and brefeldinA. Plant 148:757-70 (2006).76 / 350#14837954v1Antibody Clone Reference(s) Epitope / Notes Name1A1B2, 66IG10, • Commercially available anti-transferrin Novus Biologicals MEM- 189, receptor antibodies. 8100 SouthparkWay, A- JF0956, 29806, 8 Littleton CO 80120 1A1B2,TFRC / 1818,1E6, 66IglO,TFRC / 1059,Ql / 71, 23D10,13E4,TFRC / 1149, ER- MP21,YTA74.4, BU54,2B6, RI7217(From INSERM) • US Patent App. 2011 / 0311544A1, filed Does not compete with 6 / 15 / 2005, entitled “ANTI-CD71 OKT9BA120g MONOCLONAL ANTIBODIES ANDUSES THEREOF FOR TREATING MALIGNANT TUMOR CELLS”LUCA31 • US Patent No. 7,572,895, filed 6 / 7 / 2004, “LUCA31 epitope” entitled “TRANSFERRIN RECEPTORANTIBODIES”(Salk Institute) • Trowbridge, I. S. et al. “Anti-transferrinreceptor monoclonal antibody and toxinB3 / 25 antibody conjugates affect growth ofT58 / 30 human tumour cells.” Nature, 1981,volume 294, pages 171-173R17217.1.3, • Commercially available anti-transferrin BioXcell5E9C11, receptor antibodies. 10 Technology Dr., Suite OKT9 (BE0023 2Bclone) West Lebanon, NH 03784-1671 USA BK19.9, B3 / 25, • Gatter, K. C. et al. “Transferrin receptorsT56 / 14 and in human tissues: their distribution andT58 / 1 possible clinical relevance.” J ClinPathol. 1983 May;36(5):539-45.Anti-TfR1 antibody Additional Anti-TfRl antibody SEQ ID NOs CDRH1 (SEQ ID NO: 4063) VH / VL CDR1 CDR2 CDR3 CDRH2 (SEQ ID NO: 4064) VH1 4078 4071 4072 4065 CDRH3 (SEQ ID NO: 4065)VH2 4079 4071 4073 4065 CDRL1 (SEQ ID NO: 4066)VH3 4080 4071 4074 4065 CDRL2 (SEQ ID NO: 4067)VH4 4081 4071 4073 4065 CDRL3 (SEQ ID NO: 4068)VL1 4082 4066 4067 115 VH (SEQ ID NO: 4069)VL2 4083 4066 4067 115 VL (SEQ ID NO: 4070)VL3 4084 4066 4075 4068VL4 4085 4076 4077 406877 / 350#14837954v1

[0165] In some embodiments, anti-TfRl antibodies of the present disclosure include one or more of the CDR-H (e.g., CDR-H1, CDR-H2, and CDR-H3) amino acid sequences from any one of the anti-TfRl antibodies selected from Table 6. In some embodiments, anti-TfRl antibodies include the CDR-L1, CDR-L2, and CDR-L3 as provided for any one of the anti-TfRl antibodies selected from Table 6. In some embodiments, anti-TfRl antibodies include the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 as provided for any one of the anti-TfRl antibodies selected from Table 6.

[0166] In some embodiments, anti-TfRl antibodies of the disclosure include any antibody that includes a heavy chain variable domain and / or (e.g., and) a light chain variable domain of any anti-TfR1 antibody, such as any one of the anti-TfRl antibodies selected from Table 6. In some embodiments, anti-TfRl antibodies of the disclosure include any antibody that includes the heavy chain variable and light chain variable pairs of any anti-TfR1 antibody, such as any one of the anti-TfRl antibodies selected from Table 6.

[0167] Aspects of the disclosure provide anti-TfRl antibodies having a heavy chain variable (VH) and / or (e.g., and) a light chain variable (VL) domain amino acid sequence homologous to any of those described herein. In some embodiments, the anti-TfR1 antibody comprises a heavy chain variable sequence or a light chain variable sequence that is at least 75% (e.g., 80%, 85%, 90%, 95%, 98%, or 99%) identical to the heavy chain variable sequence and / or any light chain variable sequence of any anti-TfR1 antibody, such as any one of the anti-TfRl antibodies selected from Table 6. In some embodiments, the homologous heavy chain variable and / or (e.g., and) a light chain variable amino acid sequences do not vary within any of the CDR sequences provided herein. For example, in some embodiments, the degree of sequence variation (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) may occur within a heavy chain variable and / or (e.g., and) a light chain variable sequence excluding any of the CDR sequences provided herein. In some embodiments, any of the anti-TfRl antibodies provided herein comprise a heavy chain variable sequence and a light chain variable sequence that comprises a framework sequence that is at least 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the framework sequence of any anti-TfR1 antibody, such as any one of the anti-TfRl antibodies selected from Table 6.

[0168] An example of a transferrin receptor antibody that may be used in accordance with the present disclosure is described in International Application Publication WO 2016 / 081643, incorporated herein by reference. The amino acid sequences of this antibody are provided in Table 7.78 / 350#14837954v1Table 7. Heavy chain and light chain CDRs of an example of a known anti-TfR1 antibody Sequence Type Kabat Chothia ContactCDR-H1 SYWMH (SEQ ID GYTFTSY (SEQ ID NO: 116) TSYWMH (SEQ ID NO: 118)NO: 110)CDR-H2 EINPTNGRTNYIE NPTNGR (SEQ ID NO: 117) WIGEINPTNGRTN (SEQ ID KFKS (SEQ ID NO: 119) NO: 111)CDR-H3 GTRAYHY (SEQ GTRAYHY (SEQ ID NO: ARGTRA (SEQ ID NO: 120)ID NO: 112) 112)CDR-L1 RASDNLYSNLA RASDNLYSNLA (SEQ ID YSNLAWY (SEQ ID NO: 121)(SEQ ID NO: 113) NO: 113)CDR-L2 DATNLAD (SEQ DATNLAD (SEQ ID NO: LLVYDATNLA (SEQ ID NO:ID NO: 114) 114) 122)CDR-L3 QHFWGTPLT QHFWGTPLT (SEQ ID NO: QHFWGTPL (SEQ ID NO:(SEQ ID NO: 115) 115) 123)Murine VH QVQLQQPGAELVKPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGEINP TNGRTNYIEKFKSKATLTVDKSSSTAYMQLSSLTSEDSAVYYCARGTRAYHY WGQGTSVTVSS (SEQ ID NO: 124)Murine VL DIQMTQSPASLSVSVGETVTITCRASDNLYSNLAWYQQKQGKSPQLLVYDATNL ADGVPSRFSGSGSGTQYSLKINSLQSEDFGTYYCQHFWGTPLTFGAGTKLELK(SEQ ID NO: 125)Humanized VH EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVRQAPGQRLEWIGEIN PTNGRTNYIEKFKSRATLTVDKSASTAYMELSSLRSEDTAVYYCARGTRAYHY WGQGTMVTVSS (SEQ ID NO: 128)Humanized VL DIQMTQSPSSLSASVGDRVTITCRASDNLYSNLAWYQQKPGKSPKLLVYDATNL ADGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWGTPLTFGQGTKVEIK(SEQ ID NO: 129)HC of chimeric QVQLQQPGAELVKPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGEINP full-length IgGl TNGRTNYIEKFKSKATLTVDKSSSTAYMQLSSLTSEDSAVYYCARGTRAYHYW GQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVE PKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK (SEQ ID NO: 132)LC of chimeric DIQMTQSPASLSVSVGETVTITCRASDNLYSNLAWYQQKQGKSPQLLVYDATNL full-length IgGl ADGVPSRFSGSGSGTQYSLKINSLQSEDFGTYYCQHFWGTPLTFGAGTKLELKR TVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO: 133)HC of fully human EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVRQAPGQRLEWIGEIN full-length IgGl PTNGRTNYIEKFKSRATLTVDKSASTAYMELSSLRSEDTAVYYCARGTRAYHY WGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKV EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGK (SEQ ID NO: 134)LC of fully human DIQMTQSPSSLSASVGDRVTITCRASDNLYSNLAWYQQKPGKSPKLLVYDATNL full-length IgGl ADGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQHFWGTPLTFGQGTKVEIKRT VAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO: 135)79 / 350#14837954v1Sequence Type Kabat | Chothia | ContactHC of chimeric QVQLQQPGAELVKPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGEINP Fab TNGRTNYIEKFKSKATLTVDKSSSTAYMQLSSLTSEDSAVYYCARGTRAYHYW GQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVE PKSCDKTHTCP (SEQ ID NO: 136)HC of fully human EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVRQAPGQRLEWIGEIN Fab PTNGRTNYIEKFKSRATLTVDKSASTAYMELSSLRSEDTAVYYCARGTRAYHY WGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP (SEQ ID NO: 137)

[0169] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a CDR-H1, a CDR-H2, and a CDR-H3 that are the same as the CDR-H1, CDR-H2, and CDR-H3 shown in Table 7. Alternatively or in addition (e.g., in addition), the anti-TfR1 antibody of the present disclosure comprises a CDR-L1, a CDR-L2, and a CDR-L3 that are the same as the CDR-L1, CDR-L2, and CDR-L3 shown in Table 7.

[0170] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a CDR-L3, which contains no more than 3 amino acid variations (e.g., no more than 3, 2, or 1 amino acid variation) as compared with the CDR-L3 as shown in Table 7. In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a CDR-L3 containing one amino acid variation as compared with the CDR-L3 as shown in Table 7. In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a CDR-L3 of QHFAGTPLT (SEQ ID NO: 126) (according to the Kabat and Chothia definition system) or QHFAGTPL (SEQ ID NO: 127) (according to the Contact definition system). In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1 and a CDR-L2 that are the same as the CDR-H1, CDR-H2, and CDR-H3 shown in Table 7, and comprises a CDR-L3 of QHFAGTPLT (SEQ ID NO: 126) (according to the Kabat and Chothia definition system) or QHFAGTPL (SEQ ID NO: 127) (according to the Contact definition system).

[0171] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises heavy chain CDRs that collectively are at least 80% (e.g., 80%, 85%, 90%, 95%, or 98%) identical to the heavy chain CDRs as shown in Table 7. Alternatively or in addition (e.g., in addition), the anti-TfR1 antibody of the present disclosure comprises light chain CDRs that collectively are at least 80% (e.g., 80%, 85%, 90%, 95%, or 98%) identical to the light chain CDRs as shown in Table 7.

[0172] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 124. Alternatively or in addition (e.g., in80 / 350#14837954v1addition), the anti-TfR1 antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 125.

[0173] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 128. Alternatively or in addition (e.g., in addition), the anti-TfR1 antibody of the present disclosure comprises a VL comprising the amino acid sequence of SEQ ID NO: 129.

[0174] In some embodiments, the anti-TfR1 antibody of the present disclosure comprises a VH containing no more than 25 amino acid variations (e.g., no more than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with the VH as set forth in SEQ ID NO: 128. Alternatively or in addition (e.g., in addition), the anti-TfR1 antibody of the present disclosure comprises a VL containing no more than 15 amino acid variations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid variation) as compared with the VL as set forth in SEQ ID NO: 129.

[0175] In some embodiments, the anti-TfR1 antibody of the present disclosure is a full-length IgGl antibody, which can include a heavy constant region and a light constant region from a human antibody. In some embodiments, the heavy chain of any of the anti-TfRl antibodies as described herein may comprises a heavy chain constant region (CH) or a portion thereof (e.g., CHI, CH2, CH3, or a combination thereof). The heavy chain constant region can of any suitable origin, e.g., human, mouse, rat, or rabbit. In one specific example, the heavy chain constant region is from a human IgG (a gamma heavy chain), e.g., IgGl, IgG2, or IgG4. An example of human IgGl constant region is given below:ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ S SGLYSLS S VVTVPS S SLGTQT YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP APEL LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 81)

[0176] In some embodiments, the light chain of any of the anti-TfRl antibodies described herein may further comprise a light chain constant region (CL), which can be any CL known in the art. In some examples, the CL is a kappa light chain. In other examples, the CL is a lambda light chain. In some embodiments, the CL is a kappa light chain, the sequence of which is provided below:81 / 350#14837954v1RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 83)

[0177] In some embodiments, the anti-TfR1 antibody described herein is a chimeric antibody that comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 132.Alternatively or in addition (e.g., in addition), the anti-TfR1 antibody described herein comprises a light chain comprising the amino acid sequence of SEQ ID NO: 133.

[0178] In some embodiments, the anti-TfR1 antibody described herein is a fully human antibody that comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 134. Alternatively or in addition (e.g., in addition), the anti-TfR1 antibody described herein comprises a light chain comprising the amino acid sequence of SEQ ID NO: 135.

[0179] In some embodiments, the anti-TfR1 antibody is an antigen binding fragment (Fab) of an intact antibody (full-length antibody). In some embodiments, the anti-TfRl Fab described herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 136. Alternatively or in addition (e.g., in addition), the anti-TfRl Fab described herein comprises a light chain comprising the amino acid sequence of SEQ ID NO: 133. In some embodiments, the anti-TfRl Fab described herein comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 137. Alternatively or in addition (e.g., in addition), the anti-TfRl Fab described herein comprises a light chain comprising the amino acid sequence of SEQ ID NO: 135.

[0180] The anti-TfRl antibodies described herein can be in any antibody form, including, but not limited to, intact (i.e., full-length) antibodies, antigen-binding fragments thereof (such as Fab, Fab', F(ab')2, Fv), single chain antibodies, bi-specific antibodies, or nanobodies. In some embodiments, the anti-TfR1 antibody described herein is an scFv. In some embodiments, the anti-TfR1 antibody described herein is an scFv-Fab (e.g., scFv fused to a portion of a constant region). In some embodiments, the anti-TfR1 antibody described herein is an scFv fused to a constant region (e.g., human IgGl constant region as set forth in SEQ ID NO: 81).

[0181] In some embodiments, conservative mutations can be introduced into antibody sequences (e.g., CDRs or framework sequences) at positions where the residues are not likely to be involved in interacting with a target antigen (e.g., transferrin receptor), for example, as determined based on a crystal structure. In some embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of an anti-TfR1 antibody described herein (e.g., in a CH2 domain (residues 231-340 of human IgGl) and / or (e.g., and) CH3 domain (residues 341-447 of human IgGl) and / or (e.g., and) the hinge region, with 82 / 350#14837954v1numbering according to the Kabat numbering system (e.g., the EU index in Kabat)) to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding and / or (e.g., and) antigen-dependent cellular cytotoxicity.

[0182] In some embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the hinge region of the Fc region (CHI domain) such that the number of cysteine residues in the hinge region are altered (e.g., increased or decreased) as described in, e.g., U. S. Pat. No. 5,677,425. The number of cysteine residues in the hinge region of the CHI domain can be altered to, e.g., facilitate assembly of the light and heavy chains, or to alter (e.g., increase or decrease) the stability of the antibody or to facilitate linker conjugation.

[0183] In some embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of a TfRl -targeting antibody described herein (e.g., in a CH2 domain (residues 231-340 of human IgGl) and / or (e.g., and) CH3 domain (residues 341-447 of human IgGl) and / or (e.g., and) the hinge region, with numbering according to the Kabat numbering system (e.g., the EU index in Kabat)) to increase or decrease the affinity of the antibody for an Fc receptor (e.g., an activated Fc receptor) on the surface of an effector cell. Mutations in the Fc region of an antibody that decrease or increase the affinity of an antibody for an Fc receptor and techniques for introducing such mutations into the Fc receptor or fragment thereof are known to one of skill in the art. Examples of mutations in the Fc receptor of an antibody that can be made to alter the affinity of the antibody for an Fc receptor are described in, e.g., Smith P et al., (2012) PNAS 109: 6181-6186, U. S. Pat. No. 6,737,056, and International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631, which are incorporated herein by reference.

[0184] In some embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into an IgG constant domain, or FcRn-binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to alter (e.g., decrease or increase) half-life of the antibody in vivo. See, e.g., International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631; and U. S. Pat. Nos. 5,869,046, 6,121,022, 6,277,375 and 6,165,745 for examples of mutations that will alter (e.g., decrease or increase) the half-life of an antibody in vivo.

[0185] In some embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into an IgG constant domain, or FcRn-binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to decrease the half-life of the anti-TfR1 antibody in vivo. In some embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into an IgG constant domain, or FcRn- 83 / 350#14837954v1binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to increase the halflife of the antibody in vivo. In some embodiments, the antibodies can have one or more amino acid mutations (e.g., substitutions) in the second constant (CH2) domain (residues 231-340 of human IgGl) and / or (e.g., and) the third constant (CH3) domain (residues 341-447 of human IgGl), with numbering according to the EU index in Kabat (Kabat E A et al., (1991) supra). In some embodiments, the constant region of the IgGl of an antibody described herein comprises a methionine (M) to tyrosine (Y) substitution in position 252, a serine (S) to threonine (T) substitution in position 254, and a threonine (T) to glutamic acid (E) substitution in position 256, numbered according to the EU index as in Kabat. See U. S. Pat. No. 7,658,921, which is incorporated herein by reference. This type of mutant IgG, referred to as " YTE mutant" has been shown to display fourfold increased half-life as compared to wild-type versions of the same antibody (see Dall'Acqua W F et al., (2006) J Biol Chem 281: 23514-24). In some embodiments, an antibody comprises an IgG constant domain comprising one, two, three or more amino acid substitutions of amino acid residues at positions 251-257, 285-290, 308-314, 385-389, and 428-436, numbered according to the EU index as in Kabat.

[0186] In some embodiments, one, two or more amino acid substitutions are introduced into an IgG constant domain Fc region to alter the effector function(s) of the anti-TfR1 antibody. The effector ligand to which affinity is altered can be, for example, an Fc receptor or the Cl component of complement. This approach is described in further detail in U. S. Pat. Nos.5,624,821 and 5,648,260. In some embodiments, the deletion or inactivation (through point mutations or other means) of a constant region domain can reduce Fc receptor binding of the circulating antibody thereby increasing tumor localization. See, e.g., U. S. Pat. Nos. 5,585,097 and 8,591,886 for a description of mutations that delete or inactivate the constant domain and thereby increase tumor localization. In some embodiments, one or more amino acid substitutions may be introduced into the Fc region of an antibody described herein to remove potential glycosylation sites on Fc region, which may reduce Fc receptor binding (see, e.g., Shields R L et al., (2001) J Biol Chem 276: 6591-604).

[0187] In some embodiments, one or more amino in the constant region of an anti-TfR1 antibody described herein can be replaced with a different amino acid residue such that the antibody has altered Clq binding and / or (e.g., and) reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U. S. Pat. No. 6,194,551 (Idusogie et al). In some embodiments, one or more amino acid residues in the N-terminal region of the CH2 domain of an antibody described herein are altered to thereby alter the ability of the antibody to fix complement. This approach is described further in 84 / 350#14837954v1International Publication No. WO 94 / 29351. In some embodiments, the Fc region of an antibody described herein is modified to increase the ability of the antibody to mediate antibody dependent cellular cytotoxicity (ADCC) and / or (e.g., and) to increase the affinity of the antibody for an Fey receptor. This approach is described further in International Publication No. WO 00 / 42072.

[0188] In some embodiments, the heavy and / or (e.g., and) light chain variable domain(s) sequence(s) of the antibodies provided herein can be used to generate, for example, CDR-grafted, chimeric, humanized, or composite human antibodies or antigen-binding fragments, as described elsewhere herein. As understood by one of ordinary skill in the art, any variant, CDR-grafted, chimeric, humanized, or composite antibodies derived from any of the antibodies provided herein may be useful in the compositions and methods described herein and will maintain the ability to specifically bind transferrin receptor, such that the variant, CDR-grafted, chimeric, humanized, or composite antibody has at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or more binding to transferrin receptor relative to the original antibody from which it is derived.

[0189] In some embodiments, the antibodies provided herein comprise mutations that confer desirable properties to the antibodies. For example, to avoid potential complications due to Fab-arm exchange, which is known to occur with native IgG4 mAbs, the antibodies provided herein may comprise a stabilizing ‘Adair’ mutation (Angal S., et al., “A single amino acid substitution abolishes the heterogeneity of chimeric mouse / human (IgG4) antibody,” Mol Immunol 30, 105-108; 1993), where serine 228 (EU numbering; residue 241 Kabat numbering) is converted to proline resulting in an IgGl-like hinge sequence. Accordingly, any of the antibodies may include a stabilizing ‘Adair’ mutation.

[0190] In some embodiments, an antibody is modified, e.g., modified via glycosylation, phosphorylation, sumoylation, and / or (e.g., and) methylation. In some embodiments, an antibody is a glycosylated antibody, which is conjugated to one or more sugar or carbohydrate molecules. In some embodiments, the one or more sugar or carbohydrate molecule are conjugated to the antibody via N-glycosylation, O-glycosylation, C-glycosylation, glypiation (GPI anchor attachment), and / or (e.g., and) phosphoglycosylation. In some embodiments, the one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, the one or more sugar or carbohydrate molecule is a branched oligosaccharide or a branched glycan. In some embodiments, the one or more sugar or carbohydrate molecule includes a mannose unit, a glucose unit, an N-acetylglucosamine unit, an N-acetylgalactosamine unit, a galactose unit, a fucose unit, or a 85 / 350#14837954v1phospholipid unit. In some embodiments, there are about 1-10, about 1-5, about 5-10, about 1-4, about 1-3, or about 2 sugar molecules. In some embodiments, a glycosylated antibody is fully or partially glycosylated. In some embodiments, an antibody is glycosylated by chemical reactions or by enzymatic means. In some embodiments, an antibody is glycosylated in vitro or inside a cell, which may optionally be deficient in an enzyme in the N- or O- glycosylation pathway, e.g. a glycosyltransferase. In some embodiments, an antibody is functionalized with sugar or carbohydrate molecules as described in International Patent Application Publication WO2014065661, published on May 1, 2014, entitled, “Modified antibody, antibody-conjugate and process for the preparation thereof".

[0191] In some embodiments, any one of the anti-TfRl antibodies described herein may comprise a signal peptide in the heavy and / or (e.g., and) light chain sequence (e.g., aN-terminal signal peptide). In some embodiments, the anti-TfR1 antibody described herein comprises any one of the VH and VL sequences, any one of the IgG heavy chain and light chain sequences, or any one of the F(ab') heavy chain and light chain sequences described herein, and further comprises a signal peptide (e.g., a N-terminal signal peptide). In some embodiments, the signal peptide comprises the amino acid sequence of MGWSCIILFLVATATGVHS (SEQ ID NO: 104).

[0192] In some embodiments, the anti-TfR1 antibody provided herein may have one or more post-translational modifications. In some embodiments, N-terminal cyclization, also called pyroglutamate formation (pyro-Glu), may occur in the antibody at N-terminal Glutamate (Glu) and / or Glutamine (Gin) residues during production. As such, it should be appreciated that an antibody specified as having a sequence comprising an N-terminal glutamate or glutamine residue encompasses antibodies that have undergone pyroglutamate formation resulting from a post-translational modification. In some embodiments, pyroglutamate formation occurs in a heavy chain sequence. In some embodiments, pyroglutamate formation occurs in a light chain sequence.Antibody Features / Alterations

[0193] In some embodiments, conservative mutations can be introduced into antibody sequences (e.g., CDRs or framework sequences) at positions where the residues are not likely to be involved in interacting with a target antigen (e.g., transferrin receptor), for example, as determined based on a crystal structure. In some embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of a TfRl -targeting antibody described herein (e.g., in a CH2 domain (residues 231-340 of human IgGl) and / or (e.g., and) CH3 domain (residues 341-447 of human IgGl) and / or (e.g., and) the hinge region, with 86 / 350#14837954v1numbering according to the Kabat numbering system (e.g., the EU index in Kabat)) to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding and / or (e.g., and) antigen-dependent cellular cytotoxicity.

[0194] In some embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the hinge region of the Fc region (CHI domain) such that the number of cysteine residues in the hinge region are altered (e.g., increased or decreased) as described in, e.g., U. S. Pat. No. 5,677,425. The number of cysteine residues in the hinge region of the CHI domain can be altered to, e.g., facilitate assembly of the light and heavy chains, or to alter (e.g., increase or decrease) the stability of the antibody or to facilitate linker conjugation.

[0195] In some embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of a TfRl -targeting antibody described herein (e.g., in a CH2 domain (residues 231-340 of human IgGl) and / or (e.g., and) CH3 domain (residues 341-447 of human IgGl) and / or (e.g., and) the hinge region, with numbering according to the Kabat numbering system (e.g., the EU index in Kabat)) to increase or decrease the affinity of the antibody for an Fc receptor (e.g., an activated Fc receptor) on the surface of an effector cell. Mutations in the Fc region of an antibody that decrease or increase the affinity of an antibody for an Fc receptor and techniques for introducing such mutations into the Fc receptor or fragment thereof are known to one of skill in the art. Examples of mutations in the Fc receptor of an antibody that can be made to alter the affinity of the antibody for an Fc receptor are described in, e.g., Smith P et al., (2012) PNAS 109: 6181-6186, U. S. Pat. No. 6,737,056, and International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631, which are incorporated herein by reference.

[0196] In some embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into an IgG constant domain, or FcRn-binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to alter (e.g., decrease or increase) half-life of the antibody in vivo. See, e.g., International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631; and U. S. Pat. Nos. 5,869,046, 6,121,022, 6,277,375 and 6,165,745 for examples of mutations that will alter (e.g., decrease or increase) the half-life of an antibody in vivo.

[0197] In some embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into an IgG constant domain, or FcRn-binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to decrease the half-life of the antitransferrin receptor antibody in vivo. In some embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into an IgG constant 87 / 350#14837954v1domain, or FcRn-binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to increase the half-life of the antibody in vivo. In some embodiments, the antibodies can have one or more amino acid mutations (e.g., substitutions) in the second constant (CH2) domain (residues 231-340 of human IgGl) and / or (e.g., and) the third constant (CH3) domain (residues 341-447 of human IgGl), with numbering according to the EU index in Kabat (Kabat E A et al., (1991) supra). In some embodiments, the constant region of the IgGl of an antibody described herein comprises a methionine (M) to tyrosine (Y) substitution in position 252, a serine (S) to threonine (T) substitution in position 254, and a threonine (T) to glutamic acid (E) substitution in position 256, numbered according to the EU index as in Kabat. See U. S. Pat. No. 7,658,921, which is incorporated herein by reference. This type of mutant IgG, referred to as " YTE mutant" has been shown to display fourfold increased half-life as compared to wild-type versions of the same antibody (see Dall'Acqua W F et al., (2006) J Biol Chem 281:23514-24). In some embodiments, an antibody comprises an IgG constant domain comprising one, two, three or more amino acid substitutions of amino acid residues at positions 251-257, 285-290, 308-314, 385-389, and 428-436, numbered according to the EU index as in Kabat.

[0198] In some embodiments, one, two or more amino acid substitutions are introduced into an IgG constant domain Fc region to alter the effector function(s) of the anti -transferrin receptor antibody. The effector ligand to which affinity is altered can be, for example, an Fc receptor or the Cl component of complement. This approach is described in further detail in U. S. Pat. Nos. 5,624,821 and 5,648,260. In some embodiments, the deletion or inactivation (through point mutations or other means) of a constant region domain can reduce Fc receptor binding of the circulating antibody thereby increasing tumor localization. See, e.g., U. S. Pat. Nos.5,585,097 and 8,591,886 for a description of mutations that delete or inactivate the constant domain and thereby increase tumor localization. In some embodiments, one or more amino acid substitutions may be introduced into the Fc region of an antibody described herein to remove potential glycosylation sites on Fc region, which may reduce Fc receptor binding (see, e.g., Shields R L et al., (2001) J Biol Chem 276: 6591-604).

[0199] In some embodiments, one or more amino in the constant region of a TfRl -targeting antibody described herein can be replaced with a different amino acid residue such that the antibody has altered Clq binding and / or (e.g., and) reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U. S. Pat. No. 6,194,551 (Idusogie et al). In some embodiments, one or more amino acid residues in the N-terminal region of the CH2 domain of an antibody described herein are altered to thereby alter the ability of the antibody to fix complement. This approach is described further in88 / 350#14837954v1International Publication No. WO 94 / 29351. In some embodiments, the Fc region of an antibody described herein is modified to increase the ability of the antibody to mediate antibody dependent cellular cytotoxicity (ADCC) and / or (e.g., and) to increase the affinity of the antibody for an Fey receptor. This approach is described further in International Publication No. WO 00 / 42072.

[0200] In some embodiments, the heavy and / or (e.g., and) light chain variable domain(s) sequence(s) of the antibodies provided herein can be used to generate, for example, CDR-grafted, chimeric, humanized, or composite human antibodies or antigen-binding fragments, as described elsewhere herein. As understood by one of ordinary skill in the art, any variant, CDR-grafted, chimeric, humanized, or composite antibodies derived from any of the antibodies provided herein may be useful in the compositions and methods described herein and will maintain the ability to specifically bind transferrin receptor, such that the variant, CDR-grafted, chimeric, humanized, or composite antibody has at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or more binding to transferrin receptor relative to the original antibody from which it is derived.

[0201] In some embodiments, the antibodies provided herein comprise mutations that confer desirable properties to the antibodies. For example, to avoid potential complications due to Fab-arm exchange, which is known to occur with native IgG4 mAbs, the antibodies provided herein may comprise a stabilizing ‘Adair’ mutation (Angal S., et al., “A single amino acid substitution abolishes the heterogeneity of chimeric mouse / human (IgG4) antibody,” Mol Immunol 30, 105-108; 1993), where serine 228 (EU numbering; residue 241 Kabat numbering) is converted to proline resulting in an IgGl-like hinge sequence. Accordingly, any of the antibodies may include a stabilizing ‘Adair’ mutation.

[0202] As provided herein, antibodies of this disclosure may optionally comprise constant regions or parts thereof. For example, a VL domain may be attached at its C-terminal end to a light chain constant domain like Cκ or Cλ. Similarly, a VH domain or portion thereof may be attached to all or part of a heavy chain like IgA, IgD, IgE, IgG, and IgM, and any isotype subclass. Antibodies may include suitable constant regions (see, for example, Kabat et al., Sequences of Proteins of Immunological Interest, No. 91-3242, National Institutes of Health Publications, Bethesda, Md. (1991)). Therefore, antibodies within the scope of this may disclosure include VH and VL domains, or an antigen binding portion thereof, combined with any suitable constant regions.89 / 350#14837954v1Molecular Payloads

[0203] Some aspects of the disclosure provide molecular payloads, e.g., for modulating a biological outcome, e.g., the processing of a pre-mRNA transcript, the transcription of a DNA sequence, the stability of a pre-mRNA or mRNA transcript, the expression of a protein (e.g., translation of an mRNA), or the activity of a protein, that can be linked (e.g., covalently linked) to an anti-TfR1 antibody described herein (e.g., anti-TfR1 antibody in any one of Tables 2-7). In some embodiments, such molecular payloads are targeted to a muscle cell, e.g., via specifically binding to a nucleic acid or protein in or on the muscle cell following delivery to the muscle cell by the linked anti-TfR1 antibody. In some embodiments, such molecular payloads are targeted to a CNS cell, e.g., via specifically binding to a nucleic acid or protein in or on the CNS cell following delivery to the CNS cell by the linked anti-TfR1 antibody. It should be appreciated that various types of molecular payloads may be used in accordance with the disclosure. For example, the molecular payload may comprise, or consist of, an oligonucleotide (e.g., antisense oligonucleotide), a peptide (e.g., a peptide that binds a nucleic acid or protein associated with disease in a muscle cell), a protein (e.g., a protein that binds a nucleic acid or protein associated with disease in a muscle cell), or a small molecule (e.g., a small molecule that modulates the function of a nucleic acid or protein associated with disease in a muscle cell). In some embodiments, the molecular payload comprises or consists of an oligonucleotide that comprises a strand having a region of complementarity to a mutated dystrophin allele. In some embodiments, the molecular payload comprises or consists of an exon-skipping oligonucleotide. Exemplary molecular payloads are described in further detail herein, however, it should be appreciated that the exemplary molecular payloads provided herein are not meant to be limiting.Oligonucleotides

[0204] In some embodiments, oligonucleotides are useful in the treatment of disorders associated with mutations amenable to exon skipping. For example, in some embodiments, oligonucleotides disclosed herein facilitate alternative splicing, e.g., to skip one or more exons of a pre-mRNA transcript, resulting in restoration of a reading frame that results in expression of a functional protein.

[0205] Aspects of the disclosure relate to oligonucleotides configured to modulate (e.g., increase) expression of dystrophin, e.g., from a dystrophin allele. In some embodiments, oligonucleotides provided herein are configured to alter splicing of dystrophin pre-mRNA to promote expression of dystrophin protein (e.g., a functional truncated dystrophin protein). In some embodiments, oligonucleotides provided herein are configured to promote skipping of 90 / 350#14837954v1one or more exons in dystrophin, e.g., in a mutated dystrophin allele, in order to restore the reading frame. In some embodiments, the oligonucleotides allow for functional dystrophin protein expression (e.g., as described in Kinali M, Arechevala-Gomeza V, Feng L, et al. Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study. Lancet Neurol. 2009;8(10):918-928; Lee T, Awano H, Yagi M, et al. 2'-O-Methyl RNA / Ethylene-Bridged Nucleic Acid Chimera Antisense Oligonucleotides to Induce Dystrophin Exon 45 Skipping. Genes. 2017;8(2):67; and Watanabe N, Nagata T, Satou Y, et al. NS-065 / NCNP-01: an antisense oligonucleotide for potential treatment of exon 53 skipping in Duchenne muscular dystrophy. Mol Ther Nucleic Acids. 2018;13:442-449).

[0206] In some embodiments, oligonucleotides provided are configured to promote skipping of exon 44 to produce a shorter but functional version of dystrophin (e.g., containing an in-frame deletion). In some embodiments, oligonucleotides are provided that promote exon 44 skipping (e.g., which may be relevant in a substantial number of patients, including, for example, patients amenable to exon 44 skipping, such as those having deletions in dystrophin exons 10- 43, 11-43, 13-43, 14-43, 15-43, 16-43, 17-43, 19-43, 21-43, 23-43, 24-43, 25-43, 26-43, 27-43, 28-43, 29-43, 30-43, 31-43, 32-43, 33-43, 34-43, 35-43, 36-43, 37-43, 38-43, 39, 40-43, 41-43, 42-43, 43, 45, 45-54, 45-56, or 45-62).

[0207] In some embodiments, oligonucleotides provided are configured to promote skipping of exon 45 to produce a shorter but functional version of dystrophin (e.g., containing an in-frame deletion). In some embodiments, oligonucleotides are provided that promote exon 45 skipping (e.g., which may be relevant in a substantial number of patients, including, for example, patients amenable to exon 45 skipping, such as those having deletions in dystrophin exons 7- 44, 12-44, 18-44, 44, 46, 46-47, 46-48, 46-49, 46-51, 46-53, 46-55, 46-57, 46-59, 46-60, 46-67, 46-69, 46-75, or 46-79).

[0208] In some embodiments, oligonucleotides provided are configured to promote skipping of exon 51 to produce a shorter but functional version of dystrophin (e.g., containing an in-frame deletion). In some embodiments, oligonucleotides are provided that promote exon 51 skipping (e.g., which may be relevant in a substantial number of patients, including, for example, patients amenable to exon 51 skipping, such as those having deletions in dystrophin exons 3-50, 4-50, 5-50, 6-50, 9-50, 10-50, 11-50, 13-50, 14-50, 15-50, 16-50, 17-50, 19-50, 21-50, 23-50, 24-50, 25-50, 26-50, 27-50, 28-50, 29-50, 30-50, 31-50, 32-50, 33-50, 34-50, 35-50, 36-50, 37-50, 38-50, 39-50, 40-50, 41-50, 42-50, 43-50, 45-50, 47-50, 48-50, 49-50, 50, 52, 52-58, 52-61, 52-63, 52-64, 52-66, 52-76, or 52-77).91 / 350#14837954v1

[0209] In some embodiments, oligonucleotides provided are configured to promote skipping of exon 53 to produce a shorter but functional version of dystrophin (e.g., containing an in-frame deletion). In some embodiments, oligonucleotides are provided that promote exon 53 skipping (e.g., which may be relevant in a substantial number of patients, including, for example, patients amenable to exon 53 skipping, such as those having deletions in dystrophin exons 3-52, 4-52, 5-52, 6-52, 9-52, 10-52, 11-52, 13-52, 14-52, 16-52, 17-52, 19-52, 21-52, 23-52, 24-52, 25-52, 26-52, 27-52, 28-52, 29-52, 30-52, 31-52, 32-52, 33-52, 34-52, 35-52, 36-52, 37-52, 38-52, 39-52, 40-52, 41-52, 42-52, 43-52, 45-52, 47-52, 48-52, 49-52, 50-52, 52, 54-58, 54-61, 54-63, 54-64, 54-66, 54-76, or 54-77).

[0210] In some embodiments, oligonucleotides provided are configured to promote skipping of exon 55 to produce a shorter but functional version of dystrophin (e.g., containing an in-frame deletion). In some embodiments, oligonucleotides are provided that promote exon 55 skipping (e.g., which may be relevant in a substantial number of patients, including, for example, patients amenable to exon 55 skipping, such as those having deletions in dystrophin exons 3-54, 4-54, 5-54, 6-54, 9-54, 10-54, 11-54, 13-54, 14-54, 15-54, 16-54, 17-54, 19-54, 21-54, 23-54, 24-54, 25-54, 26-54, 27-54, 28-54, 29-54, 30-54, 31-54, 32-54, 33-54, 34-54, 35-54, 36-54, 37-54, 38-54, 39-54, 40-54, 41-54, 42-54, 43-54, 45-54, 47-54, 48-54, 49-54, 50-54, 52-54, 54, 56, 56-62, 56-65, 56-68, 56-70, 56-71, 56-72, 56-73, or 56-74).

[0211] Table 8 provides non-limiting examples of sequences of oligonucleotides that are useful for targeting dystrophin, e.g., for exon skipping, and for target sequences within dystrophin. In some embodiments, an oligonucleotide may comprise any antisense sequence provided in Table 8 or a sequence complementary to a target sequence provided in Table 8. Table 8. Oligonucleotide sequences for targeting dystrophin.SEQ SEQ SEQTarget sequence Antisense AntisenseID ID Sequence ID Sequence(5’ to 3’) Target Site NO NO (5’ to 3’) NO (5’ to 3’)CUAGAAAUGCCAU CUCCAACAUCAAG CTCCAACATCAAG160 CUUCCUUGAUGUU 1461 GAAGAUGGCAUUU 2762 GAAGATGGCATTT Exon 51GGAG CUAG CTAG AGAAAUGCCAUCU UCAAGGAAGAUGG TCAAGGAAGATGG161 UCCUUGA 1462 CAUUUCU 2763 CATTTCT Exon 51 CAGGAACUCCAGG CAAUGCCAUCCUG CAATGCCATCCTG Intron 44 / exon 45 162 AUGGCAUUG 1463 GAGUUCCUG 2764 GAGTTCCTG junction GAACACCUUCAGA GUUGCCUCCGGUU GTTGCCTCCGGTT163 ACCGGAGGCAAC 1464 CUGAAGGUGUUC 2765 CTGAAGGTGTTC Exon 53 GAACACCUUCAGA CCUCCGGUUCUGA CCTCCGGTTCTGA164 ACCGGAGG 1465 AGGUGUUC 2766 AGGTGTTC Exon 53 GACAGAUCUGUUG CGCCGCCAUUUCU CGCCGCCATTTCT165 AGAAAUGGCGGCG 1466 CAACAGAUCUGUC 2767 CAACAGATCTGTC Exon 44 CAGAUCUGUUGAG GCCGCCAUUUCUC GCCGCCATTTCTC166 1467 2768 Exon 44AAAUGGCGGC AACAGAUCUG AACAGATCTG92 / 350#14837954v1CAGAUCUGUUGAG CGCCGCCAUUUCU CGCCGCCATTTCT167 AAAUGGCGGCG 1468 CAACAGAUCUG 2769 CAACAGATCTG Exon 44 CAGAUCUGUUGAG ACGCCGCCAUUUC ACGCCGCCATTTC168 AAAUGGCGGCGU 1469 UCAACAGAUCUG 2770 TCAACAGATCTG Exon 44 AGAUCUGUUGAGA GCCGCCAUUUCUC GCCGCCATTTCTC169 AAUGGCGGC 1470 AACAGAUCU 2771 AACAGATCT Exon 44 AGAUCUGUUGAGA CGCCGCCAUUUCU CGCCGCCATTTCT170 AAUGGCGGCG 1471 CAACAGAUCU 2772 CAACAGATCT Exon 44 AGAUCUGUUGAGA ACGCCGCCAUUUC ACGCCGCCATTTC171 AAUGGCGGCGU 1472 UCAACAGAUCU 2773 TCAACAGATCT Exon 44 AGAUCUGUUGAGA AACGCCGCCAUUU AACGCCGCCATTT172 AAUGGCGGCGUU 1473 CUCAACAGAUCU 2774 CTCAACAGATCT Exon 44 GAUCUGUUGAGAA GCCGCCAUUUCUC GCCGCCATTTCTC173 AUGGCGGC 1474 AACAGAUC 2775 AACAGATC Exon 44 GAUCUGUUGAGAA CGCCGCCAUUUCU CGCCGCCATTTCT174 AUGGCGGCG 1475 CAACAGAUC 2776 CAACAGATC Exon 44 GAUCUGUUGAGAA ACGCCGCCAUUUC ACGCCGCCATTTC175 AUGGCGGCGU 1476 UCAACAGAUC 2777 TCAACAGATC Exon 44 GAUCUGUUGAGAA AACGCCGCCAUUU AACGCCGCCATTT176 AUGGCGGCGUU 1477 CUCAACAGAUC 2778 CTCAACAGATC Exon 44 GAUCUGUUGAGAA AAACGCCGCCAUU AAACGCCGCCATT177 AUGGCGGCGUUU 1478 UCUCAACAGAUC 2779 TCTCAACAGATC Exon 44 UCUGUUGAGAAAU GAAAACGCCGCCA GAAAACGCCGCCA178 GGCGGCGUUUUC 1479 UUUCUCAACAGA 2780 TTTCTCAACAGA Exon 44 CUGUUGAGAAAUG ACGCCGCCAUUUC ACGCCGCCATTTC179 GCGGCGU 1480 UCAACAG 2781 TCAACAG Exon 44 CUGUUGAGAAAUG UGAAAACGCCGCC TGAAAACGCCGCC180 GCGGCGUUUUCA 1481 AUUUCUCAACAG 2782 ATTTCTCAACAG Exon 44 UGAGAAAUGGCGG AUAAUGAAAACGC ATAATGAAAACGC181 CGUUUUCAUUAU 1482 CGCCAUUUCUCA 2783 CGCCATTTCTCA Exon 44 GAGAAAUGGCGGC CAUAAUGAAAACG CATAATGAAAACG182 GUUUUCAUUAUG 1483 CCGCCAUUUCUC 2784 CCGCCATTTCTC Exon 44 AGAAAUGGCGGCG UCAUAAUGAAAAC TCATAATGAAAAC183 UUUUCAUUAUGA 1484 GCCGCCAUUUCU 2785 GCCGCCATTTCT Exon 44 AAUCAGUGGCUAA GUUCAGCUUCUGU GTTCAGCTTCTGT184 CAGAAGCUGAAC 1485 UAGCCACUGAUU 2786 TAGCCACTGATT Exon 44 AUCAGUGGCUAAC GUUCAGCUUCUGU GTTCAGCTTCTGT185 AGAAGCUGAAC 1486 UAGCCACUGAU 2787 TAGCCACTGAT Exon 44 AUCAGUGGCUAAC UGUUCAGCUUCUG TGTTCAGCTTCTG186 AGAAGCUGAACA 1487 UUAGCCACUGAU 2788 TTAGCCACTGAT Exon 44 UCAGUGGCUAACA GUUCAGCUUCUGU GTTCAGCTTCTGT187 GAAGCUGAAC 1488 UAGCCACUGA 2789 TAGCCACTGA Exon 44 UCAGUGGCUAACA UGUUCAGCUUCUG TGTTCAGCTTCTG188 GAAGCUGAACA 1489 UUAGCCACUGA 2790 TTAGCCACTGA Exon 44 UCAGUGGCUAACA CUGUUCAGCUUCU CTGTTCAGCTTCT189 GAAGCUGAACAG 1490 GUUAGCCACUGA 2791 GTTAGCCACTGA Exon 44 CAGUGGCUAACAG GUUCAGCUUCUGU GTTCAGCTTCTGT190 AAGCUGAAC 1491 UAGCCACUG 2792 TAGCCACTG Exon 44 CAGUGGCUAACAG UGUUCAGCUUCUG TGTTCAGCTTCTG191 AAGCUGAACA 1492 UUAGCCACUG 2793 TTAGCCACTG Exon 44 CAGUGGCUAACAG CUGUUCAGCUUCU CTGTTCAGCTTCT192 AAGCUGAACAG 1493 GUUAGCCACUG 2794 GTTAGCCACTG Exon 44 CAGUGGCUAACAG ACUGUUCAGCUUC ACTGTTCAGCTTC193 AAGCUGAACAGU 1494 UGUUAGCCACUG 2795 TGTTAGCCACTG Exon 44 AGUGGCUAACAGA CUGUUCAGCUUCU CTGTTCAGCTTCT194 AGCUGAACAG 1495 GUUAGCCACU 2796 GTTAGCCACT Exon 44 AGUGGCUAACAGA ACUGUUCAGCUUC ACTGTTCAGCTTC195 AGCUGAACAGU 1496 UGUUAGCCACU 2797 TGTTAGCCACT Exon 44 AGUGGCUAACAGA AACUGUUCAGCUU AACTGTTCAGCTT196 1497 2798 Exon 44AGCUGAACAGUU CUGUUAGCCACU CTGTTAGCCACT93 / 350#14837954v1GUGGCUAACAGAA ACUGUUCAGCUUC ACTGTTCAGCTTC 197 GCUGAACAGU 1498 UGUUAGCCAC 2799 TGTTAGCCAC Exon 44 GUGGCUAACAGAA AACUGUUCAGCUU AACTGTTCAGCTT198 GCUGAACAGUU 1499 CUGUUAGCCAC 2800 CTGTTAGCCAC Exon 44 AAAGAUCAGGUUC CAUCACCCUUCAG CATCACCCTTCAG199 UGAAGGGUGAUG 1500 AACCUGAUCUUU 2801 AACCTGATCTTT Intron 44 AAGAUCAGGUUCU CAUCACCCUUCAG CATCACCCTTCAG200 GAAGGGUGAUG 1501 AACCUGAUCUU 2802 AACCTGATCTT Intron 44 AGAUCAGGUUCUG CAUCACCCUUCAG CATCACCCTTCAG201 AAGGGUGAUG 1502 AACCUGAUCU 2803 AACCTGATCT Intron 44 CUUUGCCAGUACA ACCACAUGCAGUU ACCACATGCAGTT202 ACUGCAUGUGGU 1503 GUACUGGCAAAG 2804 GTACTGGCAAAG Intron 44 UUGCCAGUACAAC UACCACAUGCAGU TACCACATGCAGT203 UGCAUGUGGUA 1504 UGUACUGGCAA 2805 TGTACTGGCAA Intron 44 UUGCCAGUACAAC CUACCACAUGCAG CTACCACATGCAG204 UGCAUGUGGUAG 1505 UUGUACUGGCAA 2806 TTGTACTGGCAA Intron 44 UGCCAGUACAACU ACCACAUGCAGUU ACCACATGCAGTT205 GCAUGUGGU 1506 GUACUGGCA 2807 GTACTGGCA Intron 44 UGCCAGUACAACU UACCACAUGCAGU TACCACATGCAGT206 GCAUGUGGUA 1507 UGUACUGGCA 2808 TGTACTGGCA Intron 44 UGCCAGUACAACU CUACCACAUGCAG CTACCACATGCAG207 GCAUGUGGUAG 1508 UUGUACUGGCA 2809 TTGTACTGGCA Intron 44 UGCCAGUACAACU GCUACCACAUGCA GCTACCACATGCA208 GCAUGUGGUAGC 1509 GUUGUACUGGCA 2810 GTTGTACTGGCA Intron 44 GCCAGUACAACUG ACCACAUGCAGUU ACCACATGCAGTT209 CAUGUGGU 1510 GUACUGGC 2811 GTACTGGC Intron 44 GCCAGUACAACUG UACCACAUGCAGU TACCACATGCAGT210 CAUGUGGUA 1511 UGUACUGGC 2812 TGTACTGGC Intron 44 GCCAGUACAACUG CUACCACAUGCAG CTACCACATGCAG211 CAUGUGGUAG 1512 UUGUACUGGC 2813 TTGTACTGGC Intron 44 GCCAGUACAACUG GCUACCACAUGCA GCTACCACATGCA212 CAUGUGGUAGC 1513 GUUGUACUGGC 2814 GTTGTACTGGC Intron 44 GCCAGUACAACUG UGCUACCACAUGC TGCTACCACATGC213 CAUGUGGUAGCA 1514 AGUUGUACUGGC 2815 AGTTGTACTGGC Intron 44 CCAGUACAACUGC CUACCACAUGCAG CTACCACATGCAG214 AUGUGGUAG 1515 UUGUACUGG 2816 TTGTACTGG Intron 44 CCAGUACAACUGC GCUACCACAUGCA GCTACCACATGCA215 AUGUGGUAGC 1516 GUUGUACUGG 2817 GTTGTACTGG Intron 44 CCAGUACAACUGC UGCUACCACAUGC TGCTACCACATGC216 AUGUGGUAGCA 1517 AGUUGUACUGG 2818 AGTTGTACTGG Intron 44 CAGUACAACUGCA GCUACCACAUGCA GCTACCACATGCA217 UGUGGUAGC 1518 GUUGUACUG 2819 GTTGTACTG Intron 44 CAGUACAACUGCA UGCUACCACAUGC TGCTACCACATGC218 UGUGGUAGCA 1519 AGUUGUACUG 2820 AGTTGTACTG Intron 44 AGUACAACUGCAU GCUACCACAUGCA GCTACCACATGCA219 GUGGUAGC 1520 GUUGUACU 2821 GTTGTACT Intron 44 AGUACAACUGCAU UGCUACCACAUGC TGCTACCACATGC220 GUGGUAGCA 1521 AGUUGUACU 2822 AGTTGTACT Intron 44 GUACAACUGCAUG GUGCUACCACAUG GTGCTACCACATG221 UGGUAGCAC 1522 CAGUUGUAC 2823 CAGTTGTAC Intron 44 GUACAACUGCAUG UGUGCUACCACAU TGTGCTACCACAT222 UGGUAGCACA 1523 GCAGUUGUAC 2824 GCAGTTGTAC Intron 44 AUAAAAAGACAUG UGAAGCCCCAUGU TGAAGCCCCATGT223 GGGCUUCA 1524 CUUUUUAU 2825 CTTTTTAT Intron 44 UCUUACAGGAACU GCCAUCCUGGAGU GCCATCCTGGAGT Intron 44 / exon 45 224 CCAGGAUGGC 1525 UCCUGUAAGA 2826 TCCTGTAAGA junction UCUUACAGGAACU UGCCAUCCUGGAG TGCCATCCTGGAG Intron 44 / exon 45 225 CCAGGAUGGCA 1526 UUCCUGUAAGA 2827 TTCCTGTAAGA junction UCUUACAGGAACU AUGCCAUCCUGGA ATGCCATCCTGGA Intron 44 / exon 45 226 1527 2828CCAGGAUGGCAU GUUCCUGUAAGA GTTCCTGTAAGA junction 94 / 350#14837954v1CUUACAGGAACUC UGCCAUCCUGGAG TGCCATCCTGGAG Intron 44 / exon 45 227 CAGGAUGGCA 1528 UUCCUGUAAG 2829 TTCCTGTAAG junction CUUACAGGAACUC AUGCCAUCCUGGA ATGCCATCCTGGA228 Intron 44 / exon 45 CAGGAUGGCAU 1529 GUUCCUGUAAG 2830 GTTCCTGTAAG junction CUUACAGGAACUC AAUGCCAUCCUGG AATGCCATCCTGG Intron 44 / exon 45 229 CAGGAUGGCAUU 1530 AGUUCCUGUAAG 2831 AGTTCCTGTAAG junction UACAGGAACUCCA GCCATCCTGGAGT GCCAUCCUGGAGU Intron 44 / exon 45 230 1531 2832 UCCUGUA TCCTGTA GGAUGGC junction UACAGGAACUCCA UGCCAUCCUGGAG TGCCATCCTGGAG Intron 44 / exon 45 231 1532 2833 GGAUGGCA UUCCUGUA TTCCTGTA junction UACAGGAACUCCA AUGCCAUCCUGGA ATGCCATCCTGGA Intron 44 / exon 45 232 1533 2834 GUUCCUGUA GTTCCTGTA GGAUGGCAU junction UACAGGAACUCCA AAUGCCAUCCUGG AATGCCATCCTGG Intron 44 / exon 45 233 1534 2835 AGUUCCUGUA AGTTCCTGTA GGAUGGCAUU junction UACAGGAACUCCA CCAATGCCATCCT CCAAUGCCAUCCU Intron 44 / exon 45 234 1535 2836 GGAGUUCCUGUA GGAGTTCCTGTA GGAUGGCAUUGG junction ACAGGAACUCCAG UGCCAUCCUGGAG TGCCATCCTGGAG Intron 44 / exon 45 235 1536 2837 GAUGGCA TTCCTGT UUCCUGU junction AUGCCAUCCUGGA ATGCCATCCTGGA ACAGGAACUCCAG Intron 44 / exon 45 236 1537 2838 GTTCCTGT GAUGGCAU GUUCCUGU junction ACAGGAACUCCAG AAUGCCAUCCUGG AATGCCATCCTGG Intron 44 / exon 45 237 1538 2839 AGTTCCTGT GAUGGCAUU AGUUCCUGU junction CCAATGCCATCCT ACAGGAACUCCAG CCAAUGCCAUCCU Intron 44 / exon 45 238 1539 2840 GGAGTTCCTGT GAUGGCAUUGG GGAGUUCCUGU junction ACAGGAACUCCAG CCCAAUGCCAUCC CCCAATGCCATCC Intron 44 / exon 45 239 1540 2841 TGGAGTTCCTGT GAUGGCAUUGGG UGGAGUUCCUGU junction AUGCCAUCCUGGA ATGCCATCCTGGA CAGGAACUCCAGG Intron 44 / exon 45 240 1541 2842 AUGGCAU GUUCCUG GTTCCTG junction CAGGAACUCCAGG AAUGCCAUCCUGG AATGCCATCCTGG Intron 44 / exon 45 241 1542 2843 AUGGCAUU AGUUCCUG AGTTCCTG junction CCAATGCCATCCT CAGGAACUCCAGG CCAAUGCCAUCCU Intron 44 / exon 45 242 1543 2844 AUGGCAUUGG GGAGUUCCUG GGAGTTCCTG junction CAGGAACUCCAGG CCCAAUGCCAUCC CCCAATGCCATCC Intron 44 / exon 45 243 1544 2845 AUGGCAUUGGG UGGAGUUCCUG TGGAGTTCCTG junction CAGGAACUCCAGG GCCCAAUGCCAUC GCCCAATGCCATC Intron 44 / exon 45 244 1545 2846 AUGGCAUUGGGCCUGGAGUUCCUG CTGGAGTTCCTG junction AGGAACUCCAGGA AAUGCCAUCCUGG AATGCCATCCTGG Intron 44 / exon 45 245 1546 2847 AGTTCCT UGGCAUU AGUUCCU junction AGGAACUCCAGGA CCAATGCCATCCT CCAAUGCCAUCCU Intron 44 / exon 45 246 1547 2848 GGAGTTCCT UGGCAUUGG GGAGUUCCU junction AGGAACUCCAGGA CCCAAUGCCAUCC CCCAATGCCATCC Intron 44 / exon 45 247 1548 2849 TGGAGTTCCT UGGCAUUGGG UGGAGUUCCU junction AGGAACUCCAGGA GCCCAAUGCCAUC GCCCAATGCCATC Intron 44 / exon 45 248 1549 2850 CTGGAGTTCCT UGGCAUUGGGCCUGGAGUUCCU junction AGGAACUCCAGGA TGCCCAATGCCAT UGCCCAAUGCCAU Intron 44 / exon 45 249 1550 2851 UGGCAUUGGGCA CCTGGAGTTCCT CCUGGAGUUCCU junction CCAATGCCATCCT GGAACUCCAGGAU CCAAUGCCAUCCU Intron 44 / exon 45 250 1551 2852 GGCAUUGG GGAGUUCC GGAGTTCC junction GGAACUCCAGGAU CCCAAUGCCAUCC CCCAATGCCATCC Intron 44 / exon 45 251 1552 2853 GGCAUUGGG UGGAGUUCC TGGAGTTCC junction TGCCCAATGCCAT GGAACUCCAGGAU UGCCCAAUGCCAU Intron 44 / exon 45 252 1553 2854 GGCAUUGGGCA CCUGGAGUUCC CCTGGAGTTCC junction CUGCCCAAUGCCA CTGCCCAATGCCA GGAACUCCAGGAU Intron 44 / exon 45 253 1554 2855 GGCAUUGGGCAG UCCUGGAGUUCC TCCTGGAGTTCC junction CCAATGCCATCCT GAACUCCAGGAUG CCAAUGCCAUCCU254 1555 2856 Exon 45 GCAUUGG GGAGUUC GGAGTTC GAACUCCAGGAUG CCCAAUGCCAUCC CCCAATGCCATCC255 1556 2857 Exon 45 GCAUUGGG UGGAGUUC TGGAGTTC95 / 350#14837954v1GAACUCCAGGAUG GCCCAAUGCCAUC GCCCAATGCCATC256 GCAUUGGGC 1557 CUGGAGUUC 2858 CTGGAGTTC Exon 45 GAACUCCAGGAUG UGCCCAAUGCCAU TGCCCAATGCCAT257 GCAUUGGGCA 1558 CCUGGAGUUC 2859 CCTGGAGTTC Exon 45 GAACUCCAGGAUG CUGCCCAAUGCCA CTGCCCAATGCCA258 GCAUUGGGCAG 1559 UCCUGGAGUUC 2860 TCCTGGAGTTC Exon 45 GAACUCCAGGAUG GCUGCCCAAUGCC GCTGCCCAATGCC259 GCAUUGGGCAGC 1560 AUCCUGGAGUUC 2861 ATCCTGGAGTTC Exon 45 AACUCCAGGAUGG CCCAAUGCCAUCC CCCAATGCCATCC260 CAUUGGG 1561 UGGAGUU 2862 TGGAGTT Exon 45 AACUCCAGGAUGG GCCCAAUGCCAUC GCCCAATGCCATC261 CAUUGGGC 1562 CUGGAGUU 2863 CTGGAGTT Exon 45 AACUCCAGGAUGG UGCCCAAUGCCAU TGCCCAATGCCAT262 CAUUGGGCA 1563 CCUGGAGUU 2864 CCTGGAGTT Exon 45 AACUCCAGGAUGG CUGCCCAAUGCCA CTGCCCAATGCCA263 CAUUGGGCAG 1564 UCCUGGAGUU 2865 TCCTGGAGTT Exon 45 AACUCCAGGAUGG GCUGCCCAAUGCC GCTGCCCAATGCC264 CAUUGGGCAGC 1565 AUCCUGGAGUU 2866 ATCCTGGAGTT Exon 45 ACUCCAGGAUGGC GCCCAAUGCCAUC GCCCAATGCCATC265 AUUGGGC 1566 CUGGAGU 2867 CTGGAGT Exon 45 ACUCCAGGAUGGC UGCCCAAUGCCAU TGCCCAATGCCAT266 AUUGGGCA 1567 CCUGGAGU 2868 CCTGGAGT Exon 45 ACUCCAGGAUGGC CUGCCCAAUGCCA CTGCCCAATGCCA267 AUUGGGCAG 1568 UCCUGGAGU 2869 TCCTGGAGT Exon 45 CUCCAGGAUGGCA UGCCCAAUGCCAU TGCCCAATGCCAT268 UUGGGCA 1569 CCUGGAG 2870 CCTGGAG Exon 45 CAGAACAUUGAAU UCCCCAGUUGCAU TCCCCAGTTGCAT269 GCAACUGGGGA 1570 UCAAUGUUCUG 2871 TCAATGTTCTG Exon 45 AGAACAUUGAAUG UCCCCAGUUGCAU TCCCCAGTTGCAT270 CAACUGGGGA 1571 UCAAUGUUCU 2872 TCAATGTTCT Exon 45 AGAACAUUGAAUG CUUCCCCAGUUGC CTTCCCCAGTTGC271 CAACUGGGGAAG 1572 AUUCAAUGUUCU 2873 ATTCAATGTTCT Exon 45 GAACAUUGAAUGC UCUUCCCCAGUUG TCTTCCCCAGTTG272 AACUGGGGAAGA 1573 CAUUCAAUGUUC 2874 CATTCAATGTTC Exon 45 CAUUGAAUGCAAC AUUUCUUCCCCAG ATTTCTTCCCCAG273 UGGGGAAGAAAU 1574 UUGCAUUCAAUG 2875 TTGCATTCAATG Exon 45 AUUGAAUGCAACU AUUUCUUCCCCAG ATTTCTTCCCCAG274 GGGGAAGAAAU 1575 UUGCAUUCAAU 2876 TTGCATTCAAT Exon 45 AUUGAAUGCAACU UAUUUCUUCCCCA TATTTCTTCCCCA275 GGGGAAGAAAUA 1576 GUUGCAUUCAAU 2877 GTTGCATTCAAT Exon 45 UUGAAUGCAACUG AUUUCUUCCCCAG ATTTCTTCCCCAG276 GGGAAGAAAU 1577 UUGCAUUCAA 2878 TTGCATTCAA Exon 45 UUGAAUGCAACUG UAUUUCUUCCCCA TATTTCTTCCCCA277 GGGAAGAAAUA 1578 GUUGCAUUCAA 2879 GTTGCATTCAA Exon 45 UUGAAUGCAACUG UUAUUUCUUCCCC TTATTTCTTCCCC278 GGGAAGAAAUAA 1579 AGUUGCAUUCAA 2880 AGTTGCATTCAA Exon 45 UGAAUGCAACUGG UUCUUCCCCAGUU TTCTTCCCCAGTT279 GGAAGAA 1580 GCAUUCA 2881 GCATTCA Exon 45 UGAAUGCAACUGG AUUUCUUCCCCAG ATTTCTTCCCCAG280 GGAAGAAAU 1581 UUGCAUUCA 2882 TTGCATTCA Exon 45 UGAAUGCAACUGG UAUUUCUUCCCCA TATTTCTTCCCCA281 GGAAGAAAUA 1582 GUUGCAUUCA 2883 GTTGCATTCA Exon 45 UGAAUGCAACUGG UUAUUUCUUCCCC TTATTTCTTCCCC282 GGAAGAAAUAA 1583 AGUUGCAUUCA 2884 AGTTGCATTCA Exon 45 GAAUGCAACUGGG AUUUCUUCCCCAG ATTTCTTCCCCAG283 GAAGAAAU 1584 UUGCAUUC 2885 TTGCATTC Exon 45 GAAUGCAACUGGG UAUUUCUUCCCCA TATTTCTTCCCCA284 GAAGAAAUA 1585 GUUGCAUUC 2886 GTTGCATTC Exon 45 GAAUGCAACUGGG UUAUUUCUUCCCC TTATTTCTTCCCC285 1586 2887 Exon 45GAAGAAAUAA AGUUGCAUUC AGTTGCATTC 96 / 350#14837954v1AAUGCAACUGGGG UAUUUCUUCCCCA TATTTCTTCCCCA286 AAGAAAUA 1587 GUUGCAUU 2888 GTTGCATT Exon 45 AUGCAACUGGGGA UAUUUCUUCCCCA TATTTCTTCCCCA287 AGAAAUA 1588 GUUGCAU 2889 GTTGCAT Exon 45 AUGCAACUGGGGA UUAUUUCUUCCCC TTATTTCTTCCCC288 AGAAAUAA 1589 AGUUGCAU 2890 AGTTGCAT Exon 45 AUGCAACUGGGGA AUUAUUUCUUCCC ATTATTTCTTCCC289 AGAAAUAAU 1590 CAGUUGCAU 2891 CAGTTGCAT Exon 45 AAUUCAGCAAUCC UCUGUUUUUGAGG TCTGTTTTTGAGG290 UCAAAAACAGA 1591 AUUGCUGAAUU 2892 ATTGCTGAATT Exon 45 AAUUCAGCAAUCC AUCUGUUUUUGAG ATCTGTTTTTGAG291 UCAAAAACAGAU 1592 GAUUGCUGAAUU 2893 GATTGCTGAATT Exon 45 AUUCAGCAAUCCU CUGUUUUUGAGGA CTGTTTTTGAGGA292 CAAAAACAG 1593 UUGCUGAAU 2894 TTGCTGAAT Exon 45 AUUCAGCAAUCCU UCUGUUUUUGAGG TCTGTTTTTGAGG293 CAAAAACAGA 1594 AUUGCUGAAU 2895 ATTGCTGAAT Exon 45 AUUCAGCAAUCCU AUCUGUUUUUGAG ATCTGTTTTTGAG294 CAAAAACAGAU 1595 GAUUGCUGAAU 2896 GATTGCTGAAT Exon 45 AUUCAGCAAUCCU CAUCUGUUUUUGA CATCTGTTTTTGA295 CAAAAACAGAUG 1596 GGAUUGCUGAAU 2897 GGATTGCTGAAT Exon 45 UUCAGCAAUCCUC UCUGUUUUUGAGG TCTGTTTTTGAGG296 AAAAACAGA 1597 AUUGCUGAA 2898 ATTGCTGAA Exon 45 UUCAGCAAUCCUC AUCUGUUUUUGAG ATCTGTTTTTGAG297 AAAAACAGAU 1598 GAUUGCUGAA 2899 GATTGCTGAA Exon 45 UUCAGCAAUCCUC CAUCUGUUUUUGA CATCTGTTTTTGA298 AAAAACAGAUG 1599 GGAUUGCUGAA 2900 GGATTGCTGAA Exon 45 UCAGCAAUCCUCA CUGUUUUUGAGGA CTGTTTTTGAGGA299 AAAACAG 1600 UUGCUGA 2901 TTGCTGA Exon 45 UCAGCAAUCCUCA UCUGUUUUUGAGG TCTGTTTTTGAGG300 AAAACAGA 1601 AUUGCUGA 2902 ATTGCTGA Exon 45 UCAGCAAUCCUCA AUCUGUUUUUGAG ATCTGTTTTTGAG301 AAAACAGAU 1602 GAUUGCUGA 2903 GATTGCTGA Exon 45 UCAGCAAUCCUCA CAUCUGUUUUUGA CATCTGTTTTTGA302 AAAACAGAUG 1603 GGAUUGCUGA 2904 GGATTGCTGA Exon 45 CAGCAAUCCUCAA UCUGUUUUUGAGG TCTGTTTTTGAGG303 AAACAGA 1604 AUUGCUG 2905 ATTGCTG Exon 45 CAGCAAUCCUCAA AUCUGUUUUUGAG ATCTGTTTTTGAG304 AAACAGAU 1605 GAUUGCUG 2906 GATTGCTG Exon 45 CAGCAAUCCUCAA CAUCUGUUUUUGA CATCTGTTTTTGA305 AAACAGAUG 1606 GGAUUGCUG 2907 GGATTGCTG Exon 45 AGCAAUCCUCAAA AUCUGUUUUUGAG ATCTGTTTTTGAG306 AACAGAU 1607 GAUUGCU 2908 GATTGCT Exon 45 AGCAAUCCUCAAA CAUCUGUUUUUGA CATCTGTTTTTGA307 AACAGAUG 1608 GGAUUGCU 2909 GGATTGCT Exon 45 GCAAUCCUCAAAA GCAUCUGUUUUUG GCATCTGTTTTTG308 ACAGAUGC 1609 AGGAUUGC 2910 AGGATTGC Exon 45 GCAAUCCUCAAAA GGCAUCUGUUUUU GGCATCTGTTTTT309 ACAGAUGCC 1610 GAGGAUUGC 2911 GAGGATTGC Exon 45 GCAAUCCUCAAAA UGGCAUCUGUUUU TGGCATCTGTTTT310 ACAGAUGCCA 1611 UGAGGAUUGC 2912 TGAGGATTGC Exon 45 CAAUCCUCAAAAA GGCAUCUGUUUUU GGCATCTGTTTTT311 CAGAUGCC 1612 GAGGAUUG 2913 GAGGATTG Exon 45 CAAUCCUCAAAAA UGGCAUCUGUUUU TGGCATCTGTTTT312 CAGAUGCCA 1613 UGAGGAUUG 2914 TGAGGATTG Exon 45 CAAUCCUCAAAAA UACUGGCAUCUGU TACTGGCATCTGT313 CAGAUGCCAGUA 1614 UUUUGAGGAUUG 2915 TTTTGAGGATTG Exon 45 AAUCCUCAAAAAC GGCAUCUGUUUUU GGCATCTGTTTTT314 AGAUGCC 1615 GAGGAUU 2916 GAGGATT Exon 45 AAUCCUCAAAAAC UGGCAUCUGUUUU TGGCATCTGTTTT315 1616 2917 Exon 45AGAUGCCA UGAGGAUU TGAGGATT 97 / 350#14837954v1AAUCCUCAAAAAC UACUGGCAUCUGU TACTGGCATCTGT316 AGAUGCCAGUA 1617 UUUUGAGGAUU 2918 TTTTGAGGATT Exon 45 AAUCCUCAAAAAC AUACUGGCAUCUG ATACTGGCATCTG317 AGAUGCCAGUAU 1618 UUUUUGAGGAUU 2919 TTTTTGAGGATT Exon 45 AUCCUCAAAAACA UGGCAUCUGUUUU TGGCATCTGTTTT318 GAUGCCA 1619 UGAGGAU 2920 TGAGGAT Exon 45 AUCCUCAAAAACA UACUGGCAUCUGU TACTGGCATCTGT319 GAUGCCAGUA 1620 UUUUGAGGAU 2921 TTTTGAGGAT Exon 45 AUCCUCAAAAACA AUACUGGCAUCUG ATACTGGCATCTG320 GAUGCCAGUAU 1621 UUUUUGAGGAU 2922 TTTTTGAGGAT Exon 45 AUCCUCAAAAACA AAUACUGGCAUCU AATACTGGCATCT321 GAUGCCAGUAUU 1622 GUUUUUGAGGAU 2923 GTTTTTGAGGAT Exon 45 UCCUCAAAAACAG UACUGGCAUCUGU TACTGGCATCTGT322 AUGCCAGUA 1623 UUUUGAGGA 2924 TTTTGAGGA Exon 45 UCCUCAAAAACAG AUACUGGCAUCUG ATACTGGCATCTG323 AUGCCAGUAU 1624 UUUUUGAGGA 2925 TTTTTGAGGA Exon 45 UCCUCAAAAACAG AAUACUGGCAUCU AATACTGGCATCT324 AUGCCAGUAUU 1625 GUUUUUGAGGA 2926 GTTTTTGAGGA Exon 45 CCUCAAAAACAGA UACUGGCAUCUGU TACTGGCATCTGT325 UGCCAGUA 1626 UUUUGAGG 2927 TTTTGAGG Exon 45 CCUCAAAAACAGA AUACUGGCAUCUG ATACTGGCATCTG326 UGCCAGUAU 1627 UUUUUGAGG 2928 TTTTTGAGG Exon 45 CCUCAAAAACAGA AAUACUGGCAUCU AATACTGGCATCT327 UGCCAGUAUU 1628 GUUUUUGAGG 2929 GTTTTTGAGG Exon 45 CCUCAAAAACAGA AGAAUACUGGCAU AGAATACTGGCAT328 UGCCAGUAUUCU 1629 CUGUUUUUGAGG 2930 CTGTTTTTGAGG Exon 45 CUCAAAAACAGAU UACUGGCAUCUGU TACTGGCATCTGT329 GCCAGUA 1630 UUUUGAG 2931 TTTTGAG Exon 45 CUCAAAAACAGAU AUACUGGCAUCUG ATACTGGCATCTG330 GCCAGUAU 1631 UUUUUGAG 2932 TTTTTGAG Exon 45 CUCAAAAACAGAU AAUACUGGCAUCU AATACTGGCATCT331 GCCAGUAUU 1632 GUUUUUGAG 2933 GTTTTTGAG Exon 45 CUCAAAAACAGAU AGAAUACUGGCAU AGAATACTGGCAT332 GCCAGUAUUCU 1633 CUGUUUUUGAG 2934 CTGTTTTTGAG Exon 45 CUCAAAAACAGAU UAGAAUACUGGCA TAGAATACTGGCA333 GCCAGUAUUCUA 1634 UCUGUUUUUGAG 2935 TCTGTTTTTGAG Exon 45 UCAAAAACAGAUG AUACUGGCAUCUG ATACTGGCATCTG334 CCAGUAU 1635 UUUUUGA 2936 TTTTTGA Exon 45 UCAAAAACAGAUG AAUACUGGCAUCU AATACTGGCATCT335 CCAGUAUU 1636 GUUUUUGA 2937 GTTTTTGA Exon 45 UCAAAAACAGAUG AGAAUACUGGCAU AGAATACTGGCAT336 CCAGUAUUCU 1637 CUGUUUUUGA 2938 CTGTTTTTGA Exon 45 UCAAAAACAGAUG UAGAAUACUGGCA TAGAATACTGGCA337 CCAGUAUUCUA 1638 UCUGUUUUUGA 2939 TCTGTTTTTGA Exon 45 UCAAAAACAGAUG GUAGAAUACUGGC GTAGAATACTGGC338 CCAGUAUUCUAC 1639 AUCUGUUUUUGA 2940 ATCTGTTTTTGA Exon 45 CAAAAACAGAUGC AGAAUACUGGCAU AGAATACTGGCAT339 CAGUAUUCU 1640 CUGUUUUUG 2941 CTGTTTTTG Exon 45 CAAAAACAGAUGC UAGAAUACUGGCA TAGAATACTGGCA340 CAGUAUUCUA 1641 UCUGUUUUUG 2942 TCTGTTTTTG Exon 45 CAAAAACAGAUGC GUAGAAUACUGGC GTAGAATACTGGC341 CAGUAUUCUAC 1642 AUCUGUUUUUG 2943 ATCTGTTTTTG Exon 45 CAAAAACAGAUGC UGUAGAAUACUGG TGTAGAATACTGG342 CAGUAUUCUACA 1643 CAUCUGUUUUUG 2944 CATCTGTTTTTG Exon 45 AAAAACAGAUGCC GUAGAAUACUGGC GTAGAATACTGGC343 AGUAUUCUAC 1644 AUCUGUUUUU 2945 ATCTGTTTTT Exon 45 AAAAACAGAUGCC UGUAGAAUACUGG TGTAGAATACTGG344 AGUAUUCUACA 1645 CAUCUGUUUUU 2946 CATCTGTTTTT Exon 45 AAAAACAGAUGCC CUGUAGAAUACUG CTGTAGAATACTG345 1646 2947 Exon 45AGUAUUCUACAG GCAUCUGUUUUU GCATCTGTTTTT 98 / 350#14837954v1AAAACAGAUGCCA GUAGAAUACUGGC GTAGAATACTGGC346 GUAUUCUAC 1647 AUCUGUUUU 2948 ATCTGTTTT Exon 45 AAAACAGAUGCCA UGUAGAAUACUGG TGTAGAATACTGG347 GUAUUCUACA 1648 CAUCUGUUUU 2949 CATCTGTTTT Exon 45 AAAACAGAUGCCA CUGUAGAAUACUG CTGTAGAATACTG348 GUAUUCUACAG 1649 GCAUCUGUUUU 2950 GCATCTGTTTT Exon 45 AAAACAGAUGCCA CCUGUAGAAUACU CCTGTAGAATACT349 GUAUUCUACAGG 1650 GGCAUCUGUUUU 2951 GGCATCTGTTTT Exon 45 AAACAGAUGCCAG GUAGAAUACUGGC GTAGAATACTGGC350 UAUUCUAC 1651 AUCUGUUU 2952 ATCTGTTT Exon 45 AAACAGAUGCCAG UGUAGAAUACUGG TGTAGAATACTGG351 UAUUCUACA 1652 CAUCUGUUU 2953 CATCTGTTT Exon 45 AAACAGAUGCCAG CUGUAGAAUACUG CTGTAGAATACTG352 UAUUCUACAG 1653 GCAUCUGUUU 2954 GCATCTGTTT Exon 45 AAACAGAUGCCAG CCUGUAGAAUACU CCTGTAGAATACT353 UAUUCUACAGG 1654 GGCAUCUGUUU 2955 GGCATCTGTTT Exon 45 AAACAGAUGCCAG UCCUGUAGAAUAC TCCTGTAGAATAC354 UAUUCUACAGGA 1655 UGGCAUCUGUUU 2956 TGGCATCTGTTT Exon 45 AACAGAUGCCAGU GUAGAAUACUGGC GTAGAATACTGGC355 AUUCUAC 1656 AUCUGUU 2957 ATCTGTT Exon 45 AACAGAUGCCAGU UGUAGAAUACUGG TGTAGAATACTGG356 AUUCUACA 1657 CAUCUGUU 2958 CATCTGTT Exon 45 AACAGAUGCCAGU CUGUAGAAUACUG CTGTAGAATACTG357 AUUCUACAG 1658 GCAUCUGUU 2959 GCATCTGTT Exon 45 AACAGAUGCCAGU CCUGUAGAAUACU CCTGTAGAATACT358 AUUCUACAGG 1659 GGCAUCUGUU 2960 GGCATCTGTT Exon 45 AACAGAUGCCAGU UCCUGUAGAAUAC TCCTGTAGAATAC359 AUUCUACAGGA 1660 UGGCAUCUGUU 2961 TGGCATCTGTT Exon 45 AACAGAUGCCAGU UUCCUGUAGAAUA TTCCTGTAGAATA360 AUUCUACAGGAA 1661 CUGGCAUCUGUU 2962 CTGGCATCTGTT Exon 45 ACAGAUGCCAGUA UGUAGAAUACUGG TGTAGAATACTGG361 UUCUACA 1662 CAUCUGU 2963 CATCTGT Exon 45 ACAGAUGCCAGUA CUGUAGAAUACUG CTGTAGAATACTG362 UUCUACAG 1663 GCAUCUGU 2964 GCATCTGT Exon 45 ACAGAUGCCAGUA CCUGUAGAAUACU CCTGTAGAATACT363 UUCUACAGG 1664 GGCAUCUGU 2965 GGCATCTGT Exon 45 ACAGAUGCCAGUA UCCUGUAGAAUAC TCCTGTAGAATAC364 UUCUACAGGA 1665 UGGCAUCUGU 2966 TGGCATCTGT Exon 45 ACAGAUGCCAGUA UUCCUGUAGAAUA TTCCTGTAGAATA365 UUCUACAGGAA 1666 CUGGCAUCUGU 2967 CTGGCATCTGT Exon 45 CAGAUGCCAGUAU UCCUGUAGAAUAC TCCTGTAGAATAC366 UCUACAGGA 1667 UGGCAUCUG 2968 TGGCATCTG Exon 45 CAGAUGCCAGUAU UUCCUGUAGAAUA TTCCTGTAGAATA367 UCUACAGGAA 1668 CUGGCAUCUG 2969 CTGGCATCTG Exon 45 CAGAUGCCAGUAU UUUUCCUGUAGAA TTTTCCTGTAGAA368 UCUACAGGAAAA 1669 UACUGGCAUCUG 2970 TACTGGCATCTG Exon 45 AGAUGCCAGUAUU UUCCUGUAGAAUA TTCCTGTAGAATA369 CUACAGGAA 1670 CUGGCAUCU 2971 CTGGCATCT Exon 45 AGAUGCCAGUAUU UUUUCCUGUAGAA TTTTCCTGTAGAA370 CUACAGGAAAA 1671 UACUGGCAUCU 2972 TACTGGCATCT Exon 45 AGAUGCCAGUAUU UUUUUCCUGUAGA TTTTTCCTGTAGA371 CUACAGGAAAAA 1672 AUACUGGCAUCU 2973 ATACTGGCATCT Exon 45 GAUGCCAGUAUUC UUUUCCUGUAGAA TTTTCCTGTAGAA372 UACAGGAAAA 1673 UACUGGCAUC 2974 TACTGGCATC Exon 45 GAUGCCAGUAUUC UUUUUCCUGUAGA TTTTTCCTGTAGA373 UACAGGAAAAA 1674 AUACUGGCAUC 2975 ATACTGGCATC Exon 45 GAUGCCAGUAUUC AUUUUUCCUGUAG ATTTTTCCTGTAG374 UACAGGAAAAAU 1675 AAUACUGGCAUC 2976 AATACTGGCATC Exon 45 CAGAAAAAAGAGG UGUCGCCCUACCU TGTCGCCCTACCT Exon 45 / intron 45 375 1676 2977UAGGGCGACA CUUUUUUCUG CTTTTTTCTG junction 99 / 350#14837954v1CAGAAAAAAGAGG CUGUCGCCCUACC CTGTCGCCCTACC Exon 45 / intron 45 376 UAGGGCGACAG 1677 UCUUUUUUCUG 2978 TCTTTTTTCTG junction CAGAAAAAAGAGG UCUGUCGCCCUAC TCTGTCGCCCTAC377 Exon 45 / intron 45 UAGGGCGACAGA 1678 CUCUUUUUUUCUG 2979 CTCTTTTTTTCTG junction AGAAAAAAGAGGU UGUCGCCCUACCU TGTCGCCCTACCT Exon 45 / intron 45 378 AGGGCGACA 1679 CUUUUUUCU 2980 CTTTTTTCT junction AGAAAAAAGAGGU CUGUCGCCCUACC CTGTCGCCCTACC Exon 45 / intron 45 379 AGGGCGACAG 1680 UCUUUUUUCU 2981 TCTTTTTTCT junction AGAAAAAAGAGGU UCUGUCGCCCUAC TCTGTCGCCCTAC Exon 45 / intron 45 380 AGGGCGACAGA 1681 CUCUUUUUUUCU 2982 CTCTTTTTTTCT junction AGAAAAAAGAGGU AUCUGUCGCCCUA ATCTGTCGCCCTA Exon 45 / intron 45 381 AGGGCGACAGAU 1682 CCUCUUUUUUUCU 2983 CCTCTTTTTTTCT junction GAAAAAAGAGGUA UGUCGCCCUACCU TGTCGCCCTACCT Exon 45 / intron 45 382 GGGCGACA 1683 CUUUUUUC 2984 CTTTTTTC junction GAAAAAAGAGGUA CUGUCGCCCUACC CTGTCGCCCTACC Exon 45 / intron 45 383 1684 2985 GGGCGACAG uCUUUUUUC TCTTTTTTC junction GAAAAAAGAGGUA UCUGUCGCCCUAC TCTGTCGCCCTAC Exon 45 / intron 45 384 GGGCGACAGA 1685 cuCUUUUUUC 2986 CTCTTTTTTTC junction GAAAAAAGAGGUA AUCUGUCGCCCUA ATCTGTCGCCCTA Exon 45 / intron 45 385 GGGCGACAGAU 1686 CCUCUUUUUUUC 2987 CCTCTTTTTTTC junction GAAAAAAGAGGUA GAUCUGUCGCCCU GATCTGTCGCCCT Exon 45 / intron 45 386 GGGCGACAGAUC 1687 ACCUCUUUUUUUC 2988 ACCTCTTTTTTTC junction AAAAAAGAGGUAG UGUCGCCCUACCU TGTCGCCCTACCT Exon 45 / intron 45 387 1688 2989 GGCGACA CUUUUUU CTTTTTT junction AAAAAAGAGGUAG CUGUCGCCCUACC CTGTCGCCCTACC388 Exon 45 / intron 45 GGCGA 1689 2990 TCTTTTTTT UCUUUUUU junction AAAAAAGAGGUAG UCUGUCGCCCUAC TCTGTCGCCCTAC Exon 45 / intron 45 389 1690 2991 GGCGACAGA CTCTTTTTTT CUCUUUUUUU junction AUCUGUCGCCCUA ATCTGTCGCCCTA AAAAAAGAGGUAG Exon 45 / intron 45 390 1691 2992 CCTCTTTTTTT GGCGACAGAU CCUCUUUUUUU junction GATCTGTCGCCCT AAAAAAGAGGUAG GAUCUGUCGCCCU Exon 45 / intron 45 391 1692 2993 ACCTCTTTTTTT GGCGACAGAUC ACCUCUUUUUUU junction AAAAAAGAGGUAG AGAUCUGUCGCCC AGATCTGTCGCCC Exon 45 / intron 45 392 1693 2994 TACCTCTTTTTTT GGCGACAGAUCU UACCUCUUUUUUU junction AAAAAGAGGUAGG CUGUCGCCCUACC CTGTCGCCCTACC Exon 45 / intron 45 393 1694 2995 TCTTTTT GCGACAG UCUUUUU junction AAAAAGAGGUAGG UCUGUCGCCCUAC TCTGTCGCCCTAC Exon 45 / intron 45 394 1695 2996 GCGACAGA CTCTTTTT CUCUUUUU junction AUCUGUCGCCCUA ATCTGTCGCCCTA AAAAAGAGGUAGG Exon 45 / intron 45 395 1696 2997 CCTCTTTTT GCGACAGAU C CUCUUUUU junction GATCTGTCGCCCT AAAAAGAGGUAGG GAUCUGUCGCCCU Exon 45 / intron 45 396 1697 2998 ACCTCTTTTT GCGACAGAUC AC CUCUUUUU junction AAAAAGAGGUAGG AGAUCUGUCGCCC AGATCTGTCGCCC Exon 45 / intron 45 397 1698 2999 TACCTCTTTTT GCGACAGAUCU UAC CUCUUUUU junction AAAAGAGGUAGGG UCUGUCGCCCUAC TCTGTCGCCCTAC Exon 45 / intron 45 398 1699 3000 CGACAGA CTCTTTT CUCUUUU junction AUCUGUCGCCCUA ATCTGTCGCCCTA AAAAGAGGUAGGG Exon 45 / intron 45 399 1700 3001 CCTCTTTT CGACAGAU C CUCUUUU junction GATCTGTCGCCCT AAAAGAGGUAGGG GAUCUGUCGCCCU Exon 45 / intron 45 400 1701 3002 ACCTCTTTT CGACAGAUC AC CUCUUUU junction AAAAGAGGUAGGG AGAUCUGUCGCCC AGATCTGTCGCCC Exon 45 / intron 45 401 1702 3003 TACCTCTTTT CGACAGAUCU UAC CUCUUUU junction AUCUGUCGCCCUA ATCTGTCGCCCTA AAAGAGGUAGGGC Exon 45 / intron 45 402 1703 3004 CCTCTTT GACAGAU CCUCUUU junction GATCTGTCGCCCT AAAGAGGUAGGGC GAUCUGUCGCCCU Exon 45 / intron 45 403 1704 3005 ACCTCTTT GACAGAUC ACCUCUUU junction AAAGAGGUAGGGC AGAUCUGUCGCCC AGATCTGTCGCCC Exon 45 / intron 45 404 1705 3006 TACCTCTTT GACAGAUCU UACCUCUUU junction100 / 350#14837954v1AAGAGGUAGGGCG GAUCUGUCGCCCU GATCTGTCGCCCT Exon 45 / intron 45 405 ACAGAUC 1706 ACCUCUU 3007 ACCTCTT junction AAGAGGUAGGGCG AGAUCUGUCGCCC AGATCTGTCGCCC406 Exon 45 / intron 45 ACAGAUCU 1707 UACCUCUU 3008 TACCTCTT junction AGAGGUAGGGCGA AGAUCUGUCGCCC AGATCTGTCGCCC Exon 45 / intron 45 407 CAGAUCU 1708 UACCUCU 3009 TACCTCT junction AGAGGUAGGGCGA CUAUUAGAUCUGU CTATTAGATCTGT Exon 45 / intron 45 408 CAGAUCUAAUAG 1709 CGCCCUACCUCU 3010 CGCCCTACCTCT junction GAGGUAGGGCGAC CUAUUAGAUCUGU CTATTAGATCTGT Exon 45 / intron 45 409 AGAUCUAAUAG 1710 CGCCCUACCUC 3011 CGCCCTACCTC junction GAGGUAGGGCGAC CCUAUUAGAUCUG CCTATTAGATCTG Exon 45 / intron 45 410 AGAUCUAAUAGG 1711 UCGCCCUACCUC 3012 TCGCCCTACCTC junction AGGUAGGGCGACA CUAUUAGAUCUGU CTATTAGATCTGT Exon 45 / intron 45 411 GAUCUAAUAG 1712 CGCCCUACCU 3013 CGCCCTACCT junction AGGUAGGGCGACA CCUAUUAGAUCUG CCTATTAGATCTG Exon 45 / intron 45 412 GAUCUAAUAGG 1713 UCGCCCUACCU 3014 TCGCCCTACCT junction AGGUAGGGCGACA UCCUAUUAGAUCU TCCTATTAGATCT Exon 45 / intron 45 413 GAUCUAAUAGGA 1714 GUCGCCCUACCU 3015 GTCGCCCTACCT junction GGUAGGGCGACAG CUAUUAGAUCUGU CTATTAGATCTGT Exon 45 / intron 45 414 AUCUAAUAG 1715 CGCCCUACC 3016 CGCCCTACC junction GGUAGGGCGACAG CCUAUUAGAUCUG CCTATTAGATCTG Exon 45 / intron 45 415 AUCUAAUAGG 1716 UCGCCCUACC 3017 TCGCCCTACC junction GGUAGGGCGACAG UCCUAUUAGAUCU TCCTATTAGATCT Exon 45 / intron 45 416 AUCUAAUAGGA 1717 GUCGCCCUACC 3018 GTCGCCCTACC junction GGUAGGGCGACAG UUCCUAUUAGAUC TTCCTATTAGATC417 Exon 45 / intron 45 AUCUAAUAGGAA 1718 UGUCGCCCUACC 3019 TGTCGCCCTACC junction GUAGGGCGACAGA CUAUUAGAUCUGU CTATTAGATCTGT418 UCUAAUAG 1719 CGCCCUAC 3020 CGCCCTAC Intron 45 GUAGGGCGACAGA CCUAUUAGAUCUG CCTATTAGATCTG419 UCUAAUAGG 1720 UCGCCCUAC 3021 TCGCCCTAC Intron 45 GUAGGGCGACAGA UCCUAUUAGAUCU TCCTATTAGATCT420 UCUAAUAGGA 1721 GUCGCCCUAC 3022 GTCGCCCTAC Intron 45 GUAGGGCGACAGA UUCCUAUUAGAUC TTCCTATTAGATC421 UCUAAUAGGAA 1722 UGUCGCCCUAC 3023 TGTCGCCCTAC Intron 45 GUAGGGCGACAGA AUUCCUAUUAGAU ATTCCTATTAGAT422 UCUAAUAGGAAU 1723 CUGUCGCCCUAC 3024 CTGTCGCCCTAC Intron 45 UAGGGCGACAGAU UCCUAUUAGAUCU TCCTATTAGATCT423 CUAAUAGGA 1724 GUCGCCCUA 3025 GTCGCCCTA Intron 45 UAGGGCGACAGAU UUCCUAUUAGAUC TTCCTATTAGATC424 CUAAUAGGAA 1725 UGUCGCCCUA 3026 TGTCGCCCTA Intron 45 UAGGGCGACAGAU AUUCCUAUUAGAU ATTCCTATTAGAT425 CUAAUAGGAAU 1726 CUGUCGCCCUA 3027 CTGTCGCCCTA Intron 45 AGGGCGACAGAUC UCCUAUUAGAUCU TCCTATTAGATCT426 UAAUAGGA 1727 GUCGCCCU 3028 GTCGCCCT Intron 45 AGGGCGACAGAUC UUCCUAUUAGAUC TTCCTATTAGATC427 UAAUAGGAA 1728 UGUCGCCCU 3029 TGTCGCCCT Intron 45 AGGGCGACAGAUC AUUCCUAUUAGAU ATTCCTATTAGAT428 UAAUAGGAAU 1729 CUGUCGCCCU 3030 CTGTCGCCCT Intron 45 GGGCGACAGAUCU UCCUAUUAGAUCU TCCTATTAGATCT429 AAUAGGA 1730 GUCGCCC 3031 GTCGCCC Intron 45 GGGCGACAGAUCU UUCCUAUUAGAUC TTCCTATTAGATC430 AAUAGGAA 1731 UGUCGCCC 3032 TGTCGCCC Intron 45 GGGCGACAGAUCU AUUCCUAUUAGAU ATTCCTATTAGAT431 AAUAGGAAU 1732 CUGUCGCCC 3033 CTGTCGCCC Intron 45 AGAUUAUAAGCAG CUUUCACCCUGCU CTTTCACCCTGCT432 GGUGAAAG 1733 UAUAAUCU 3034 TATAATCT Intron 45 AGAUUAUAAGCAG CCUUUCACCCUGC CCTTTCACCCTGC433 GGUGAAAGG 1734 UUAUAAUCU 3035 TTATAATCT Intron 45 AGAUUAUAAGCAG GCCUUUCACCCUG GCCTTTCACCCTG434 1735 3036 Intron 45GGUGAAAGGC CUUAUAAUCU CTTATAATCT101 / 350#14837954v1AGAUUAUAAGCAG UGCCUUUCACCCU TGCCTTTCACCCT435 GGUGAAAGGCA 1736 GCUUAUAAUCU 3037 GCTTATAATCT Intron 45 AGAUUAUAAGCAG GUGCCUUUCACCC GTGCCTTTCACCC436 GGUGAAAGGCAC 1737 UGCUUAUAAUCU 3038 TGCTTATAATCT Intron 45 GAUUAUAAGCAGG CUUUCACCCUGCU CTTTCACCCTGCT437 GUGAAAG 1738 UAUAAUC 3039 TATAATC Intron 45 GAUUAUAAGCAGG CCUUUCACCCUGC CCTTTCACCCTGC438 GUGAAAGG 1739 UUAUAAUC 3040 TTATAATC Intron 45 GAUUAUAAGCAGG GCCUUUCACCCUG GCCTTTCACCCTG439 GUGAAAGGC 1740 CUUAUAAUC 3041 CTTATAATC Intron 45 GAUUAUAAGCAGG UGCCUUUCACCCU TGCCTTTCACCCT440 GUGAAAGGCA 1741 GCUUAUAAUC 3042 GCTTATAATC Intron 45 GAUUAUAAGCAGG GUGCCUUUCACCC GTGCCTTTCACCC441 GUGAAAGGCAC 1742 UGCUUAUAAUC 3043 TGCTTATAATC Intron 45 GUAAGUAUACUGG GAAUGGGAUCCAG GAATGGGATCCAG442 AUCCCAUUC 1743 UAUACUUAC 3044 TATACTTAC Intron 50 GUAAGUAUACUGG AGAAUGGGAUCCA AGAATGGGATCCA443 AUCCCAUUCU 1744 GUAUACUUAC 3045 GTATACTTAC Intron 50 GUAAGUAUACUGG GAGAAUGGGAUCC GAGAATGGGATCC444 AUCCCAUUCUC 1745 AGUAUACUUAC 3046 AGTATACTTAC Intron 50 GUAAGUAUACUGG AGAGAAUGGGAUC AGAGAATGGGATC445 AUCCCAUUCUCU 1746 CAGUAUACUUAC 3047 CAGTATACTTAC Intron 50 UAAGUAUACUGGA GAGAAUGGGAUCC GAGAATGGGATCC446 UCCCAUUCUC 1747 AGUAUACUUA 3048 AGTATACTTA Intron 50 AAGUAUACUGGAU GAGAAUGGGAUCC GAGAATGGGATCC447 CCCAUUCUC 1748 AGUAUACUU 3049 AGTATACTT Intron 50 AGUAUACUGGAUC GAGAAUGGGAUCC GAGAATGGGATCC448 CCAUUCUC 1749 AGUAUACU 3050 AGTATACT Intron 50 GUAUACUGGAUCC CCAAAGAGAAUGG CCAAAGAGAATGG449 CAUUCUCUUUGG 1750 GAUCCAGUAUAC 3051 GATCCAGTATAC Intron 50 UACUGGAUCCCAU GAGCCAAAGAGAA GAGCCAAAGAGAA450 UCUCUUUGGCUC 1751 UGGGAUCCAGUA 3052 TGGGATCCAGTA Intron 50 ACUGGAUCCCAUU GAGCCAAAGAGAA GAGCCAAAGAGAA451 CUCUUUGGCUC 1752 UGGGAUCCAGU 3053 TGGGATCCAGT Intron 50 UGUGGUUACUAAG AUGGCAGUUUCCU ATGGCAGTTTCCT452 GAAACUGCCAU 1753 UAGUAACCACA 3054 TAGTAACCACA Exon 51 UGUGGUUACUAAG GAUGGCAGUUUCC GATGGCAGTTTCC453 GAAACUGCCAUC 1754 UUAGUAACCACA 3055 TTAGTAACCACA Exon 51 GUGGUUACUAAGG AUGGCAGUUUCCU ATGGCAGTTTCCT454 AAACUGCCAU 1755 UAGUAACCAC 3056 TAGTAACCAC Exon 51 GUGGUUACUAAGG GAUGGCAGUUUCC GATGGCAGTTTCC455 AAACUGCCAUC 1756 UUAGUAACCAC 3057 TTAGTAACCAC Exon 51 GUGGUUACUAAGG AGAUGGCAGUUUC AGATGGCAGTTTC456 AAACUGCCAUCU 1757 CUUAGUAACCAC 3058 CTTAGTAACCAC Exon 51 UGGUUACUAAGGA GAUGGCAGUUUCC GATGGCAGTTTCC457 AACUGCCAUC 1758 UUAGUAACCA 3059 TTAGTAACCA Exon 51 GGUUACUAAGGAA GAUGGCAGUUUCC GATGGCAGTTTCC458 ACUGCCAUC 1759 UUAGUAACC 3060 TTAGTAACC Exon 51 GAAACUGCCAUCU UUCUAGUUUGGAG TTCTAGTTTGGAG459 CCAAACUAGAA 1760 AUGGCAGUUUC 3061 ATGGCAGTTTC Exon 51 AAACUGCCAUCUC CUAGUUUGGAGAU CTAGTTTGGAGAT460 CAAACUAG 1761 GGCAGUUU 3062 GGCAGTTT Exon 51 AAACUGCCAUCUC UCUAGUUUGGAGA TCTAGTTTGGAGA461 CAAACUAGA 1762 UGGCAGUUU 3063 TGGCAGTTT Exon 51 AAACUGCCAUCUC UUCUAGUUUGGAG TTCTAGTTTGGAG462 CAAACUAGAA 1763 AUGGCAGUUU 3064 ATGGCAGTTT Exon 51 AACUGCCAUCUCC CUAGUUUGGAGAU CTAGTTTGGAGAT463 AAACUAG 1764 GGCAGUU 3065 GGCAGTT Exon 51 AACUGCCAUCUCC UCUAGUUUGGAGA TCTAGTTTGGAGA464AAACUAGA 1765 UGGCAGUU 3066 TGGCAGTT Exon 51102 / 350#14837954v1AACUGCCAUCUCC UUCUAGUUUGGAG TTCTAGTTTGGAG465 AAACUAGAA 1766 AUGGCAGUU 3067 ATGGCAGTT Exon 51 ACUGCCAUCUCCA UCUAGUUUGGAGA TCTAGTTTGGAGA466 AACUAGA 1767 UGGCAGU 3068 TGGCAGT Exon 51 ACUGCCAUCUCCA UUCUAGUUUGGAG TTCTAGTTTGGAG467 AACUAGAA 1768 AUGGCAGU 3069 ATGGCAGT Exon 51 UCUCCAAACUAGA GAUGGCAUUUCUA GATGGCATTTCTA468 AAUGCCAUC 1769 GUUUGGAGA 3070 GTTTGGAGA Exon 51 CUCCAAACUAGAA GAUGGCAUUUCUA GATGGCATTTCTA469 AUGCCAUC 1770 GUUUGGAG 3071 GTTTGGAG Exon 51 UCCAAACUAGAAA GAUGGCAUUUCUA GATGGCATTTCTA470 UGCCAUC 1771 GUUUGGA 3072 GTTTGGA Exon 51 GAUUUCAACCGGG UCUGUCCAAGCCC TCTGTCCAAGCCC471 CUUGGACAGA 1772 GGUUGAAAUC 3073 GGTTGAAATC Exon 51 GAUUUCAACCGGG UUCUGUCCAAGCC TTCTGTCCAAGCC472 CUUGGACAGAA 1773 CGGUUGAAAUC 3074 CGGTTGAAATC Exon 51 AUUUCAACCGGGC UCUGUCCAAGCCC TCTGTCCAAGCCC473 UUGGACAGA 1774 GGUUGAAAU 3075 GGTTGAAAT Exon 51 AUUUCAACCGGGC AGUUCUGUCCAAG AGTTCTGTCCAAG474 UUGGACAGAACU 1775 CCCGGUUGAAAU 3076 CCCGGTTGAAAT Exon 51 UUCAACCGGGCUU AGUUCUGUCCAAG AGTTCTGTCCAAG475 GGACAGAACU 1776 CCCGGUUGAA 3077 CCCGGTTGAA Exon 51 UCAACCGGGCUUG UUCUGUCCAAGCC TTCTGTCCAAGCC476 GACAGAA 1777 CGGUUGA 3078 CGGTTGA Exon 51 UCAACCGGGCUUG AGUUCUGUCCAAG AGTTCTGTCCAAG477 GACAGAACU 1778 CCCGGUUGA 3079 CCCGGTTGA Exon 51 UCAACCGGGCUUG GUAAGUUCUGUCC GTAAGTTCTGTCC478 GACAGAACUUAC 1779 AAGCCCGGUUGA 3080 AAGCCCGGTTGA Exon 51 CAACCGGGCUUGG AGUUCUGUCCAAG AGTTCTGTCCAAG479 ACAGAACU 1780 CCCGGUUG 3081 CCCGGTTG Exon 51 CAACCGGGCUUGG GUAAGUUCUGUCC GTAAGTTCTGTCC480 ACAGAACUUAC 1781 AAGCCCGGUUG 3082 AAGCCCGGTTG Exon 51 CAACCGGGCUUGG GGUAAGUUCUGUC GGTAAGTTCTGTC481 ACAGAACUUACC 1782 CAAGCCCGGUUG 3083 CAAGCCCGGTTG Exon 51 AUGAUCAUCAAGC UACCUUCUGCUUG TACCTTCTGCTTG Exon 51 / intron 51 482 AGAAGGUA 1783 AUGAUCAU 3084 ATGATCAT junction AUGAUCAUCAAGC CAUACCUUCUGCU CATACCTTCTGCT Exon 51 / intron 51 483 AGAAGGUAUG 1784 UGAUGAUCAU 3085 TGATGATCAT junction AUGAUCAUCAAGC UCAUACCUUCUGC TCATACCTTCTGC Exon 51 / intron 51 484 AGAAGGUAUGA 1785 UUGAUGAUCAU 3086 TTGATGATCAT junction AUGAUCAUCAAGC CUCAUACCUUCUG CTCATACCTTCTG Exon 51 / intron 51 485 AGAAGGUAUGAG 1786 CUUGAUGAUCAU 3087 CTTGATGATCAT junction UGAUCAUCAAGCA UACCUUCUGCUUG TACCTTCTGCTTG Exon 51 / intron 51 486 GAAGGUA 1787 AUGAUCA 3088 ATGATCA junction UGAUCAUCAAGCA CAUACCUUCUGCU CATACCTTCTGCT Exon 51 / intron 51 487 GAAGGUAUG 1788 UGAUGAUCA 3089 TGATGATCA junction UGAUCAUCAAGCA UCAUACCUUCUGC TCATACCTTCTGC Exon 51 / intron 51 488 GAAGGUAUGA 1789 UUGAUGAUCA 3090 TTGATGATCA junction UGAUCAUCAAGCA CUCAUACCUUCUG CTCATACCTTCTG Exon 51 / intron 51 489 GAAGGUAUGAG 1790 CUUGAUGAUCA 3091 CTTGATGATCA junction UGAUCAUCAAGCA UCUCAUACCUUCU TCTCATACCTTCT Exon 51 / intron 51 490 GAAGGUAUGAGA 1791 GCUUGAUGAUCA 3092 GCTTGATGATCA junction GAUCAUCAAGCAG CAUACCUUCUGCU CATACCTTCTGCT Exon 51 / intron 51 491 AAGGUAUG 1792 UGAUGAUC 3093 TGATGATC junction GAUCAUCAAGCAG UCAUACCUUCUGC TCATACCTTCTGC Exon 51 / intron 51 492 AAGGUAUGA 1793 UUGAUGAUC 3094 TTGATGATC junction GAUCAUCAAGCAG CUCAUACCUUCUG CTCATACCTTCTG Exon 51 / intron 51 493 AAGGUAUGAG 1794 CUUGAUGAUC 3095 CTTGATGATC junction GAUCAUCAAGCAG UCUCAUACCUUCU TCTCATACCTTCT Exon 51 / intron 51 494 1795 3096AAGGUAUGAGA GCUUGAUGAUC GCTTGATGATC junction 103 / 350#14837954v1GAUCAUCAAGCAG UUCUCAUACCUUC TTCTCATACCTTC Exon 51 / intron 51 495 AAGGUAUGAGAA 1796 UGCUUGAUGAUC 3097 TGCTTGATGATC junction AUCAUCAAGCAGA CATACCTTCTGCT CAUACCUUCUGCU496 Exon 51 / intron 51AGGUAU 1797 3098 TGATGATG UGAUGAU junction AUCAUCAAGCAGA UCAUACCUUCUGC TCATACCTTCTGC Exon 51 / intron 51 497 1798 3099 AGGUAUGA TTGATGAT UUGAUGAU junction AUCAUCAAGCAGA CUCAUACCUUCUG CTCATACCTTCTG Exon 51 / intron 51 498 1799 3100 CTTGATGAT AGGUAUGAG CUUGAUGAU junction AUCAUCAAGCAGA TCTCATACCTTCT UCUCAUACCUUCU Exon 51 / intron 51 499 1800 3101 AGGUAUGAGA GCTTGATGAT GCUUGAUGAU junction AUCAUCAAGCAGA UUCUCAUACCUUC TTCTCATACCTTC Exon 51 / intron 51 500 1801 3102 AGGUAUGAGAA TGCTTGATGAT UGCUUGAUGAU junction AUCAUCAAGCAGA TTTCTCATACCTT UUUCUCAUACCUU Exon 51 / intron 51 501 1802 3103 AGGUAUGAGAAA CTGCTTGATGAT CUGCUUGAUGAU junction UCAUCAAGCAGAA UCAUACCUUCUGC TCATACCTTCTGC Exon 51 / intron 51 502 1803 3104 GGUAUGA UUGAUGA TTGATGA junction UCAUCAAGCAGAA CUCAUACCUUCUG CTCATACCTTCTG Exon 51 / intron 51 503 1804 3105 CUUGAUGA CTTGATGA GGUAUGAG junction UCAUCAAGCAGAA TCTCATACCTTCT UCUCAUACCUUCU Exon 51 / intron 51 504 1805 3106 GGUAUGAGA GCUUGAUGA GCTTGATGA junction UCAUCAAGCAGAA UUCUCAUACCUUC TTCTCATACCTTC Exon 51 / intron 51 505 1806 3107 GGUAUGAGAA UGCUUGAUGA TGCTTGATGA junction UCAUCAAGCAGAA TTTCTCATACCTT UUUCUCAUACCUU Exon 51 / intron 51 506 1807 3108 GGUAUGAGAAA CUGCUUGAUGA CTGCTTGATGA junction UCAUCAAGCAGAA TTTTCTCATACCT UUUUCUCAUACCU Exon 51 / intron 51 507 1808 3109 GGUAUGAGAAAA UCUGCUUGAUGA TCTGCTTGATGA junction CAUCAAGCAGAAG CUCAUACCUUCUG CTCATACCTTCTG Exon 51 / intron 51 508 1809 3110 GUAUGAG CUUGAUG CTTGATG junction TCTCATACCTTCT CAUCAAGCAGAAG UCUCAUACCUUCU Exon 51 / intron 51 509 1810 3111 GUAUGAGA GCUUGAUG GCTTGATG junction CAUCAAGCAGAAG UUCUCAUACCUUC TTCTCATACCTTC Exon 51 / intron 51 510 1811 3112 GUAUGAGAA UGCUUGAUG TGCTTGATG junction TTTCTCATACCTT CAUCAAGCAGAAG UUUCUCAUACCUU Exon 51 / intron 51 511 1812 3113 GUAUGAGAAA CUGCUUGAUG CTGCTTGATG junction TTTTCTCATACCT CAUCAAGCAGAAG UUUUCUCAUACCU Exon 51 / intron 51 512 1813 3114 GUAUGAGAAAA UCUGCUUGAUG TCTGCTTGATG junction CAUCAAGCAGAAG UUUUUCUCAUACC TTTTTCTCATACC Exon 51 / intron 51 513 1814 3115 GUAUGAGAAAAA UUCUGCUUGAUG TTCTGCTTGATG junction TCTCATACCTTCT AUCAAGCAGAAGG UCUCAUACCUUCU Exon 51 / intron 51 514 1815 3116 UAUGAGA GCTTGAT GCUUGAU junction AUCAAGCAGAAGG UUCUCAUACCUUC TTCTCATACCTTC Exon 51 / intron 51 515 1816 3117 UAUGAGAA TGCTTGAT UGCUUGAU junction TTTCTCATACCTT AUCAAGCAGAAGG UUUCUCAUACCUU Exon 51 / intron 51 516 1817 3118 UAUGAGAAA CTGCTTGAT CUGCUUGAU junction TTTTCTCATACCT AUCAAGCAGAAGG UUUUCUCAUACCU Exon 51 / intron 51 517 1818 3119 UAUGAGAAAA TCTGCTTGAT UCUGCUUGAU junction AUCAAGCAGAAGG UUUUUCUCAUACC TTTTTCTCATACC Exon 51 / intron 51 518 1819 3120 UAUGAGAAAAA TTCTGCTTGAT UUCUGCUUGAU junction AUCAAGCAGAAGG UUUUUUCUCAUAC TTTTTTCTCATAC Exon 51 / intron 51 519 1820 3121 UAUGAGAAAAAA CTTCTGCTTGAT CUUCUGCUUGAU junction UCAAGCAGAAGGU UUCUCAUACCUUC TTCTCATACCTTC Exon 51 / intron 51 520 1821 3122 AUGAGAA UGCUUGA TGCTTGA junction TTTCTCATACCTT UCAAGCAGAAGGU UUUCUCAUACCUU Exon 51 / intron 51 521 1822 3123 AUGAGAAA CUGCUUGA CTGCTTGA junction TTTTCTCATACCT UCAAGCAGAAGGU UUUUCUCAUACCU Exon 51 / intron 51 522 1823 3124 AUGAGAAAA UCUGCUUGA TCTGCTTGA junction UCAAGCAGAAGGU UUUUUCUCAUACC TTTTTCTCATACC Exon 51 / intron 51 523 1824 3125 AUGAGAAAAA UUCUGCUUGA TTCTGCTTGA junction104 / 350#14837954v1UCAAGCAGAAGGU UUUUUUCUCAUAC TTTTTTCTCATAC Exon 51 / intron 51 524 AUGAGAAAAAA 1825 CUUCUGCUUGA 3126 CTTCTGCTTGA junction UCAAGCAGAAGGU AUUUUUUCUCAUAATTTTTTCTCATAExon 5 525 1826 C 3127 1 / intron 51 AUGAGAAAAAAU CUUCUGCUUGA CCTTCTGCTTGA junction CAAGCAGAAGGUA TTTCTCATACCTT UUUCUCAUACCUU Exon 51 / intron 51 526 1827 3128 UGAGAAA CUGCUUG CTGCTTG junction CAAGCAGAAGGUA TTTTCTCATACCT UUUUCUCAUACCU Exon 51 / intron 51 527 1828 3129 UGAGAAAA UCUGCUUG TCTGCTTG junction CAAGCAGAAGGUA UUUUUCUCAUACC TTTTTCTCATACC Exon 51 / intron 51 528 1829 3130 UGAGAAAAA UUCUGCUUG TTCTGCTTG junction CAAGCAGAAGGUA UUUUUUCUCAUAC TTTTTTCTCATAC Exon 51 / intron 51 529 1830 3131 UGAGAAAAAA CUUCUGCUUG CTTCTGCTTG junctionATTTTTTCTCATACAAGCAGAAGGUA AUUUUUUCUCAUA Exon 51 / intron 51 530 1831 3132 UGAGAAAAAAU CCUUCUGCUUG CCTTCTGCTTG junction TTTTCTCATACCT AAGCAGAAGGUAU UUUUCUCAUACCU Exon 51 / intron 51 531 1832 3133 GAGAAAA TCTGCTT UCUGCUU junction AAGCAGAAGGUAU UUUUUCUCAUACC TTTTTCTCATACC Exon 51 / intron 51 532 1833 3134 GAGAAAAA TTCTGCTT UUCUGCUU junction AAGCAGAAGGUAU UUUUUUCUCAUAC TTTTTTCTCATAC Exon 51 / intron 51 533 1834 3135 GAGAAAAAA CTTCTGCTT CUUCUGCUU junctionATTTTTTCTCATAAUUUUUUCUCAUA AAGCAGAAGGUAU Exon 51 / intron 51 534 1835 3136 CCTTCTGCTT GAGAAAAAAU CCUUCUGCUU junction AGCAGAAGGUAUG UUUUUCUCAUACC TTTTTCTCATACC Exon 51 / intron 51 535 1836 3137 AGAAAAA TTCTGCT UUCUGCU junction AGCAGAAGGUAUG UUUUUUCUCAUAC TTTTTTCTCATAC Exon 51 / intron 51 536 1837 3138 AGAAAAAA CTTCTGCT CUUCUGCU junctionATTTTTTCTCATAAUUUUUUCUCAUA AGCAGAAGGUAUG Exon 51 / intron 51 537 1838 3139 CCTTCTGCT AGAAAAAAU CCUUCUGCU junction GCAGAAGGUAUGA UUUUUUCUCAUAC TTTTTTCTCATAC Exon 51 / intron 51 538 1839 3140 GAAAAAA CUUCUGC CTTCTGC junctionATTTTTTCTCATAGCAGAAGGUAUGA AUUUUUUCUCAUA Exon 51 / intron 51 539 1840 3141 GAAAAAAU CCUUCUGC CCTTCTGC junctionATTTTTTCTCATAAUUUUUUCUCAUA CAGAAGGUAUGAG Exon 51 / intron 51 540 1841 3142 AAAAAAU CCUUCUG CCTTCTG junction ACTTCTGCCAACT AAAUGAUAAAAGU ACUUCUGCCAACU541 1842 3143 Intron 51 TTTATCATTT UGGCAGAAGU UUUAUCAUUUAUGGUCUAGGAGA ATGGTCTAGGAGA UCACUUUACUCUC542 1843 3144 Intron 51 GUAAAGUGA GTAAAGTGA CUAGACCAUUCACUUUACUCUC AAUGGUCUAGGAG AATGGTCTAGGAG543 1844 3145 Intron 51 AGUAAAGUGA AGTAAAGTGA CUAGACCAUUAAAUGGUCUAGGA AAATGGTCTAGGA UCACUUUACUCUC544 1845 3146 Intron 51 GAGUAAAGUGA GAGTAAAGTGA CUAGACCAUUUCACUUUACUCUCC GGAAAUGGUCUAG GGAAATGGTCTAG545 1846 3147 Intron 51 UAGACCAUUUCC GAGAGUAAAGUG GAGAGTAAAGTG ACUUUACUCUCCU GGAAAUGGUCUAG GGAAATGGTCTAG546 1847 3148 Intron 51 GAGAGTAAAGT AGACCAUUUCC GAGAGUAAAGUCUUUACUCUCCUA TGGGAAATGGTCT UGGGAAAUGGUCU547 1848 3149 Intron 51 GACCAUUUCCCA AGGAGAGUAAAG AGGAGAGTAAAG UUACUCUCCUAGA TGGGAAATGGTCT UGGGAAAUGGUCU548 1849 3150 Intron 51 CCAUUUCCCA AGGAGAGUAA AGGAGAGTAA UUACUCUCCUAGA GUGGGAAAUGGUC GTGGGAAATGGTC549 1850 3151 Intron 51 UAGGAGAGUAA TAGGAGAGTAA CCAUUUCCCACUUACUCUCCUAGA GGTGGGAAATGGT GGUGGGAAAUGGU550 1851 3152 Intron 51 CUAGGAGAGUAA CTAGGAGAGTAA CCAUUUCCCACCTGGGAAATGGTCT UACUCUCCUAGAC UGGGAAAUGGUCU551 1852 3153 Intron 51 CAUUUCCCA AGGAGAGUA AGGAGAGTA UACUCUCCUAGAC GUGGGAAAUGGUC GTGGGAAATGGTC552 1853 3154 Intron 51 UAGGAGAGUA TAGGAGAGTA CAUUUCCCAC105 / 350#14837954v1UACUCUCCUAGAC GGUGGGAAAUGGU GGTGGGAAATGGT553 CAUUUCCCACC 1854 CUAGGAGAGUA 3155 CTAGGAGAGTA Intron 51 UACUCUCCUAGAC UGGUGGGAAAUGG TGGTGGGAAATGG554 CAUUUCCCACC A 1855 UCUAGGAGAGUA 3156 TCTAGGAGAGTA Intron 51 ACUCUCCUAGACC UGGGAAAUGGUCU TGGGAAATGGTCT555 AUUUCCCA 1856 AGGAGAGU 3157 AGGAGAGT Intron 51 ACUCUCCUAGACC GUGGGAAAUGGUC GTGGGAAATGGTC556 AUUUCCCAC 1857 UAGGAGAGU 3158 TAGGAGAGT Intron 51 ACUCUCCUAGACC GGUGGGAAAUGGU GGTGGGAAATGGT557 AUUUCCCACC 1858 CUAGGAGAGU 3159 CTAGGAGAGT Intron 51 ACUCUCCUAGACC UGGUGGGAAAUGG TGGTGGGAAATGG558 AUUUCCCACC A 1859 UCUAGGAGAGU 3160 TCTAGGAGAGT Intron 51 ACUCUCCUAGACC CUGGUGGGAAAUG CTGGTGGGAAATG559 AUUUCCCACC AG 1860 GUCUAGGAGAGU 3161 GTCTAGGAGAGT Intron 51 CUCUCCUAGACCA UGGGAAAUGGUCU TGGGAAATGGTCT560 UUUCCCA 1861 AGGAGAG 3162 AGGAGAG Intron 51 CUCUCCUAGACCA GUGGGAAAUGGUC GTGGGAAATGGTC561 UUUCCCAC 1862 UAGGAGAG 3163 TAGGAGAG Intron 51 CUCUCCUAGACCA GGUGGGAAAUGGU GGTGGGAAATGGT562 UUUCCCACC 1863 CUAGGAGAG 3164 CTAGGAGAG Intron 51 CUCUCCUAGACCA UGGUGGGAAAUGG TGGTGGGAAATGG563 UUUCCCACC A 1864 UCUAGGAGAG 3165 TCTAGGAGAG Intron 51 CUCUCCUAGACCA CUGGUGGGAAAUG CTGGTGGGAAATG564 UUUCCCACC AG 1865 GUCUAGGAGAG 3166 GTCTAGGAGAG Intron 51 UCUCCUAGACCAU GUGGGAAAUGGUC GTGGGAAATGGTC565 UUCCCAC 1866 UAGGAGA 3167 TAGGAGA Intron 51 UCUCCUAGACCAU GGUGGGAAAUGGU GGTGGGAAATGGT566 UUCCCACC 1867 CUAGGAGA 3168 CTAGGAGA Intron 51 UCUCCUAGACCAU UGGUGGGAAAUGG TGGTGGGAAATGG567 UUCCCACC A 1868 UCUAGGAGA 3169 TCTAGGAGA Intron 51 UCUCCUAGACCAU CUGGUGGGAAAUG CTGGTGGGAAATG568 UUCCCACC AG 1869 GUCUAGGAGA 3170 GTCTAGGAGA Intron 51 UCUCCUAGACCAU AACUGGUGGGAAA AACTGGTGGGAAA569 UUCCCACCAGUU 1870 UGGUCUAGGAGA 3171 TGGTCTAGGAGA Intron 51 CUCCUAGACCAUU GGUGGGAAAUGGU GGTGGGAAATGGT570 UCCCACC 1871 CUAGGAG 3172 CTAGGAG Intron 51 CUCCUAGACCAUU UGGUGGGAAAUGG TGGTGGGAAATGG571 UCCCACC A 1872 UCUAGGAG 3173 TCTAGGAG Intron 51 CUCCUAGACCAUU CUGGUGGGAAAUG CTGGTGGGAAATG572 UCCCACC AG 1873 GUCUAGGAG 3174 GTCTAGGAG Intron 51 CUCCUAGACCAUU AACUGGUGGGAAA AACTGGTGGGAAA573 UCCCACCAGUU 1874 UGGUCUAGGAG 3175 TGGTCTAGGAG Intron 51 UCCUAGACCAUUU UGGUGGGAAAUGG TGGTGGGAAATGG574 CCCACCA 1875 UCUAGGA 3176 TCTAGGA Intron 51 UCCUAGACCAUUU CUGGUGGGAAAUG CTGGTGGGAAATG575 CCCACCAG 1876 GUCUAGGA 3177 GTCTAGGA Intron 51 UCCUAGACCAUUU AACUGGUGGGAAA AACTGGTGGGAAA576 CCCACCAGUU 1877 UGGUCUAGGA 3178 TGGTCTAGGA Intron 51 UCCUAGACCAUUU AGAACUGGUGGGA AGAACTGGTGGGA577 CCCACCAGUUCU 1878 AAUGGUCUAGGA 3179 AATGGTCTAGGA Intron 51 CCUAGACCAUUUC CUGGUGGGAAAUG CTGGTGGGAAATG578 CCACCAG 1879 GUCUAGG 3180 GTCTAGG Intron 51 CCUAGACCAUUUC AACUGGUGGGAAA AACTGGTGGGAAA579 CCACCAGUU 1880 UGGUCUAGG 3181 TGGTCTAGG Intron 51 CCUAGACCAUUUC AGAACUGGUGGGA AGAACTGGTGGGA580 CCACCAGUUCU 1881 AAUGGUCUAGG 3182 AATGGTCTAGG Intron 51 CCUAGACCAUUUC AAGAACUGGUGGG AAGAACTGGTGGG581 CCACCAGUUCUU 1882 AAAUGGUCUAGG 3183 AAATGGTCTAGG Intron 51 CUAGACCAUUUCC AACUGGUGGGAAA AACTGGTGGGAAA582 1883 3184 Intron 51CACCAGUU UGGUCUAG TGGTCTAG 106 / 350#14837954v1CUAGACCAUUUCC AGAACUGGUGGGA AGAACTGGTGGGA583 CACCAGUUCU 1884 AAUGGUCUAG 3185 AATGGTCTAG Intron 51 CUAGACCAUUUCC AAGAACUGGUGGG AAGAACTGGTGGG584 CACCAGUUCUU 1885 AAAUGGUCUAG 3186 AAATGGTCTAG Intron 51 UAGACCAUUUCCC AACUGGUGGGAAA AACTGGTGGGAAA585 ACCAGUU 1886 UGGUCUA 3187 TGGTCTA Intron 51 UAGACCAUUUCCC AGAACUGGUGGGA AGAACTGGTGGGA586 ACCAGUUCU 1887 AAUGGUCUA 3188 AATGGTCTA Intron 51 UAGACCAUUUCCC AAGAACUGGUGGG AAGAACTGGTGGG587 ACCAGUUCUU 1888 AAAUGGUCUA 3189 AAATGGTCTA Intron 51 UAGACCAUUUCCC CUAAGAACUGGUG CTAAGAACTGGTG588 ACCAGUUCUUAG 1889 GGAAAUGGUCUA 3190 GGAAATGGTCTA Intron 51 AGACCAUUUCCCA AGAACUGGUGGGA AGAACTGGTGGGA589 CCAGUUCU 1890 AAUGGUCU 3191 AATGGTCT Intron 51 AGACCAUUUCCCA AAGAACUGGUGGG AAGAACTGGTGGG590 CCAGUUCUU 1891 AAAUGGUCU 3192 AAATGGTCT Intron 51 AGACCAUUUCCCA CUAAGAACUGGUG CTAAGAACTGGTG591 CCAGUUCUUAG 1892 GGAAAUGGUCU 3193 GGAAATGGTCT Intron 51 AGACCAUUUCCCA CCUAAGAACUGGU CCTAAGAACTGGT592 CCAGUUCUUAGG 1893 GGGAAAUGGUCU 3194 GGGAAATGGTCT Intron 51 GACCAUUUCCCAC AGAACUGGUGGGA AGAACTGGTGGGA593 CAGUUCU 1894 AAUGGUC 3195 AATGGTC Intron 51 GACCAUUUCCCAC AAGAACUGGUGGG AAGAACTGGTGGG594 CAGUUCUU 1895 AAAUGGUC 3196 AAATGGTC Intron 51 GACCAUUUCCCAC CUAAGAACUGGUG CTAAGAACTGGTG595 CAGUUCUUAG 1896 GGAAAUGGUC 3197 GGAAATGGTC Intron 51 GACCAUUUCCCAC CCUAAGAACUGGU CCTAAGAACTGGT596 CAGUUCUUAGG 1897 GGGAAAUGGUC 3198 GGGAAATGGTC Intron 51 GACCAUUUCCCAC GCCUAAGAACUGG GCCTAAGAACTGG597 CAGUUCUUAGGC 1898 UGGGAAAUGGUC 3199 TGGGAAATGGTC Intron 51 ACCAUUUCCCACC GCCUAAGAACUGG GCCTAAGAACTGG598 AGUUCUUAGGC 1899 UGGGAAAUGGU 3200 TGGGAAATGGT Intron 51 ACCAUUUCCCACC UGCCUAAGAACUG TGCCTAAGAACTG599 AGUUCUUAGGCA 1900 GUGGGAAAUGGU 3201 GTGGGAAATGGT Intron 51 CCAUUUCCCACCA GCCUAAGAACUGG GCCTAAGAACTGG600 GUUCUUAGGC 1901 UGGGAAAUGG 3202 TGGGAAATGG Intron 51 CCAUUUCCCACCA UGCCUAAGAACUG TGCCTAAGAACTG601 GUUCUUAGGCA 1902 GUGGGAAAUGG 3203 GTGGGAAATGG Intron 51 CCAUUUCCCACCA UUGCCUAAGAACU TTGCCTAAGAACT602 GUUCUUAGGCAA 1903 GGUGGGAAAUGG 3204 GGTGGGAAATGG Intron 51 CAUUUCCCACCAG UGCCUAAGAACUG TGCCTAAGAACTG603 UUCUUAGGCA 1904 GUGGGAAAUG 3205 GTGGGAAATG Intron 51 CAUUUCCCACCAG UUGCCUAAGAACU TTGCCTAAGAACT604 UUCUUAGGCAA 1905 GGUGGGAAAUG 3206 GGTGGGAAATG Intron 51 AGUGUUUUGGCUG GUGAGACCAGCCA GTGAGACCAGCCA605 GUCUCAC 1906 AAACACU 3207 AAACACT Intron 51 AGUGUUUUGGCUG UGUGAGACCAGCC TGTGAGACCAGCC606 GUCUCACA 1907 AAAACACU 3208 AAAACACT Intron 51 AGUGUUUUGGCUG UUGUGAGACCAGC TTGTGAGACCAGC607 GUCUCACAA 1908 CAAAACACU 3209 CAAAACACT Intron 51 AGUGUUUUGGCUG AUUGUGAGACCAG ATTGTGAGACCAG608 GUCUCACAAU 1909 CCAAAACACU 3210 CCAAAACACT Intron 51 GUGUUUUGGCUGG AUUGUGAGACCAG ATTGTGAGACCAG609 UCUCACAAU 1910 CCAAAACAC 3211 CCAAAACAC Intron 51 GUUUUGGCUGGUC GUACAAUUGUGAG GTACAATTGTGAG610 UCACAAUUGUAC 1911 ACCAGCCAAAAC 3212 ACCAGCCAAAAC Intron 51 UUUGGCUGGUCUC GUACAAUUGUGAG GTACAATTGTGAG611 ACAAUUGUAC 1912 ACCAGCCAAA 3213 ACCAGCCAAA Intron 51 UUGGCUGGUCUCA GUACAAUUGUGAG GTACAATTGTGAG612 1913 3214 Intron 51CAAUUGUAC ACCAGCCAA ACCAGCCAA 107 / 350#14837954v1UUGGCUGGUCUCA AGUACAAUUGUGA AGTACAATTGTGA613 CAAUUGUACU 1914 GACCAGCCAA 3215 GACCAGCCAA Intron 51 UGGCUGGUCUCAC GUACAAUUGUGAG GTACAATTGTGAG614 AAUUGUAC 1915 ACCAGCCA 3216 ACCAGCCA Intron 51 UGGCUGGUCUCAC AGUACAAUUGUGA AGTACAATTGTGA615 AAUUGUACU 1916 GACCAGCCA 3217 GACCAGCCA Intron 51 UGGCUGGUCUCAC AAGUACAAUUGUG AAGTACAATTGTG616 AAUUGUACUU 1917 AGACCAGCCA 3218 AGACCAGCCA Intron 51 UGGCUGGUCUCAC AAAGUACAAUUGU AAAGTACAATTGT617 AAUUGUACUUU 1918 GAGACCAGCCA 3219 GAGACCAGCCA Intron 51 GGCUGGUCUCACA GUACAAUUGUGAG GTACAATTGTGAG618 AUUGUAC 1919 ACCAGCC 3220 ACCAGCC Intron 51 GGCUGGUCUCACA AGUACAAUUGUGA AGTACAATTGTGA619 AUUGUACU 1920 GACCAGCC 3221 GACCAGCC Intron 51 GGCUGGUCUCACA AAGUACAAUUGUG AAGTACAATTGTG620 AUUGUACUU 1921 AGACCAGCC 3222 AGACCAGCC Intron 51 GGCUGGUCUCACA AAAGUACAAUUGU AAAGTACAATTGT621 AUUGUACUUU 1922 GAGACCAGCC 3223 GAGACCAGCC Intron 51 GGCUGGUCUCACA GUAAAGUACAAUU GTAAAGTACAATT622 AUUGUACUUUAC 1923 GUGAGACCAGCC 3224 GTGAGACCAGCC Intron 51 GCUGGUCUCACAA GUAAAGUACAAUU GTAAAGTACAATT623 UUGUACUUUAC 1924 GUGAGACCAGC 3225 GTGAGACCAGC Intron 51 GCUGGUCUCACAA AGUAAAGUACAAU AGTAAAGTACAAT624 UUGUACUUUACU 1925 UGUGAGACCAGC 3226 TGTGAGACCAGC Intron 51 UGUAAAAGGAAUA UCAGCGUUGUGUA TCAGCGTTGTGTA625 CACAACGCUGA 1926 UUCCUUUUACA 3227 TTCCTTTTACA Intron 51 UGUAAAAGGAAUA UUCAGCGUUGUGU TTCAGCGTTGTGT626 CACAACGCUGAA 1927 AUUCCUUUUACA 3228 ATTCCTTTTACA Intron 51 GUAAAAGGAAUAC UCAGCGUUGUGUA TCAGCGTTGTGTA627 ACAACGCUGA 1928 UUCCUUUUAC 3229 TTCCTTTTAC Intron 51 GUAAAAGGAAUAC UUCAGCGUUGUGU TTCAGCGTTGTGT628 ACAACGCUGAA 1929 AUUCCUUUUAC 3230 ATTCCTTTTAC Intron 51 GUAAAAGGAAUAC CUUCAGCGUUGUG CTTCAGCGTTGTG629 ACAACGCUGAAG 1930 UAUUCCUUUUAC 3231 TATTCCTTTTAC Intron 51 UAAAAGGAAUACA UCAGCGUUGUGUA TCAGCGTTGTGTA630 CAACGCUGA 1931 UUCCUUUUA 3232 TTCCTTTTA Intron 51 UAAAAGGAAUACA UUCAGCGUUGUGU TTCAGCGTTGTGT631 CAACGCUGAA 1932 AUUCCUUUUA 3233 ATTCCTTTTA Intron 51 UAAAAGGAAUACA CUUCAGCGUUGUG CTTCAGCGTTGTG632 CAACGCUGAAG 1933 UAUUCCUUUUA 3234 TATTCCTTTTA Intron 51 UAAAAGGAAUACA UCUUCAGCGUUGU TCTTCAGCGTTGT633 CAACGCUGAAGA 1934 GUAUUCCUUUUA 3235 GTATTCCTTTTA Intron 51 AAAAGGAAUACAC UCAGCGUUGUGUA TCAGCGTTGTGTA634 AACGCUGA 1935 UUCCUUUU 3236 TTCCTTTT Intron 51 AAAAGGAAUACAC UUCAGCGUUGUGU TTCAGCGTTGTGT635 AACGCUGAA 1936 AUUCCUUUU 3237 ATTCCTTTT Intron 51 AAAAGGAAUACAC CUUCAGCGUUGUG CTTCAGCGTTGTG636 AACGCUGAAG 1937 UAUUCCUUUU 3238 TATTCCTTTT Intron 51 AAAAGGAAUACAC UCUUCAGCGUUGU TCTTCAGCGTTGT637 AACGCUGAAGA 1938 GUAUUCCUUUU 3239 GTATTCCTTTT Intron 51 AAAAGGAAUACAC UUCUUCAGCGUUG TTCTTCAGCGTTG638 AACGCUGAAGAA 1939 UGUAUUCCUUUU 3240 TGTATTCCTTTT Intron 51 AAAGGAAUACACA UCAGCGUUGUGUA TCAGCGTTGTGTA639 ACGCUGA 1940 UUCCUUU 3241 TTCCTTT Intron 51 AAAGGAAUACACA UUCAGCGUUGUGU TTCAGCGTTGTGT640 ACGCUGAA 1941 AUUCCUUU 3242 ATTCCTTT Intron 51 AAAGGAAUACACA CUUCAGCGUUGUG CTTCAGCGTTGTG641 ACGCUGAAG 1942 UAUUCCUUU 3243 TATTCCTTT Intron 51 AAAGGAAUACACA UCUUCAGCGUUGU TCTTCAGCGTTGT642 1943 3244 Intron 51ACGCUGAAGA GUAUUCCUUU GTATTCCTTT 108 / 350#14837954v1AAAGGAAUACACA UUCUUCAGCGUUG TTCTTCAGCGTTG643 ACGCUGAAGAA 1944 UGUAUUCCUUU 3245 TGTATTCCTTT Intron 51 AAAGGAAUACACA GUUCUUCAGCGUU GTTCTTCAGCGTT644 ACGCUGAAGAAC 1945 GUGUAUUCCUUU 3246 GTGTATTCCTTT Intron 51 AAGGAAUACACAA UUCAGCGUUGUGU TTCAGCGTTGTGT645 CGCUGAA 1946 AUUCCUU 3247 ATTCCTT Intron 51 AAGGAAUACACAA CUUCAGCGUUGUG CTTCAGCGTTGTG646 CGCUGAAG 1947 UAUUCCUU 3248 TATTCCTT Intron 51 AAGGAAUACACAA UCUUCAGCGUUGU TCTTCAGCGTTGT647 CGCUGAAGA 1948 GUAUUCCUU 3249 GTATTCCTT Intron 51 AAGGAAUACACAA UUCUUCAGCGUUG TTCTTCAGCGTTG648 CGCUGAAGAA 1949 UGUAUUCCUU 3250 TGTATTCCTT Intron 51 AAGGAAUACACAA GUUCUUCAGCGUU GTTCTTCAGCGTT649 CGCUGAAGAAC 1950 GUGUAUUCCUU 3251 GTGTATTCCTT Intron 51 AGGAAUACACAAC CUUCAGCGUUGUG CTTCAGCGTTGTG650 GCUGAAG 1951 UAUUCCU 3252 TATTCCT Intron 51 AGGAAUACACAAC UCUUCAGCGUUGU TCTTCAGCGTTGT651 GCUGAAGA 1952 GUAUUCCU 3253 GTATTCCT Intron 51 AGGAAUACACAAC UUCUUCAGCGUUG TTCTTCAGCGTTG652 GCUGAAGAA 1953 UGUAUUCCU 3254 TGTATTCCT Intron 51 AGGAAUACACAAC GUUCUUCAGCGUU GTTCTTCAGCGTT653 GCUGAAGAAC 1954 GUGUAUUCCU 3255 GTGTATTCCT Intron 51 GGAAUACACAACG UCUUCAGCGUUGU TCTTCAGCGTTGT654 CUGAAGA 1955 GUAUUCC 3256 GTATTCC Intron 51 GGAAUACACAACG UUCUUCAGCGUUG TTCTTCAGCGTTG655 CUGAAGAA 1956 UGUAUUCC 3257 TGTATTCC Intron 51 GGAAUACACAACG GUUCUUCAGCGUU GTTCTTCAGCGTT656 CUGAAGAAC 1957 GUGUAUUCC 3258 GTGTATTCC Intron 51 GGAAUACACAACG GGGUUCUUCAGCG GGGTTCTTCAGCG657 CUGAAGAAC CC 1958 UUGUGUAUUCC 3259 TTGTGTATTCC Intron 51 GGAAUACACAACG AGGGUUCUUCAGC AGGGTTCTTCAGC658 CUGAAGAAC CCU 1959 GUUGUGUAUUCC 3260 GTTGTGTATTCC Intron 51 GAAUACACAACGC GUUCUUCAGCGUU GTTCTTCAGCGTT659 UGAAGAAC 1960 GUGUAUUC 3261 GTGTATTC Intron 51 GAAUACACAACGC GGGUUCUUCAGCG GGGTTCTTCAGCG660 UGAAGAAC CC 1961 UUGUGUAUUC 3262 TTGTGTATTC Intron 51 GAAUACACAACGC AGGGUUCUUCAGC AGGGTTCTTCAGC661 UGAAGAACCCU 1962 GUUGUGUAUUC 3263 GTTGTGTATTC Intron 51 AAUACACAACGCU GGGUUCUUCAGCG GGGTTCTTCAGCG662 GAAGAACCC 1963 UUGUGUAUU 3264 TTGTGTATT Intron 51 AUACACAACGCUG GGGUUCUUCAGCG GGGTTCTTCAGCG663 AAGAACCC 1964 UUGUGUAU 3265 TTGTGTAT Intron 51 UACACAACGCUGA GGGUUCUUCAGCG GGGTTCTTCAGCG664 AGAACCC 1965 UUGUGUA 3266 TTGTGTA Intron 51 ACACAACGCUGAA AUCAGGGUUCUUC ATCAGGGTTCTTC665 GAACCCUGAU 1966 AGCGUUGUGU 3267 AGCGTTGTGT Intron 51 GAGUCAUGGAAGG AUAGGGACCCUCC ATAGGGACCCTCC666 AGGGUCCCUAU 1967 UUCCAUGACUC 3268 TTCCATGACTC Exon 53 GGAGGGUCCCUAU CAUCUACUGUAUA CATCTACTGTATA667 ACAGUAGAUG 1968 GGGACCCUCC 3269 GGGACCCTCC Exon 53 AGGAGGGUCCCUA CAUCUACUGUAUA CATCTACTGTATA668 UACAGUAGAUG 1969 GGGACCCUCCU 3270 GGGACCCTCCT Exon 53 GCUUGAGUCAUGG CCCUCCUUCCAUG CCCTCCTTCCATG669 AAGGAGGG 1970 ACUCAAGC 3271 ACTCAAGC Exon 53 AGCUUGAGUCAUG CCCUCCUUCCAUG CCCTCCTTCCATG670 GAAGGAGGG 1971 ACUCAAGCU 3272 ACTCAAGCT Exon 53 GCUUGAGUCAUGG CCUCCUUCCAUGA CCTCCTTCCATGA671 AAGGAGG 1972 CUCAAGC 3273 CTCAAGC Exon 53 AGCUUGAGUCAUG CCUCCUUCCAUGA CCTCCTTCCATGA672 1973 3274 Exon 53GAAGGAGG CUCAAGCU CTCAAGCT 109 / 350#14837954v1CAACACAAUGGCU CCUUAGCUUCCAG CCTTAGCTTCCAG673 GGAAGCUAAGG 1974 CCAUUGUGUUG 3275 CCATTGTGTTG Exon 53 UCAACACAAUGGC CCUUAGCUUCCAG CCTTAGCTTCCAG674 UGGAAGCUAAGG 1975 CCAUUGUGUUG A 3276 CCATTGTGTTGA Exon 53 AGCUUGAGUCAUG CUCCUUCCAUGAC CTCCTTCCATGAC675 GAAGGAG 1976 UCAAGCU 3277 TCAAGCT Exon 53 AUCAGUGGGAUGA CUUGUACUUCAUC CTTGTACTTCATC676 AGUACAAG 1977 CCACUGAU 3278 CCACTGAT Exon 53 GAAUCAGUGGGAU CUUGUACUUCAUC CTTGTACTTCATC677 GAAGUACAAG 1978 CCACUGAUUC 3279 CCACTGATTC Exon 53 UGAGUCAUGGAAG GACCCUCCUUCCA GACCCTCCTTCCA678 GAGGGUC 1979 UGACUCA 3280 TGACTCA Exon 53 UUGAGUCAUGGAA GACCCUCCUUCCA GACCCTCCTTCCA679 GGAGGGUC 1980 UGACUCAA 3281 TGACTCAA Exon 53 CUUGAGUCAUGGA GACCCUCCUUCCA GACCCTCCTTCCA680 AGGAGGGUC 1981 UGACUCAAG 3282 TGACTCAAG Exon 53 GCUUGAGUCAUGG GACCCUCCUUCCA GACCCTCCTTCCA681 AAGGAGGGUC 1982 UGACUCAAGC 3283 TGACTCAAGC Exon 53 GGGUCCCUAUACA GAUUGCAUCUACU GATTGCATCTACT682 GUAGAUGCAAUC 1983 GUAUAGGGACCC 3284 GTATAGGGACCC Exon 53 GGAGGGUCCCUAU GCAUCUACUGUAU GCATCTACTGTAT683 ACAGUAGAUGC 1984 AGGGACCCUCC 3285 AGGGACCCTCC Exon 53 AAGCAUGGGACAC GCUUUGUGUGUCC GCTTTGTGTGTCC684 ACAAAGC 1985 CAUGCUU 3286 CATGCTT Intron 52 CAAGCAUGGGACA GCUUUGUGUGUCC GCTTTGTGTGTCC685 CACAAAGC 1986 CAUGCUUG 3287 CATGCTTG Intron 52 ACAAGCAUGGGAC GCUUUGUGUGUCC GCTTTGTGTGTCC686 ACACAAAGC 1987 CAUGCUUGU 3288 CATGCTTGT Intron 52 AACAAGCAUGGGA GCUUUGUGUGUCC GCTTTGTGTGTCC687 CACACAAAGC 1988 CAUGCUUGUU 3289 CATGCTTGTT Intron 52 UAACAAGCAUGGG GCUUUGUGUGUCC GCTTTGTGTGTCC688 ACACACAAAGC 1989 CAUGCUUGUUA 3290 CATGCTTGTTA Intron 52 GAGUCAUGGAAGG GGACCCUCCUUCC GGACCCTCCTTCC689 AGGGUCC 1990 AUGACUC 3291 ATGACTC Exon 53 GGUCCCUAUACAG GGAUUGCAUCUAC GGATTGCATCTAC690 UAGAUGCAAUCC 1991 UGUAUAGGGACC 3292 TGTATAGGGACC Exon 53 UGAGUCAUGGAAG GGGACCCUCCUUC GGGACCCTCCTTC691 GAGGGUC CC 1992 CAUGACUCA 3293 CATGACTCA Exon 53 AAGUUUGUCCUGA GUAACCCACCUUU GTAACCCACCTTT692 AAGGUGGGUUAC 1993 CAGGACAAACUU 3294 CAGGACAAACTT Intron 53 GAAUCAGUGGGAU GUACUUCAUCCCA GTACTTCATCCCA693 GAAGUAC 1994 CUGAUUC 3295 CTGATTC Exon 53 GUUCAUCAUCCUA GUGUUAUGGCUAG GTGTTATGGCTAG694 GCCAUAACAC 1995 GAUGAUGAAC 3296 GATGATGAAC Intron 52 CAGUGGGAUGAAG UCUUGUACUUCAU TCTTGTACTTCAT695 UACAAGA 1996 CCCACUG 3297 CCCACTG Exon 53 UCAGUGGGAUGAA UCUUGUACUUCAU TCTTGTACTTCAT696 GUACAAGA 1997 CCCACUGA 3298 CCCACTGA Exon 53 AUCAGUGGGAUGA UCUUGUACUUCAU TCTTGTACTTCAT697 AGUACAAGA 1998 CCCACUGAU 3299 CCCACTGAT Exon 53 AAUCAGUGGGAUG UCUUGUACUUCAU TCTTGTACTTCAT698 AAGUACAAGA 1999 CCCACUGAUU 3300 CCCACTGATT Exon 53 GAAUCAGUGGGAU UCUUGUACUUCAU TCTTGTACTTCAT699 GAAGUACAAGA 2000 CCCACUGAUUC 3301 CCCACTGATTC Exon 53 AGAACACCUUCAG UGCCUCCGGUUCU TGCCTCCGGTTCT700 AACCGGAGGCA 2001 GAAGGUGUUCU 3302 GAAGGTGTTCT Exon 53 AAGAACACCUUCA UGCCUCCGGUUCU TGCCTCCGGTTCT701 GAACCGGAGGCA 2002 GAAGGUGUUCUU 3303 GAAGGTGTTCTT Exon 53 AGCAUGGGACACA UGCUUUGUGUGUC TGCTTTGTGTGTC702 2003 3304 Intron 52CAAAGCA CCAUGCU CCATGCT110 / 350#14837954v1AAGCAUGGGACAC UGCUUUGUGUGUC TGCTTTGTGTGTC703 ACAAAGCA 2004 CCAUGCUU 3305 CCATGCTT Intron 52 CAAGCAUGGGACA UGCUUUGUGUGUC TGCTTTGTGTGTC704 CACAAAGCA 2005 CCAUGCUUG 3306 CCATGCTTG Intron 52 ACAAGCAUGGGAC UGCUUUGUGUGUC TGCTTTGTGTGTC705 ACACAAAGCA 2006 CCAUGCUUGU 3307 CCATGCTTGT Intron 52 AACAAGCAUGGGA UGCUUUGUGUGUC TGCTTTGTGTGTC706 CACACAAAGCA 2007 CCAUGCUUGUU 3308 CCATGCTTGTT Intron 52 UAACAAGCAUGGG UGCUUUGUGUGUC TGCTTTGTGTGTC707 ACACACAAAGCA 2008 CCAUGCUUGUUA 3309 CCATGCTTGTTA Intron 52 GAAUCAGUGGGAU UGUACUUCAUCCC TGTACTTCATCCC708 GAAGUACA 2009 ACUGAUUC 3310 ACTGATTC Exon 53 UAACAAGCAUGGG UGUGUGUCCCAUG TGTGTGTCCCATG709 ACACACA 2010 CUUGUUA 3311 CTTGTTA Intron 52 GUUCAUCAUCCUA UGUGUUAUGGCUA TGTGTTATGGCTA710 GCCAUAACACA 2011 GGAUGAUGAAC 3312 GGATGATGAAC Intron 52 AGUGGGAUGAAGU UGUUCUUGUACUU TGTTCTTGTACTT711 ACAAGAACA 2012 CAUCCCACU 3313 CATCCCACT Exon 53 CAGUGGGAUGAAG UGUUCUUGUACUU TGTTCTTGTACTT712 UACAAGAACA 2013 CAUCCCACUG 3314 CATCCCACTG Exon 53 UCAGUGGGAUGAA UGUUCUUGUACUU TGTTCTTGTACTT713 GUACAAGAACA 2014 CAUCCCACUGA 3315 CATCCCACTGA Exon 53 AUCAGUGGGAUGA UGUUCUUGUACUU TGTTCTTGTACTT714 AGUACAAGAACA 2015 CAUCCCACUGAU 3316 CATCCCACTGAT Exon 53 CAGUGGGAUGAAG UUCUUGUACUUCA TTCTTGTACTTCA715 UACAAGAA 2016 UCCCACUG 3317 TCCCACTG Exon 53 UCAGUGGGAUGAA UUCUUGUACUUCA TTCTTGTACTTCA716 GUACAAGAA 2017 UCCCACUGA 3318 TCCCACTGA Exon 53 AUCAGUGGGAUGA UUCUUGUACUUCA TTCTTGTACTTCA717 AGUACAAGAA 2018 UCCCACUGAU 3319 TCCCACTGAT Exon 53 AAUCAGUGGGAUG UUCUUGUACUUCA TTCTTGTACTTCA718 AAGUACAAGAA 2019 UCCCACUGAUU 3320 TCCCACTGATT Exon 53 GAAUCAGUGGGAU UUCUUGUACUUCA TTCTTGTACTTCA719 GAAGUACAAGAA 2020 UCCCACUGAUUC 3321 TCCCACTGATTC Exon 53 GAAUCAGUGGGAU UUGUACUUCAUCC TTGTACTTCATCC720 GAAGUACAA 2021 CACUGAUUC 3322 CACTGATTC Exon 53 UAACAAGCAUGGG UUGUGUGUCCCAU TTGTGTGTCCCAT721 ACACACAA 2022 GCUUGUUA 3323 GCTTGTTA Intron 52 GUUCAUCAUCCUA UUGUGUUAUGGCU TTGTGTTATGGCT722 GCCAUAACACAA 2023 AGGAUGAUGAAC 3324 AGGATGATGAAC Intron 52 ACAAGCAUGGGAC UUUGUGUGUCCCA TTTGTGTGTCCCA723 ACACAAA 2024 UGCUUGU 3325 TGCTTGT Intron 52 AACAAGCAUGGGA UUUGUGUGUCCCA TTTGTGTGTCCCA724 CACACAAA 2025 UGCUUGUU 3326 TGCTTGTT Intron 52 UAACAAGCAUGGG UUUGUGUGUCCCA TTTGTGTGTCCCA725 ACACACAAA 2026 UGCUUGUUA 3327 TGCTTGTTA Intron 52 AUGUCUCCUCCAG AAAUGCUAGUCUG AAATGCTAGTCTG726 ACUAGCAUUU 2027 GAGGAGACAU 3328 GAGGAGACAT Intron 52 AAUGUCUCCUCCA AAAUGCUAGUCUG AAATGCTAGTCTG727 GACUAGCAUUU 2028 GAGGAGACAUU 3329 GAGGAGACATT Intron 52 AAAUGUCUCCUCC AAAUGCUAGUCUG AAATGCTAGTCTG728 AGACUAGCAUUU 2029 GAGGAGACAUUU 3330 GAGGAGACATTT Intron 52 AAAGUUUGUCCUG AACCCACCUUUCA AACCCACCTTTCA729 AAAGGUGGGUU 2030 GGACAAACUUU 3331 GGACAAACTTT Intron 53 CCUUCAGAACCGG AACUGUUGCCUCC AACTGTTGCCTCC730 AGGCAACAGUU 2031 GGUUCUGAAGG 3332 GGTTCTGAAGG Exon 53 GAGUCAUGGAAGG AGGGACCCUCCUU AGGGACCCTCCTT731 AGGGUCCCU 2032 CCAUGACUC 3333 CCATGACTC Exon 53 AGUCAUGGAAGGA AUAGGGACCCUCC ATAGGGACCCTCC732GGGUCCCUAU 2033 UUCCAUGACU 3334 TTCCATGACT Exon 53111 / 350#14837954v1GGAGGGUCCCUAU AUCUACUGUAUAG ATCTACTGTATAG733 ACAGUAGAU 2034 GGACCCUCC 3335 GGACCCTCC Exon 53 AGGAGGGUCCCUA AUCUACUGUAUAG ATCTACTGTATAG734 UACAGUAGAU 2035 GGACCCUCCU 3336 GGACCCTCCT Exon 53 ACCAAGGUUAGUA AUCUUUGAUACUA ATCTTTGATACTA Exon 53 / intron 53 735 UCAAAGAU 2036 ACCUUGGU 3337 ACCTTGGT junction AACCAAGGUUAGU AUCUUUGAUACUA ATCTTTGATACTA Exon 53 / intron 53 736 AUCAAAGAU 2037 ACCUUGGUU 3338 ACCTTGGTT junction UCAUCAUCCUAGC AUUGUGUUAUGGC ATTGTGTTATGGC737 CAUAACACAAU 2038 UAGGAUGAUGA 3339 TAGGATGATGA Intron 52 CCUUCAGAACCGG CAACUGUUGCCUC CAACTGTTGCCTC738 AGGCAACAGUUG 2039 CGGUUCUGAAGG 3340 CGGTTCTGAAGG Exon 53 AGAACACCUUCAG CCUCCGGUUCUGA CCTCCGGTTCTGA739 AACCGGAGG 2040 AGGUGUUCU 3341 AGGTGTTCT Exon 53 AAGAACACCUUCA CCUCCGGUUCUGA CCTCCGGTTCTGA740 GAACCGGAGG 2041 AGGUGUUCUU 3342 AGGTGTTCTT Exon 53 CAAGAACACCUUC CCUCCGGUUCUGA CCTCCGGTTCTGA741 AGAACCGGAGG 2042 AGGUGUUCUUG 3343 AGGTGTTCTTG Exon 53 ACACAAUGGCUGG CCUUAGCUUCCAG CCTTAGCTTCCAG742 AAGCUAAGG 2043 CCAUUGUGU 3344 CCATTGTGT Exon 53 AACACAAUGGCUG CCUUAGCUUCCAG CCTTAGCTTCCAG743 GAAGCUAAGG 2044 CCAUUGUGUU 3345 CCATTGTGTT Exon 53 CAAGAACACCUUC CUCCGGUUCUGAA CTCCGGTTCTGAA744 AGAACCGGAG 2045 GGUGUUCUUG 3346 GGTGTTCTTG Exon 53 UACAAGAACACCU CUCCGGUUCUGAA CTCCGGTTCTGAA745 UCAGAACCGGAG 2046 GGUGUUCUUGUA 3347 GGTGTTCTTGTA Exon 53 CAACACAAUGGCU CUUAGCUUCCAGC CTTAGCTTCCAGC746 GGAAGCUAAG 2047 CAUUGUGUUG 3348 CATTGTGTTG Exon 53 UCAACACAAUGGC CUUAGCUUCCAGC CTTAGCTTCCAGC747 UGGAAGCUAAG 2048 CAUUGUGUUGA 3349 CATTGTGTTGA Exon 53 UCAGUGGGAUGAA CUUGUACUUCAUC CTTGTACTTCATC748 GUACAAG 2049 CCACUGA 3350 CCACTGA Exon 53 AAUCAGUGGGAUG CUUGUACUUCAUC CTTGTACTTCATC749 AAGUACAAG 2050 CCACUGAUU 3351 CCACTGATT Exon 53 AUACAGUAGAUGC CUUUUGGAUUGCA CTTTTGGATTGCA750 AAUCCAAAAG 2051 UCUACUGUAU 3352 TCTACTGTAT Exon 53 GGUCCCUAUACAG GAUUGCAUCUACU GATTGCATCTACT751 UAGAUGCAAUC 2052 GUAUAGGGACC 3353 GTATAGGGACC Exon 53 GAGGGUCCCUAUA GCAUCUACUGUAU GCATCTACTGTAT752 CAGUAGAUGC 2053 AGGGACCCUC 3354 AGGGACCCTC Exon 53 AAUGUCUCCUCCA GCUAGUCUGGAGG GCTAGTCTGGAGG753 GACUAGC 2054 AGACAUU 3355 AGACATT Intron 52 AAAUGUCUCCUCC GCUAGUCUGGAGG GCTAGTCTGGAGG754 AGACUAGC 2055 AGACAUUU 3356 AGACATTT Intron 52 AAAAUGUCUCCUC GCUAGUCUGGAGG GCTAGTCTGGAGG755 CAGACUAGC 2056 AGACAUUUU 3357 AGACATTTT Intron 52 UAAAAUGUCUCCU GCUAGUCUGGAGG GCTAGTCTGGAGG756 CCAGACUAGC 2057 AGACAUUUUA 3358 AGACATTTTA Intron 52 UGAGUCAUGGAAG GGACCCUCCUUCC GGACCCTCCTTCC757 GAGGGUCC 2058 AUGACUCA 3359 ATGACTCA Exon 53 UUGAGUCAUGGAA GGACCCUCCUUCC GGACCCTCCTTCC758 GGAGGGUCC 2059 AUGACUCAA 3360 ATGACTCAA Exon 53 GUCCCUAUACAGU GGAUUGCAUCUAC GGATTGCATCTAC759 AGAUGCAAUCC 2060 UGUAUAGGGAC 3361 TGTATAGGGAC Exon 53 AGUCAUGGAAGGA GGGACCCUCCUUC GGGACCCTCCTTC760 GGGUCCC 2061 CAUGACU 3362 CATGACT Exon 53 UUGAGUCAUGGAA GGGACCCUCCUUC GGGACCCTCCTTC761 GGAGGGUCCC 2062 CAUGACUCAA 3363 CATGACTCAA Exon 53 AACUUAAGUUCAU GGGAUAUAUGAAC GGGATATATGAAC762 2063 3364 Intron 52AUAUCCC UUAAGUU TTAAGTT112 / 350#14837954v1AGUUUGUCCUGAA GGUAACCCACCUU GGTAACCCACCTT763 AGGUGGGUUACC 2064 UCAGGACAAACU 3365 TCAGGACAAACT Intron 53 AGUUUGUCCUGAA GUAACCCACCUUU GTAACCCACCTTT764 AGGUGGGUUAC 2065 CAGGACAAACU 3366 CAGGACAAACT Intron 53 UCAUCAUCCUAGC GUGUUAUGGCUAG GTGTTATGGCTAG765 CAUAACAC 2066 GAUGAUGA 3367 GATGATGA Intron 52 UUCAUCAUCCUAG GUGUUAUGGCUAG GTGTTATGGCTAG766 CCAUAACAC 2067 GAUGAUGAA 3368 GATGATGAA Intron 52 GUUCAUCAUCCUA GUUAUGGCUAGGA GTTATGGCTAGGA767 GCCAUAAC 2068 UGAUGAAC 3369 TGATGAAC Intron 52 AUGUCUCCUCCAG UAAAUGCUAGUCU TAAATGCTAGTCT768 ACUAGCAUUUA 2069 GGAGGAGACAU 3370 GGAGGAGACAT Intron 52 AAUGUCUCCUCCA UAAAUGCUAGUCU TAAATGCTAGTCT769 GACUAGCAUUUA 2070 GGAGGAGACAUU 3371 GGAGGAGACATT Intron 52 AAGUUUGUCCUGA UAACCCACCUUUC TAACCCACCTTTC770 AAGGUGGGUUA 2071 AGGACAAACUU 3372 AGGACAAACTT Intron 53 AAAGUUUGUCCUG UAACCCACCUUUC TAACCCACCTTTC771 AAAGGUGGGUUA 2072 AGGACAAACUUU 3373 AGGACAAACTTT Intron 53 GAGUCAUGGAAGG UAGGGACCCUCCU TAGGGACCCTCCT772 AGGGUCCCUA 2073 UCCAUGACUC 3374 TCCATGACTC Exon 53 ACCAAGGUUAGUA UAUCUUUGAUACU TATCTTTGATACT Exon 53 / intron 53 773 UCAAAGAUA 2074 AACCUUGGU 3375 AACCTTGGT junction UACAGUAGAUGCA UCUUUUGGAUUGC TCTTTTGGATTGC774 AUCCAAAAGA 2075 AUCUACUGUA 3376 ATCTACTGTA Exon 53 GUCCCUAUACAGU UGGAUUGCAUCUA TGGATTGCATCTA775 AGAUGCAAUCCA 2076 CUGUAUAGGGAC 3377 CTGTATAGGGAC Exon 53 AAUCAGUGGGAUG UGUACUUCAUCCC TGTACTTCATCCC776 AAGUACA 2077 ACUGAUU 3378 ACTGATT Exon 53 CAUCAUCCUAGCC UGUGUUAUGGCUA TGTGTTATGGCTA777 AUAACACA 2078 GGAUGAUG 3379 GGATGATG Intron 52 UCAUCAUCCUAGC UGUGUUAUGGCUA TGTGTTATGGCTA778 CAUAACACA 2079 GGAUGAUGA 3380 GGATGATGA Intron 52 UUCAUCAUCCUAG UGUGUUAUGGCUA TGTGTTATGGCTA779 CCAUAACACA 2080 GGAUGAUGAA 3381 GGATGATGAA Intron 52 GUGGGAUGAAGUA UGUUCUUGUACUU TGTTCTTGTACTT780 CAAGAACA 2081 CAUCCCAC 3382 CATCCCAC Exon 53 AGUGGGAUGAAGU UUCUUGUACUUCA TTCTTGTACTTCA781 ACAAGAA 2082 UCCCACU 3383 TCCCACT Exon 53 AUCAGUGGGAUGA UUGUACUUCAUCC TTGTACTTCATCC782 AGUACAA 2083 CACUGAU 3384 CACTGAT Exon 53 AAUCAGUGGGAUG UUGUACUUCAUCC TTGTACTTCATCC783 AAGUACAA 2084 CACUGAUU 3385 CACTGATT Exon 53 AACAAGCAUGGGA UUGUGUGUCCCAU TTGTGTGTCCCAT784 CACACAA 2085 GCUUGUU 3386 GCTTGTT Intron 52 UCAUCAUCCUAGC UUGUGUUAUGGCU TTGTGTTATGGCT785 CAUAACACAA 2086 AGGAUGAUGA 3387 AGGATGATGA Intron 52 AAGUUUGUCCUGA AACCCACCUUUCA AACCCACCTTTCA786 AAGGUGGGUU 2087 GGACAAACUU 3388 GGACAAACTT Intron 53 AAAAGUUUGUCCU AACCCACCUUUCA AACCCACCTTTCA787 GAAAGGUGGGUU 2088 GGACAAACUUUU 3389 GGACAAACTTTT Intron 53 CCUAGCCAUAACA AAUUAUUCAUUGU AATTATTCATTGT788 CAAUGAAUAAUU 2089 GUUAUGGCUAGG 3390 GTTATGGCTAGG Intron 52 AAGGAUUCAACAC AGCCAUUGUGUUG AGCCATTGTGTTG789 AAUGGCU 2090 AAUCCUU 3391 AATCCTT Exon 53 UAAAGGAUUCAAC AGCCAUUGUGUUG AGCCATTGTGTTG790 ACAAUGGCU 2091 AAUCCUUUA 3392 AATCCTTTA Exon 53 ACCAAGGUUAGUA AGGUAUCUUUGAU AGGTATCTTTGAT Exon 53 / intron 53 791 UCAAAGAUACCU 2092 ACUAACCUUGGU 3393 ACTAACCTTGGT junction GUCAUGGAAGGAG AUAGGGACCCUCC ATAGGGACCCTCC792 GGUCCCUAU 2093 UUCCAUGAC 3394 TTCCATGAC Exon 53113 / 350#14837954v1AUAUAUGUAUUCU AUCCUCAGGUCAG ATCCTCAGGTCAG793 GACCUGAGGAU 2094 AAUACAUAUAU 3395 AATACATATAT Intron 53 AAACCAAGGUUAG AUCUUUGAUACUA ATCTTTGATACTA Exon 53 / intron 53 794 UAUCAAAGAU 2095 ACCUUGGUUU 3396 ACCTTGGTTT junction CUAGCCAUAACAC AUUAUUCAUUGUG ATTATTCATTGTG795 AAUGAAUAAU 2096 UUAUGGCUAG 3397 TTATGGCTAG Intron 52 CCUAGCCAUAACA AUUAUUCAUUGUG ATTATTCATTGTG796 CAAUGAAUAAU 2097 UUAUGGCUAGG 3398 TTATGGCTAGG Intron 52 UCCUAGCCAUAAC AUUAUUCAUUGUG ATTATTCATTGTG797 ACAAUGAAUAAU 2098 UUAUGGCUAGGA 3399 TTATGGCTAGGA Intron 52 UUCAUCAUCCUAG AUUGUGUUAUGGC ATTGTGTTATGGC798 CCAUAACACAAU 2099 UAGGAUGAUGAA 3400 TAGGATGATGAA Intron 52 AGCUGAAAUGAAC CAAAGUCUACUGU CAAAGTCTACTGT799 AGUAGACUUUG 2100 UCAUUUCAGCU 3401 TCATTTCAGCT Intron 53 UAAAGGAUUCAAC CAGCCAUUGUGUU CAGCCATTGTGTT800 ACAAUGGCUG 2101 GAAUCCUUUA 3402 GAATCCTTTA Exon 53 GAGGGUCCCUAUA CAUCUACUGUAUA CATCTACTGTATA801 CAGUAGAUG 2102 GGGACCCUC 3403 GGGACCCTC Exon 53 UGAAAAGUUUGUC CCACCUUUCAGGA CCACCTTTCAGGA802 CUGAAAGGUGG 2103 CAAACUUUUCA 3404 CAAACTTTTCA Intron 53 AGGAUUCAACACA CCAGCCAUUGUGU CCAGCCATTGTGT803 AUGGCUGG 2104 UGAAUCCU 3405 TGAATCCT Exon 53 AAGGAUUCAACAC CCAGCCAUUGUGU CCAGCCATTGTGT804 AAUGGCUGG 2105 UGAAUCCUU 3406 TGAATCCTT Exon 53 AAAGGAUUCAACA CCAGCCAUUGUGU CCAGCCATTGTGT805 CAAUGGCUGG 2106 UGAAUCCUUU 3407 TGAATCCTTT Exon 53 UAAAGGAUUCAAC CCAGCCAUUGUGU CCAGCCATTGTGT806 ACAAUGGCUGG 2107 UGAAUCCUUUA 3408 TGAATCCTTTA Exon 53 GAAAAGUUUGUCC CCCACCUUUCAGG CCCACCTTTCAGG807 UGAAAGGUGGG 2108 ACAAACUUUUC 3409 ACAAACTTTTC Intron 53 UGAAAAGUUUGUC CCCACCUUUCAGG CCCACCTTTCAGG808 CUGAAAGGUGGG 2109 ACAAACUUUUCA 3410 ACAAACTTTTCA Intron 53 CUUGAGUCAUGGA CCCUCCUUCCAUG CCCTCCTTCCATG809 AGGAGGG 2110 ACUCAAG 3411 ACTCAAG Exon 53 AGAACACCUUCAG CUCCGGUUCUGAA CTCCGGTTCTGAA810 AACCGGAG 2111 GGUGUUCU 3412 GGTGTTCT Exon 53 AAGAACACCUUCA CUCCGGUUCUGAA CTCCGGTTCTGAA811 GAACCGGAG 2112 GGUGUUCUU 3413 GGTGTTCTT Exon 53 GGAUUCAACACAA CUUCCAGCCAUUG CTTCCAGCCATTG812 UGGCUGGAAG 2113 UGUUGAAUCC 3414 TGTTGAATCC Exon 53 AGGAUUCAACACA CUUCCAGCCAUUG CTTCCAGCCATTG813 AUGGCUGGAAG 2114 UGUUGAAUCCU 3415 TGTTGAATCCT Exon 53 AAGGAUUCAACACCUUCCAGCCAUUG CTTCCAGCCATTG814 AAUGGCUGGAAG 2115 UGUUGAAUCCUU 3416 TGTTGAATCCTT Exon 53 AGCUUGAGUCAUG GACCCUCCUUCCA GACCCTCCTTCCA815 GAAGGAGGGUC 2116 UGACUCAAGCU 3417 TGACTCAAGCT Exon 53 GGGUCCCUAUACA GCAUCUACUGUAU GCATCTACTGTAT816 GUAGAUGC 2117 AGGGACCC 3418 AGGGACCC Exon 53 UAAAGGAUUCAAC GCCAUUGUGUUGA GCCATTGTGTTGA817 ACAAUGGC 2118 AUCCUUUA 3419 ATCCTTTA Exon 53 UUAAAAUGUCUCC GCUAGUCUGGAGG GCTAGTCTGGAGG818 UCCAGACUAGC 2119 AGACAUUUUAA 3420 AGACATTTTAA Intron 52 GAUUCAACACAAU GCUUCCAGCCAUU GCTTCCAGCCATT819 GGCUGGAAGC 2120 GUGUUGAAUC 3421 GTGTTGAATC Exon 53 GGAUUCAACACAA GCUUCCAGCCAUU GCTTCCAGCCATT820 UGGCUGGAAGC 2121 GUGUUGAAUCC 3422 GTGTTGAATCC Exon 53 AGGAUUCAACACA GCUUCCAGCCAUU GCTTCCAGCCATT821 AUGGCUGGAAGC 2122 GUGUUGAAUCCУ 3423 GTGTTGAATCCT Exon 53 CUUGAGUCAUGGA GGACCCUCCUUCC GGACCCTCCTTCC822 2123 3424 Exon 53AGGAGGGUCC AUGACUCAAG ATGACTCAAG114 / 350#14837954v1GCUUGAGUCAUGG GGACCCUCCUUCC GGACCCTCCTTCC823 AAGGAGGGUCC 2124 AUGACUCAAGC 3425 ATGACTCAAGC Exon 53 AGCUUGAGUCAUG GGACCCUCCUUCC GGACCCTCCTTCC824 GAAGGAGGGUCC 2125 AUGACUCAAGCU 3426 ATGACTCAAGCT Exon 53 CUUGAGUCAUGGA GGGACCCUCCUUC GGGACCCTCCTTC825 AGGAGGGUCCC 2126 CAUGACUCAAG 3427 CATGACTCAAG Exon 53 GCUUGAGUCAUGG GGGACCCUCCUUC GGGACCCTCCTTC826 AAGGAGGGUCCC 2127 CAUGACUCAAGC 3428 CATGACTCAAGC Exon 53 GUCUCCUCCAGAC GUAAAUGCUAGUC GTAAATGCTAGTC827 UAGCAUUUAC 2128 UGGAGGAGAC 3429 TGGAGGAGAC Intron 52 GUAAGUUUUUUAA GUCCCAUGCUUGU GTCCCATGCTTGT828 CAAGCAUGGGAC 2129 UAAAAAACUUAC 3430 TAAAAAACTTAC Intron 52 AGCUGAAAUGAAC GUCUACUGUUCAU GTCTACTGTTCAT829 AGUAGAC 2130 UUCAGCU 3431 TTCAGCT Intron 53 CAUCAUCCUAGCC GUGUUAUGGCUAG GTGTTATGGCTAG830 AUAACAC 2131 GAUGAUG 3432 GATGATG Intron 52 GAUUCAACACAAU UAGCUUCCAGCCA TAGCTTCCAGCCA831 GGCUGGAAGCUA 2132 UUGUGUUGAAUC 3433 TTGTGTTGAATC Exon 53 AACCAAGGUUAGU UAUCUUUGAUACU TATCTTTGATACT Exon 53 / intron 53 832 AUCAAAGAUA 2133 AACCUUGGUU 3434 AACCTTGGTT junction AGGAUUCAACACA UCCAGCCAUUGUG TCCAGCCATTGTG833 AUGGCUGGA 2134 UUGAAUCCU 3435 TTGAATCCT Exon 53 AAGGAUUCAACAC UCCAGCCAUUGUG TCCAGCCATTGTG834 AAUGGCUGGA 2135 UUGAAUCCUU 3436 TTGAATCCTT Exon 53 AAAGGAUUCAACA UCCAGCCAUUGUG TCCAGCCATTGTG835 CAAUGGCUGGA 2136 UUGAAUCCUUU 3437 TTGAATCCTTT Exon 53 UAAAGGAUUCAAC UCCAGCCAUUGUG TCCAGCCATTGTG836 ACAAUGGCUGGA 2137 UUGAAUCCUUUA 3438 TTGAATCCTTTA Exon 53 AUAUAUGUAUUCU UCCUCAGGUCAGA TCCTCAGGTCAGA837 GACCUGAGGA 2138 AUACAUAUAU 3439 ATACATATAT Intron 53 GAACACCUUCAGA UGCCUCCGGUUCU TGCCTCCGGTTCT838 ACCGGAGGCA 2139 GAAGGUGUUC 3440 GAAGGTGTTC Exon 53 GUUCAUCAUCCUA UUAUGGCUAGGAU TTATGGCTAGGAT839 GCCAUAA 2140 GAUGAAC 3441 GATGAAC Intron 52 UUCAUCAUCCUAG UUGUGUUAUGGCU TTGTGTTATGGCT840 CCAUAACACAA 2141 AGGAUGAUGAA 3442 AGGATGATGAA Intron 52 GGAAGAAACUCAU UGCAGUAAUCUAU TGCAGTAATCTAT841 AGAUUACUGCA 2142 GAGUUUCUUCC 3443 GAGTTTCTTCC Exon 55 GAAACAACUGCCA GUAGGACAUUGGC GTAGGACATTGGC842 AUGUCCUAC 2143 AGUUGUUUC 3444 AGTTGTTTC Exon 55 GAAACAACUGCCA UGUAGGACAUUGG TGTAGGACATTGG843 AUGUCCUACA 2144 CAGUUGUUUC 3445 CAGTTGTTTC Exon 55 GAAACAACUGCCA CUGUAGGACAUUG CTGTAGGACATTG844 AUGUCCUACAG 2145 GCAGUUGUUUC 3446 GCAGTTGTTTC Exon 55 GAAACAACUGCCA CCUGUAGGACAUU CCTGTAGGACATT845 AUGUCCUACAGG 2146 GGCAGUUGUUUC 3447 GGCAGTTGTTTC Exon 55 AAACAACUGCCAA CCUGUAGGACAUU CCTGTAGGACATT846 UGUCCUACAGG 2147 GGCAGUUGUUU 3448 GGCAGTTGTTT Exon 55 AAACAACUGCCAA UCCUGUAGGACAU TCCTGTAGGACAT847 UGUCCUACAGGA 2148 UGGCAGUUGUUU 3449 TGGCAGTTGTTT Exon 55 AACAACUGCCAAU CUGUAGGACAUUG CTGTAGGACATTG848 GUCCUACAG 2149 GCAGUUGUU 3450 GCAGTTGTT Exon 55 AACAACUGCCAAU CCUGUAGGACAUU CCTGTAGGACATT849 GUCCUACAGG 2150 GGCAGUUGUU 3451 GGCAGTTGTT Exon 55 AACAACUGCCAAU UCCUGUAGGACAU TCCTGTAGGACAT850 GUCCUACAGG A 2151 UGGCAGUUGUU 3452 TGGCAGTTGTT Exon 55 ACAACUGCCAAUG UGUAGGACAUUGG TGTAGGACATTGG851 UCCUACA 2152 CAGUUGU 3453 CAGTTGT Exon 55 ACAACUGCCAAUG CUGUAGGACAUUG CTGTAGGACATTG852UCCUACAG 2153 GCAGUUGU 3454 GCAGTTGT Exon 55115 / 350#14837954v1ACAACUGCCAAUG CCUGUAGGACAUU CCTGTAGGACATT853 UCCUACAGG 2154 GGCAGUUGU 3455 GGCAGTTGT Exon 55 ACAACUGCCAAUG UCCUGUAGGACAU TCCTGTAGGACAT854 UCCUACAGGA 2155 UGGCAGUUGU 3456 TGGCAGTTGT Exon 55 CAACUGCCAAUGU CCUGUAGGACAUU CCTGTAGGACATT855 CCUACAGG 2156 GGCAGUUG 3457 GGCAGTTG Exon 55 CAACUGCCAAUGU UCCUGUAGGACAU TCCTGTAGGACAT856 CCUACAGGA 2157 UGGCAGUUG 3458 TGGCAGTTG Exon 55 AACUGCCAAUGUC UCCUGUAGGACAU TCCTGTAGGACAT857 CUACAGGA 2158 UGGCAGUU 3459 TGGCAGTT Exon 55 ACUGCCAAUGUCC UCCUGUAGGACAU TCCTGTAGGACAT858 UACAGGA 2159 UGGCAGU 3460 TGGCAGT Exon 55 AGAAACUCAUAGA UGUUGCAGUAAUC TGTTGCAGTAATC859 UUACUGCAACA 2160 UAUGAGUUUCU 3461 TATGAGTTTCT Exon 55 AGAAACUCAUAGA CUGUUGCAGUAAU CTGTTGCAGTAAT860 UUACUGCAACAG 2161 CUAUGAGUUUCU 3462 CTATGAGTTTCT Exon 55 GAAACUCAUAGAU CUGUUGCAGUAAU CTGTTGCAGTAAT861 UACUGCAACAG 2162 CUAUGAGUUUC 3463 CTATGAGTTTC Exon 55 GAUGAUACCAGAA AUGUGGACUUUUC ATGTGGACTTTTC862 AAGUCCACAU 2163 UGGUAUCAUC 3464 TGGTATCATC Exon 54 GAUGAUACCAGAA UCAUGUGGACUUU TCATGTGGACTTT863 AAGUCCACAUGA 2164 UCUGGUAUCAUC 3465 TCTGGTATCATC Exon 54 AUGAUACCAGAAA UCAUGUGGACUUU TCATGTGGACTTT864 AGUCCACAUGA 2165 UCUGGUAUCAU 3466 TCTGGTATCAT Exon 54 AUGAUACCAGAAA AUCAUGUGGACUU ATCATGTGGACTT865 AGUCCACAUGAU 2166 UUCUGGUAUCAU 3467 TTCTGGTATCAT Exon 54 UGAUACCAGAAAA UCAUGUGGACUUU TCATGTGGACTTT866 GUCCACAUGA 2167 UCUGGUAUCA 3468 TCTGGTATCA Exon 54 UGAUACCAGAAAA AUCAUGUGGACUU ATCATGTGGACTT867 GUCCACAUGAU 2168 UUCUGGUAUCA 3469 TTCTGGTATCA Exon 54 GAUACCAGAAAAG UCAUGUGGACUUU TCATGTGGACTTT868 UCCACAUGA 2169 UCUGGUAUC 3470 TCTGGTATC Exon 54 GAUACCAGAAAAG AUCAUGUGGACUU ATCATGTGGACTT869 UCCACAUGAU 2170 UUCUGGUAUC 3471 TTCTGGTATC Exon 54 GAUACCAGAAAAG UUAUCAUGUGGAC TTATCATGTGGAC870 UCCACAUGAUAA 2171 UUUUCUGGUAUC 3472 TTTTCTGGTATC Exon 54 AUACCAGAAAAGU UCAUGUGGACUUU TCATGTGGACTTT871 CCACAUGA 2172 UCUGGUAU 3473 TCTGGTAT Exon 54 AUACCAGAAAAGU AUCAUGUGGACUU ATCATGTGGACTT872 CCACAUGAU 2173 UUCUGGUAU 3474 TTCTGGTAT Exon 54 AUACCAGAAAAGU GUUAUCAUGUGGA GTTATCATGTGGA873 CCACAUGAUAAC 2174 CUUUUCUGGUAU 3475 CTTTTCTGGTAT Exon 54 UACCAGAAAAGUC UCAUGUGGACUUU TCATGTGGACTTT874 CACAUGA 2175 UCUGGUA 3476 TCTGGTA Exon 54 UACCAGAAAAGUC AUCAUGUGGACUU ATCATGTGGACTT875 CACAUGAU 2176 UUCUGGUA 3477 TTCTGGTA Exon 54 UACCAGAAAAGUC UUAUCAUGUGGAC TTATCATGTGGAC876 CACAUGAUAA 2177 UUUUCUGGUA 3478 TTTTCTGGTA Exon 54 UACCAGAAAAGUC GUUAUCAUGUGGA GTTATCATGTGGA877 CACAUGAUAAC 2178 CUUUUCUGGUA 3479 CTTTTCTGGTA Exon 54 UACCAGAAAAGUC UGUUAUCAUGUGG TGTTATCATGTGG878 CACAUGAUAACA 2179 ACUUUUCUGGUA 3480 ACTTTTCTGGTA Exon 54 ACCAGAAAAGUCCAUCAUGUGGACUU ATCATGTGGACTT879 ACAUGAU 2180 UUCUGGU 3481 TTCTGGT Exon 54 ACCAGAAAAGUCC UUAUCAUGUGGAC TTATCATGTGGAC880 ACAUGAUAA 2181 UUUUCUGGU 3482 TTTTCTGGT Exon 54 ACCAGAAAAGUCC GUUAUCAUGUGGA GTTATCATGTGGA881 ACAUGAUAAC 2182 CUUUUCUGGU 3483 CTTTTCTGGT Exon 54 ACCAGAAAAGUCC UGUUAUCAUGUGG TGTTATCATGTGG882 2183 3484 Exon 54ACAUGAUAACA ACUUUUCUGGU ACTTTTCTGGT 116 / 350#14837954v1ACCAGAAAAGUCC CUGUUAUCAUGUG CTGTTATCATGTG883 ACAUGAUAACAG 2184 GACUUUUCUGGU 3485 GACTTTTCTGGT Exon 54 CCAGAAAAGUCCA UUAUCAUGUGGAC TTATCATGTGGAC884 CAUGAUAA 2185 UUUUCUGG 3486 TTTTCTGG Exon 54 CCAGAAAAGUCCA GUUAUCAUGUGGA GTTATCATGTGGA885 CAUGAUAAC 2186 CUUUUCUGG 3487 CTTTTCTGG Exon 54 CCAGAAAAGUCCA UGUUAUCAUGUGG TGTTATCATGTGG886 CAUGAUAACA 2187 ACUUUUCUGG 3488 ACTTTTCTGG Exon 54 CCAGAAAAGUCCA CUGUUAUCAUGUG CTGTTATCATGTG887 CAUGAUAACAG 2188 GACUUUUCUGG 3489 GACTTTTCTGG Exon 54 CCAGAAAAGUCCA UCUGUUAUCAUGU TCTGTTATCATGT888 CAUGAUAACAGA 2189 GGACUUUUCUGG 3490 GGACTTTTCTGG Exon 54 CAGAAAAGUCCAC GUUAUCAUGUGGA GTTATCATGTGGA889 AUGAUAAC 2190 CUUUUCUG 3491 CTTTTCTG Exon 54 CAGAAAAGUCCAC UGUUAUCAUGUGG TGTTATCATGTGG890 AUGAUAACA 2191 ACUUUUCUG 3492 ACTTTTCTG Exon 54 CAGAAAAGUCCAC CUGUUAUCAUGUG CTGTTATCATGTG891 AUGAUAACAG 2192 GACUUUUCUG 3493 GACTTTTCTG Exon 54 CAGAAAAGUCCAC UCUGUUAUCAUGU TCTGTTATCATGT892 AUGAUAACAGA 2193 GGACUUUUCUG 3494 GGACTTTTCTG Exon 54 CAGAAAAGUCCAC CUCUGUUAUCAUG CTCTGTTATCATG893 AUGAUAACAGAG 2194 UGGACUUUUCUG 3495 TGGACTTTTCTG Exon 54 AGAAAAGUCCACA UCUGUUAUCAUGU TCTGTTATCATGT894 UGAUAACAGA 2195 GGACUUUUCU 3496 GGACTTTTCT Exon 54 AGAAAAGUCCACA CUCUGUUAUCAUG CTCTGTTATCATG895 UGAUAACAGAG 2196 UGGACUUUUCU 3497 TGGACTTTTCT Exon 54 AGAAAAGUCCACA UCUCUGUUAUCAU TCTCTGTTATCAT896 UGAUAACAGAGA 2197 GUGGACUUUUCU 3498 GTGGACTTTTCT Exon 54 GAAAAGUCCACAU CUGUUAUCAUGUG CTGTTATCATGTG897 GAUAACAG 2198 GACUUUUC 3499 GACTTTTC Exon 54 GAAAAGUCCACAU UCUGUUAUCAUGU TCTGTTATCATGT898 GAUAACAGA 2199 GGACUUUUC 3500 GGACTTTTC Exon 54 GAAAAGUCCACAU CUCUGUUAUCAUG CTCTGTTATCATG899 GAUAACAGAG 2200 UGGACUUUUC 3501 TGGACTTTTC Exon 54 GAAAAGUCCACAU UCUCUGUUAUCAU TCTCTGTTATCAT900 GAUAACAGAGA 2201 GUGGACUUUUC 3502 GTGGACTTTTC Exon 54 GAAAAGUCCACAU UUCUCUGUUAUCA TTCTCTGTTATCA901 GAUAACAGAGAA 2202 UGUGGACUUUUC 3503 TGTGGACTTTTC Exon 54 AAAAGUCCACAUG CUCUGUUAUCAUG CTCTGTTATCATG902 AUAACAGAG 2203 UGGACUUUU 3504 TGGACTTTT Exon 54 AAAAGUCCACAUG UCUCUGUUAUCAU TCTCTGTTATCAT903 AUAACAGAGA 2204 GUGGACUUUU 3505 GTGGACTTTT Exon 54 AAAAGUCCACAUG UUCUCUGUUAUCA TTCTCTGTTATCA904 AUAACAGAGAA 2205 UGUGGACUUUU 3506 TGTGGACTTTT Exon 54 AAAAGUCCACAUG AUUCUCUGUUAUC ATTCTCTGTTATC905 AUAACAGAGAAU 2206 AUGUGGACUUUU 3507 ATGTGGACTTTT Exon 54 AAAGUCCACAUGA CUCUGUUAUCAUG CTCTGTTATCATG906 UAACAGAG 2207 UGGACUUU 3508 TGGACTTT Exon 54 AAAGUCCACAUGA UCUCUGUUAUCAU TCTCTGTTATCAT907 UAACAGAGA 2208 GUGGACUUU 3509 GTGGACTTT Exon 54 AAAGUCCACAUGA UUCUCUGUUAUCA TTCTCTGTTATCA908 UAACAGAGAA 2209 UGUGGACUUU 3510 TGTGGACTTT Exon 54 AAAGUCCACAUGA AUUCUCUGUUAUC ATTCTCTGTTATC909 UAACAGAGAAU 2210 AUGUGGACUUU 3511 ATGTGGACTTT Exon 54 AAAGUCCACAUGA UAUUCUCUGUUAU TATTCTCTGTTAT910 UAACAGAGAAUA 2211 CAUGUGGACUUU 3512 CATGTGGACTTT Exon 54 AAGUCCACAUGAU CUCUGUUAUCAUG CTCTGTTATCATG911 AACAGAG 2212 UGGACUU 3513 TGGACTT Exon 54 AAGUCCACAUGAU UCUCUGUUAUCAU TCTCTGTTATCAT912 2213 3514 Exon 54AACAGAGA GUGGACUU GTGGACTT 117 / 350#14837954v1AAGUCCACAUGAU UUCUCUGUUAUCA TTCTCTGTTATCA913 AACAGAGAA 2214 UGUGGACUU 3515 TGTGGACTT Exon 54 AAGUCCACAUGAU AUUCUCUGUUAUC ATTCTCTGTTATC914 AACAGAGAAU 2215 AUGUGGACUU 3516 ATGTGGACTT Exon 54 AAGUCCACAUGAU UAUUCUCUGUUAU TATTCTCTGTTAT915 AACAGAGAAUA 2216 CAUGUGGACUU 3517 CATGTGGACTT Exon 54 AAGUCCACAUGAU AUAUUCUCUGUUA ATATTCTCTGTTA916 AACAGAGAAUAU 2217 UCAUGUGGACUU 3518 TCATGTGGACTT Exon 54 AGUCCACAUGAUA UUCUCUGUUAUCA TTCTCTGTTATCA917 ACAGAGAA 2218 UGUGGACU 3519 TGTGGACT Exon 54 AGUCCACAUGAUA AUUCUCUGUUAUC ATTCTCTGTTATC918 ACAGAGAAU 2219 AUGUGGACU 3520 ATGTGGACT Exon 54 AGUCCACAUGAUA UAUUCUCUGUUAU TATTCTCTGTTAT919 ACAGAGAAUA 2220 CAUGUGGACU 3521 CATGTGGACT Exon 54 AGUCCACAUGAUA AUAUUCUCUGUUA ATATTCTCTGTTA920 ACAGAGAAUAU 2221 UCAUGUGGACU 3522 TCATGTGGACT Exon 54 AGUCCACAUGAUA GAUAUUCUCUGUU GATATTCTCTGTT921 ACAGAGAAUAUC 2222 AUCAUGUGGACU 3523 ATCATGTGGACT Exon 54 GUCCACAUGAUAA GAUAUUCUCUGUU GATATTCTCTGTT922 CAGAGAAUAUC 2223 AUCAUGUGGAC 3524 ATCATGTGGAC Exon 54 GUCCACAUGAUAA UGAUAUUCUCUGU TGATATTCTCTGT923 CAGAGAAUAUCA 2224 UAUCAUGUGGAC 3525 TATCATGTGGAC Exon 54 GGAAGAAACUCAU UUGCAGUAAUCUA TTGCAGTAATCTA924 AGAUUACUGCAA 2225 UGAGUUUCUUCC 3526 TGAGTTTCTTCC Exon 55 GCUGAAACAACUG UAGGACAUUGGCA TAGGACATTGGCA925 CCAAUGUCCUA 2226 GUUGUUUCAGC 3527 GTTGTTTCAGC Exon 55 GCUGAAACAACUG GUAGGACAUUGGC GTAGGACATTGGC926 CCAAUGUCCUAC 2227 AGUUGUUUCAGC 3528 AGTTGTTTCAGC Exon 55 UGAAACAACUGCC GUAGGACAUUGGC GTAGGACATTGGC927 AAUGUCCUAC 2228 AGUUGUUUCA 3529 AGTTGTTTCA Exon 55 UGAAACAACUGCC UGUAGGACAUUGG TGTAGGACATTGG928 AAUGUCCUACA 2229 CAGUUGUUUCA 3530 CAGTTGTTTCA Exon 55 UGAAACAACUGCC CUGUAGGACAUUG CTGTAGGACATTG929 AAUGUCCUACAG 2230 GCAGUUGUUUCA 3531 GCAGTTGTTTCA Exon 55 AACAACUGCCAAU AUCCUGUAGGACA ATCCTGTAGGACA930 GUCCUACAGGAU 2231 UUGGCAGUUGUU 3532 TTGGCAGTTGTT Exon 55 ACAACUGCCAAUG AUCCUGUAGGACA ATCCTGTAGGACA931 UCCUACAGGAU 2232 UUGGCAGUUGU 3533 TTGGCAGTTGT Exon 55 CAACUGCCAAUGU AUCCUGUAGGACA ATCCTGTAGGACA932 CCUACAGGAU 2233 UUGGCAGUUG 3534 TTGGCAGTTG Exon 55 AACUGCCAAUGUC AUCCUGUAGGACA ATCCTGTAGGACA933 CUACAGGAU 2234 UUGGCAGUU 3535 TTGGCAGTT Exon 55 AACUGCCAAUGUC AGCAUCCUGUAGG AGCATCCTGTAGG934 CUACAGGAUGCU 2235 ACAUUGGCAGUU 3536 ACATTGGCAGTT Exon 55 ACUGCCAAUGUCC AUCCUGUAGGACA ATCCTGTAGGACA935 UACAGGAU 2236 UUGGCAGU 3537 TTGGCAGT Exon 55 ACUGCCAAUGUCC AGCAUCCUGUAGG AGCATCCTGTAGG936 UACAGGAUGCU 2237 ACAUUGGCAGU 3538 ACATTGGCAGT Exon 55 CUGCCAAUGUCCU AGCAUCCUGUAGG AGCATCCTGTAGG937 ACAGGAUGCU 2238 ACAUUGGCAG 3539 ACATTGGCAG Exon 55 UGCCAAUGUCCUA AGCAUCCUGUAGG AGCATCCTGTAGG938 CAGGAUGCU 2239 ACAUUGGCA 3540 ACATTGGCA Exon 55 GCCAAUGUCCUACAGCAUCCUGUAGG AGCATCCTGTAGG939 AGGAUGCU 2240 ACAUUGGC 3541 ACATTGGC Exon 55 AGAUGAUACCAGA GGACUUUUCUGGU GGACTTTTCTGGT940 AAAGUCC 2241 AUCAUCU 3542 ATCATCT Exon 54 AGAUGAUACCAGA UGUGGACUUUUCU TGTGGACTTTTCT941 AAAGUCCACA 2242 GGUAUCAUCU 3543 GGTATCATCT Exon 54 AGAUGAUACCAGA AUGUGGACUUUUC ATGTGGACTTTTC942 2243 3544 Exon 54AAAGUCCACAU UGGUAUCAUCU TGGTATCATCT 118 / 350#14837954v1CUGAAACAACUGC GUAGGACAUUGGC GTAGGACATTGGC943 CAAUGUCCUAC 2244 AGUUGUUUCAG 3545 AGTTGTTTCAG Exon 55 CUGAAACAACUGC UGUAGGACAUUGG TGTAGGACATTGG944 CAAUGUCCUACA 2245 CAGUUGUUUCAG 3546 CAGTTGTTTCAG Exon 55 ACAACUGCCAAUG CAUCCUGUAGGAC CATCCTGTAGGAC945 UCCUACAGGAUG 2246 AUUGGCAGUUGU 3547 ATTGGCAGTTGT Exon 55 CAACUGCCAAUGU CAUCCUGUAGGAC CATCCTGTAGGAC946 CCUACAGGAUG 2247 AUUGGCAGUUG 3548 ATTGGCAGTTG Exon 55 AACUGCCAAUGUCCAUCCUGUAGGAC CATCCTGTAGGAC947 CUACAGGAUG 2248 AUUGGCAGUU 3549 ATTGGCAGTT Exon 55 ACUGCCAAUGUCC CAUCCUGUAGGAC CATCCTGTAGGAC948 UACAGGAUG 2249 AUUGGCAGU 3550 ATTGGCAGT Exon 55 ACUGCCAAUGUCC UAGCAUCCUGUAG TAGCATCCTGTAG949 UACAGGAUGCUA 2250 GACAUUGGCAGU 3551 GACATTGGCAGT Exon 55 CUGCCAAUGUCCU CAUCCUGUAGGAC CATCCTGTAGGAC950 ACAGGAUG 2251 AUUGGCAG 3552 ATTGGCAG Exon 55 CUGCCAAUGUCCU UAGCAUCCUGUAG TAGCATCCTGTAG951 ACAGGAUGCUA 2252 GACAUUGGCAG 3553 GACATTGGCAG Exon 55 UGCCAAUGUCCUA UAGCAUCCUGUAG TAGCATCCTGTAG952 CAGGAUGCUA 2253 GACAUUGGCA 3554 GACATTGGCA Exon 55 UGCCAAUGUCCUA GGUAGCAUCCUGU GGTAGCATCCTGT953 CAGGAUGCUACC 2254 AGGACAUUGGCA 3555 AGGACATTGGCA Exon 55 GCCAAUGUCCUAC UAGCAUCCUGUAG TAGCATCCTGTAG954 AGGAUGCUA 2255 GACAUUGGC 3556 GACATTGGC Exon 55 GCCAAUGUCCUAC GGUAGCAUCCUGU GGTAGCATCCTGT955 AGGAUGCUACC 2256 AGGACAUUGGC 3557 AGGACATTGGC Exon 55 CCAAGGGAGUAAA UCAGCUCUUUUAC TCAGCTCTTTTAC956 AGAGCUGA 2257 UCCCUUGG 3558 TCCCTTGG Exon 55 CCAAGGGAGUAAA AUCAGCUCUUUUA ATCAGCTCTTTTA957 AGAGCUGAU 2258 CUCCCUUGG 3559 CTCCCTTGG Exon 55 CCAAGGGAGUAAA CAUCAGCUCUUUU CATCAGCTCTTTT958 AGAGCUGAUG 2259 ACUCCCUUGG 3560 ACTCCCTTGG Exon 55 CCAAGGGAGUAAA UCAUCAGCUCUUU TCATCAGCTCTTT959 AGAGCUGAUGA 2260 UACUCCCUUGG 3561 TACTCCCTTGG Exon 55 CAAGGGAGUAAAA UCAUCAGCUCUUU TCATCAGCTCTTT960 GAGCUGAUGA 2261 UACUCCCUUG 3562 TACTCCCTTG Exon 55 CAAGGGAGUAAAA UUCAUCAGCUCUU TTCATCAGCTCTT961 GAGCUGAUGAA 2262 UUACUCCCUUG 3563 TTACTCCCTTG Exon 55 AGGGAGUAAAAGA UUUCAUCAGCUCU TTTCATCAGCTCT962 GCUGAUGAAA 2263 UUUACUCCCU 3564 TTTACTCCCT Exon 55 CUGAUGAAACAAU GACUUACUUGCCA GACTTACTTGCCA Exon 55 / intron 55 963 GGCAAGUAAGUC 2264 UUGUUUCAUCAG 3565 TTGTTTCATCAG junction UGAUGAAACAAUG GACUUACUUGCCA GACTTACTTGCCA Exon 55 / intron 55 964 GCAAGUAAGUC 2265 UUGUUUCAUCA 3566 TTGTTTCATCA junction GAUGAAACAAUGG GACUUACUUGCCA GACTTACTTGCCA Exon 55 / intron 55 965 CAAGUAAGUC 2266 UUGUUUCAUC 3567 TTGTTTCATC junction CCUGGAAGGUUCC GCAUCAUCGGAAC GCATCATCGGAAC966 GAUGAUGC 2267 CUUCCAGG 3568 CTTCCAGG Exon 56 CCUGGAAGGUUCC UGCAUCAUCGGAA TGCATCATCGGAA967 GAUGAUGCA 2268 CCUUCCAGG 3569 CCTTCCAGG Exon 56 CAGAUGAUACCAG UGUGGACUUUUCU TGTGGACTTTTCT968 AAAAGUCCACA 2269 GGUAUCAUCUG 3570 GGTATCATCTG Exon 54 CAGAUGAUACCAG AUGUGGACUUUUC ATGTGGACTTTTC969 AAAAGUCCACAU 2270 UGGUAUCAUCUG 3571 TGGTATCATCTG Exon 54 CUGCCAAUGUCCU GUAGCAUCCUGUA GTAGCATCCTGTA970 ACAGGAUGCUAC 2271 GGACAUUGGCAG 3572 GGACATTGGCAG Exon 55 UGCCAAUGUCCUA GUAGCAUCCUGUA GTAGCATCCTGTA971 CAGGAUGCUAC 2272 GGACAUUGGCA 3573 GGACATTGGCA Exon 55 GCCAAUGUCCUAC GUAGCAUCCUGUA GTAGCATCCTGTA972 AGGAUGCUAC 2273 GGACAUUGGC 3574 GGACATTGGC Exon 55119 / 350#14837954v1CCAAUGUCCUACA GUAGCAUCCUGUA GTAGCATCCTGTA973 GGAUGCUAC 2274 GGACAUUGG 3575 GGACATTGG Exon 55 AGGGAGUAAAAGA GUUUCAUCAGCUC GTTTCATCAGCTC974 GCUGAUGAAAC 2275 UUUUACUCCCU 3576 TTTTACTCCCT Exon 55 UGAUGAAACAAUG UGACUUACUUGCC TGACTTACTTGCC Exon 55 / intron 55 975 GCAAGUAAGUCA 2276 AUUGUUUCAUCA 3577 ATTGTTTCATCA junction GAUGAAACAAUGG UGACUUACUUGCC TGACTTACTTGCC Exon 55 / intron 55 976 CAAGUAAGUCA 2277 AUUGUUUCAUC 3578 ATTGTTTCATC junction CCUGGAAGGUUCC CUGCAUCAUCGGA CTGCATCATCGGA977 GAUGAUGCAG 2278 ACCUUCCAGG 3579 ACCTTCCAGG Exon 56 GGAAGGUUCCGAU CUGCAUCAUCGGA CTGCATCATCGGA978 GAUGCAG 2279 ACCUUCC 3580 ACCTTCC Exon 56 GAUCCAAUUGAAC UGCUGAGAAUUGU TGCTGAGAATTGT979 AAUUCUCAGCA 2280 UCAAUUGGAUC 3581 TCAATTGGATC Intron 55 AGGUUCCGAUGAU ACAGGACUGCAUC ACAGGACTGCATC980 GCAGUCCUGU 2281 AUCGGAACCU 3582 ATCGGAACCT Exon 56 GGUUCCGAUGAUG ACAGGACUGCAUC ACAGGACTGCATC981 CAGUCCUGU 2282 AUCGGAACC 3583 ATCGGAACC Exon 56 CCUGGAAGGUUCC ACUGCAUCAUCGG ACTGCATCATCGG982 GAUGAUGCAGU 2283 AACCUUCCAGG 3584 AACCTTCCAGG Exon 56 CUGGAAGGUUCCG ACUGCAUCAUCGG ACTGCATCATCGG983 AUGAUGCAGU 2284 AACCUUCCAG 3585 AACCTTCCAG Exon 56 GGAAGGUUCCGAU ACUGCAUCAUCGG ACTGCATCATCGG984 GAUGCAGU 2285 AACCUUCC 3586 AACCTTCC Exon 56 GAAGGUUCCGAUG ACAGGACUGCAUC ACAGGACTGCATC985 AUGCAGUCCUGU 2286 AUCGGAACCUUC 3587 ATCGGAACCTTC Exon 56 GGUUCCGAUGAUG GUAACAGGACUGC GTAACAGGACTGC986 CAGUCCUGUUAC 2287 AUCAUCGGAACC 3588 ATCATCGGAACC Exon 56 GUUCCGAUGAUGC GUAACAGGACUGC GTAACAGGACTGC987 AGUCCUGUUAC 2288 AUCAUCGGAAC 3589 ATCATCGGAAC Exon 56 GUGGAUCCAAUUG GAGAAUUGUUCAA GAGAATTGTTCAA988 AACAAUUCUC 2289 UUGGAUCCAC 3590 TTGGATCCAC Intron 55 GGAUCCAAUUGAA UGCUGAGAAUUGU TGCTGAGAATTGT989 CAAUUCUCAGCA 2290 UCAAUUGGAUC C 3591 TCAATTGGATCC Intron 55 GAUCCAAUUGAAC AUGCUGAGAAUUG ATGCTGAGAATTG990 AAUUCUCAGCAU 2291 UUCAAUUGGAUC 3592 TTCAATTGGATC Intron 55 AAGGUUCCGAUGA ACAGGACUGCAUC ACAGGACTGCATC991 UGCAGUCCUGU 2292 AUCGGAACCUU 3593 ATCGGAACCTT Exon 56 AGGUUCCGAUGAU GGACUGCAUCAUC GGACTGCATCATC992 GCAGUCC 2293 GGAACCU 3594 GGAACCT Exon 56 GUGGAUCCAAUUG UGAGAAUUGUUCA TGAGAATTGTTCA993 AACAAUUCUCA 2294 AUUGGAUCCAC 3595 ATTGGATCCAC Intron 55 AGGUUCCGAUGAU UAACAGGACUGCA TAACAGGACTGCA994 GCAGUCCUGUUA 2295 UCAUCGGAACCU 3596 TCATCGGAACCT Exon 56 GGUUCCGAUGAUG UAACAGGACUGCA TAACAGGACTGCA995 CAGUCCUGUUA 2296 UCAUCGGAACC 3597 TCATCGGAACC Exon 56 CUGGAAGGUUCCG GGACUGCAUCAUC GGACTGCATCATC996 AUGAUGCAGUCC 2297 GGAACCUUCCAG 3598 GGAACCTTCCAG Exon 56 UGGAAGGUUCCGA GGACUGCAUCAUC GGACTGCATCATC997 UGAUGCAGUCC 2298 GGAACCUUCCA 3599 GGAACCTTCCA Exon 56 GGAAGGUUCCGAU GGACUGCAUCAUC GGACTGCATCATC998 GAUGCAGUCC 2299 GGAACCUUCC 3600 GGAACCTTCC Exon 56 UGUGGAUCCAAUU GAGAAUUGUUCAA GAGAATTGTTCAA999 GAACAAUUCUC 2300 UUGGAUCCACA 3601 TTGGATCCACA Intron 55 UUGUGGAUCCAAU GAGAAUUGUUCAA GAGAATTGTTCAA1000 UGAACAAUUCUC 2301 UUGGAUCCACAA 3602 TTGGATCCACAA Intron 55 UGUGGAUCCAAUU UGAGAAUUGUUCA TGAGAATTGTTCA1001 GAACAAUUCUCA 2302 AUUGGAUCCACA 3603 ATTGGATCCACA Intron 55 GUUCCGAUGAUGC ACAGGACUGCAUC ACAGGACTGCATC1002 2303 3604 Exon 56AGUCCUGU AUCGGAAC ATCGGAAC120 / 350#14837954v1UCCGAUGAUGCAG UAACAGGACUGCA TAACAGGACTGCA1003 UCCUGUUA 2304 UCAUCGGA 3605 TCATCGGA Exon 56 UCCGAUGAUGCAG GUAACAGGACUGC GTAACAGGACTGC1004 UCCUGUUAC 2305 AUCAUCGGA 3606 ATCATCGGA Exon 56 GUUCCGAUGAUGC UAACAGGACUGCA TAACAGGACTGCA1005 AGUCCUGUUA 2306 UCAUCGGAAC 3607 TCATCGGAAC Exon 56 UUCCGAUGAUGCA GUAACAGGACUGC GTAACAGGACTGC1006 GUCCUGUUAC 2307 AUCAUCGGAA 3608 ATCATCGGAA Exon 56 CUCCAAAUUCACA CAAGCGAUGAAUG CAAGCGATGAATG1007 UUCAUCGCUUG 2308 UGAAUUUGGAG 3609 TGAATTTGGAG Intron 55 GAAGGUUCCGAUG GGACUGCAUCAUC GGACTGCATCATC1008 AUGCAGUCC 2309 GGAACCUUC 3610 GGAACCTTC Exon 56 AAGGUUCCGAUGA GGACUGCAUCAUC GGACTGCATCATC1009 UGCAGUCC 2310 GGAACCUU 3611 GGAACCTT Exon 56 GGAGCUUGGGAGG UCGUCUUGAACCC TCGTCTTGAACCC1010 GUUCAAGACGA 2311 UCCCAAGCUCC 3612 TCCCAAGCTCC Intron 54 GGAGCUUGGGAGG AUCGUCUUGAACC ATCGTCTTGAACC1011 GUUCAAGACGAU 2312 CUCCCAAGCUCC 3613 CTCCCAAGCTCC Intron 54 UGGCUGUAAUAAU CACCACCCCAUUA CACCACCCCATTA1012 GGGGUGGUG 2313 UUACAGCCA 3614 TTACAGCCA Intron 54 UGGCUGUAAUAAU UCACCACCCCAUU TCACCACCCCATT1013 GGGGUGGUGA 2314 AUUACAGCCA 3615 ATTACAGCCA Intron 54 GGCUGUAAUAAUG UCACCACCCCAUU TCACCACCCCATT1014 GGGUGGUGA 2315 AUUACAGCC 3616 ATTACAGCC Intron 54 GGGGUGGUGAAAC CCAUCCAGUUUCA CCATCCAGTTTCA1015 UGGAUGG 2316 CCACCCC 3617 CCACCCC Intron 54 UUGGCUGUAAUAA UCACCACCCCAUU TCACCACCCCATT1016 UGGGGUGGUGA 2317 AUUACAGCCAA 3618 ATTACAGCCAA Intron 54 GGGGUGGUGAAAC UCCAUCCAGUUUC TCCATCCAGTTTC1017 UGGAUGGA 2318 ACCACCCC 3619 ACCACCCC Intron 54 GCUGUAAUAAUGG UCACCACCCCAUU TCACCACCCCATT1018 GGUGGUGA 2319 AUUACAGC 3620 ATTACAGC Intron 54 UGGGGUGGUGAAA CCAUCCAGUUUCA CCATCCAGTTTCA1019 CUGGAUGG 2320 CCACCCCA 3621 CCACCCCA Intron 54 UGGCUGUAAUAAU UUUCACCACCCCA TTTCACCACCCCA1020 GGGGUGGUGAAA 2321 UUAUUACAGCCA 3622 TTATTACAGCCA Intron 54 GGCUGUAAUAAUG UUUCACCACCCCA TTTCACCACCCCA1021 GGGUGGUGAAA 2322 UUAUUACAGCC 3623 TTATTACAGCC Intron 54 UGGGGUGGUGAAA CAUCCAGUUUCAC CATCCAGTTTCAC1022 CUGGAUG 2323 CACCCCA 3624 CACCCCA Intron 54 UGGGGUGGUGAAA UCCAUCCAGUUUC TCCATCCAGTTTC1023 CUGGAUGGA 2324 ACCACCCCA 3625 ACCACCCCA Intron 54 AUGGCAAGUAAGU GGAAAUGCCUGAC GGAAATGCCTGAC Exon 55 / intron 55 1024 CAGGCAUUUCC 2325 UUACUUGCCAU 3626 TTACTTGCCAT junction GCUGUAAUAAUGG AGUUUCACCACCC AGTTTCACCACCC1025 GGUGGUGAAACU 2326 CAUUAUUACAGC 3627 CATTATTACAGC Intron 54 AUGGGGUGGUGAA CAUCCAGUUUCAC CATCCAGTTTCAC1026 ACUGGAUG 2327 CACCCCAU 3628 CACCCCAT Intron 54 AUGGGGUGGUGAA CCAUCCAGUUUCA CCATCCAGTTTCA1027 ACUGGAUGG 2328 CCACCCCAU 3629 CCACCCCAT Intron 54 GCAAGUAAGUCAG GCGGAAAUGCCUG GCGGAAATGCCTG Exon 55 / intron 55 1028 GCAUUUCCGC 2329 ACUUACUUGC 3630 ACTTACTTGC junction GGCUGUAAUAAUG GUUUCACCACCCC GTTTCACCACCCC1029 GGGUGGUGAAAC 2330 AUUAUUACAGCC 3631 ATTATTACAGCC Intron 54 AAUGGGGUGGUGA CAUCCAGUUUCAC CATCCAGTTTCAC1030 AACUGGAUG 2331 CACCCCAUU 3632 CACCCCATT Intron 54 AUGGGGUGGUGAA UCCAUCCAGUUUC TCCATCCAGTTTC1031 ACUGGAUGGA 2332 ACCACCCCAU 3633 ACCACCCCAT Intron 54 UGGCAAGUAAGUC GCGGAAAUGCCUG GCGGAAATGCCTG Exon 55 / intron 55 1032 2333AGGCAUUUCCGC ACUUACUUGCCA 3634 ACTTACTTGCCA junction 121 / 350#14837954v1GCUGUAAUAAUGG UUUCACCACCCCA TTTCACCACCCCA1033 GGUGGUGAAA 2334 UUAUUACAGC 3635 TTATTACAGC Intron 54 UAAUGGGGUGGUG CAUCCAGUUUCAC CATCCAGTTTCAC1034 AAACUGGAUG 2335 CACCCCAUUA 3636 CACCCCATTA Intron 54 UAAUGGGGUGGUG CCAUCCAGUUUCA CCATCCAGTTTCA1035 AAACUGGAUGG 2336 CCACCCCAUUA 3637 CCACCCCATTA Intron 54 AAUGGGGUGGUGA CCAUCCAGUUUCA CCATCCAGTTTCA1036 AACUGGAUGG 2337 CCACCCCAUU 3638 CCACCCCATT Intron 54 AUGGCAAGUAAGU GAAAUGCCUGACU GAAATGCCTGACT Exon 55 / intron 55 1037 CAGGCAUUUC 2338 UACUUGCCAU 3639 TACTTGCCAT junction GGCAAGUAAGUCA GCGGAAAUGCCUG GCGGAAATGCCTG Exon 55 / intron 55 1038 GGCAUUUCCGC 2339 ACUUACUUGCC 3640 ACTTACTTGCC junction GGCAAGUAAGUCA AGCGGAAAUGCCU AGCGGAAATGCCT Exon 55 / intron 55 1039 GGCAUUUCCGCU 2340 GACUUACUUGCC 3641 GACTTACTTGCC junction AAUGGGGUGGUGA UCCAUCCAGUUUC TCCATCCAGTTTC1040 AACUGGAUGGA 2341 ACCACCCCAUU 3642 ACCACCCCATT Intron 54 GGGUGGUGAAACU UCCAUCCAGUUUC TCCATCCAGTTTC1041 GGAUGGA 2342 ACCACCC 3643 ACCACCC Intron 54 AUAAUGGGGUGGU CAUCCAGUUUCAC CATCCAGTTTCAC1042 GAAACUGGAUG 2343 CACCCCAUUAU 3644 CACCCCATTAT Intron 54 AUAAUGGGGUGGU CCAUCCAGUUUCA CCATCCAGTTTCA1043 GAAACUGGAUGG 2344 CCACCCCAUUAU 3645 CCACCCCATTAT Intron 54 UAAUGGGGUGGUG UCCAUCCAGUUUC TCCATCCAGTTTC1044 AAACUGGAUGGA 2345 ACCACCCCAUUA 3646 ACCACCCCATTA Intron 54 AAUGGCAAGUAAG GAAAUGCCUGACU GAAATGCCTGACT Exon 55 / intron 55 1045 UCAGGCAUUUC 2346 UACUUGCCAUU 3647 TACTTGCCATT junction AAUAAUGGGGUGG CAUCCAGUUUCAC CATCCAGTTTCAC1046 UGAAACUGGAUG 2347 CACCCCAUUAUU 3648 CACCCCATTATT Intron 54 AAUGGCAAGUAAG GGAAAUGCCUGAC GGAAATGCCTGAC Exon 55 / intron 55 1047 UCAGGCAUUUCC 2348 UUACUUGCCAUU 3649 TTACTTGCCATT junction UGGCAAGUAAGUC GGAAAUGCCUGAC GGAAATGCCTGAC Exon 55 / intron 55 1048 AGGCAUUUCC 2349 UUACUUGCCA 3650 TTACTTGCCA junction CCGAUGAUGCAGU GUAACAGGACUGC GTAACAGGACTGC1049 CCUGUUAC 2350 AUCAUCGG 3651 ATCATCGG Exon 56 UCCAAAUUCACAU ACAAGCGAUGAAU ACAAGCGATGAAT1050 UCAUCGCUUGU 2351 GUGAAUUUGGA 3652 GTGAATTTGGA Intron 55 GUAAUAAUGGGGU GUUUCACCACCCC GTTTCACCACCCC1051 GGUGAAAC 2352 AUUAUUAC 3653 ATTATTAC Intron 54 GCUGUAAUAAUGG GUUUCACCACCCC GTTTCACCACCCC1052 GGUGGUGAAAC 2353 AUUAUUACAGC 3654 ATTATTACAGC Intron 54 GCUUUGGAAGAAA GUAAUCUAUGAGU GTAATCTATGAGT1053 CUCAUAGAUUAC 2354 UUCUUCCAAAGC 3655 TTCTTCCAAAGC Exon 55 UUGGAAGAAACUC GCAGUAAUCUAUG GCAGTAATCTATG1054 AUAGAUUACUGC 2355 AGUUUCUUCCAA 3656 AGTTTCTTCCAA Exon 55 UGGAAGAAACUCA GCAGUAAUCUAUG GCAGTAATCTATG1055 UAGAUUACUGC 2356 AGUUUCUUCCA 3657 AGTTTCTTCCA Exon 55 UGGAAGAAACUCA UGCAGUAAUCUAU TGCAGTAATCTAT1056 UAGAUUACUGCA 2357 GAGUUUCUUCCA 3658 GAGTTTCTTCCA Exon 55 GGAAGAAACUCAU GCAGUAAUCUAUG GCAGTAATCTATG1057 AGAUUACUGC 2358 AGUUUCUUCC 3659 AGTTTCTTCC Exon 55 GAAGAAACUCAUA UGCAGUAAUCUAU TGCAGTAATCTAT1058 GAUUACUGCA 2359 GAGUUUCUUC 3660 GAGTTTCTTC Exon 55 AAACAACUGCCAA UGUAGGACAUUGG TGTAGGACATTGG1059 UGUCCUACA 2360 CAGUUGUUU 3661 CAGTTGTTT Exon 55 AAACAACUGCCAA CUGUAGGACAUUG CTGTAGGACATTG1060 UGUCCUACAG 2361 GCAGUUGUUU 3662 GCAGTTGTTT Exon 55 AACAACUGCCAAU GUAGGACAUUGGC GTAGGACATTGGC1061 GUCCUAC 2362 AGUUGUU 3663 AGTTGTT Exon 55 AACAACUGCCAAU UGUAGGACAUUGG TGTAGGACATTGG1062 2363 3664 Exon 55GUCCUACA CAGUUGUU CAGTTGTT122 / 350#14837954v1CAACUGCCAAUGU CUGUAGGACAUUG CTGTAGGACATTG 1063 CCUACAG 2364 GCAGUUG 3665 GCAGTTG Exon 55 AACUGCCAAUGUCCCUGUAGGACAUU CCTGTAGGACATT1064 CUACAGG 2365 GGCAGUU 3666 GGCAGTT Exon 55 GAUGAAAACAGCC GGAUUUUUUGGCU GGATTTTTTGGCT1065 AAAAAAUCC 2366 GUUUUCAUC 3667 GTTTTCATC Exon 56 GAUGAAAACAGCC AGGAUUUUUUGGC AGGATTTTTTGGC1066 AAAAAAUCCU 2367 UGUUUUCAUC 3668 TGTTTTCATC Exon 56 GAUGAAAACAGCC CAGGAUUUUUUGG CAGGATTTTTTGG1067 AAAAAAUCCUG 2368 CUGUUUUCAUC 3669 CTGTTTTCATC Exon 56 GAUGAAAACAGCC UCAGGAUUUUUUG TCAGGATTTTTTG1068 AAAAAAUCCUGA 2369 GCUGUUUUCAUC 3670 GCTGTTTTCATC Exon 56 AUGAAAACAGCCA CUCAGGAUUUUUU CTCAGGATTTTTT1069 AAAAAUCCUGAG 2370 GGCUGUUUUCAU 3671 GGCTGTTTTCAT Exon 56 UGAAAACAGCCAA CUCAGGAUUUUUU CTCAGGATTTTTT1070 AA...

Claims

1. CLAIMSWhat is claimed is:

1. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject:(i) a complex comprising an anti-TfR1 antibody covalently linked to a molecular payload, wherein the anti-TfR1 antibody comprises:(a) a heavy chain complementarity determining region 1 (CDR-H1) having the amino acid sequence of SEQ ID NO: 27, a heavy chain complementarity determining region 2 (CDR-H2) having the amino acid sequence of SEQ ID NO: 28, a heavy chain complementarity determining region 3 (CDR-H3) having the amino acid sequence of SEQ ID NO: 29, a light chain complementarity determining region 1 (CDR-L1) having the amino acid sequence of SEQ ID NO: 30, a light chain complementarity determining region 2 (CDR-L2) having the amino acid sequence of SEQ ID NO: 31, and a light chain complementarity determining region 3 (CDR-L3) having the amino acid sequence of SEQ ID NO: 32;(b) a CDR-H1 having the amino acid sequence of SEQ ID NO: 33, a CDR-H2 having the amino acid sequence of SEQ ID NO: 34, a CDR-H3 having the amino acid sequence of SEQ ID NO: 35, a CDR-L1 having the amino acid sequence of SEQ ID NO: 36, a CDR-L2 having the amino acid sequence of SEQ ID NO: 37, and a CDR- L3 having the amino acid sequence of SEQ ID NO: 32; or(c) a CDR-H1 having the amino acid sequence of SEQ ID NO: 38, a CDR-H2 having the amino acid sequence of SEQ ID NO: 39, a CDR-H3 having the amino acid sequence of SEQ ID NO: 40, a CDR-L1 having the amino acid sequence of SEQ ID NO: 41, a CDR-L2 having the amino acid sequence of SEQ ID NO: 31, and a CDR- L3 having the amino acid sequence of SEQ ID NO: 42; and(ii) a GCN2 inhibitor.

2. The method of claim 1, wherein the anti-TfR1 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 76 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 75.318 / 350#14837954v13. The method of claim 1 or claim 2, wherein the anti-TfR1 antibody comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 101 and a light chain comprising an amino acid sequence of SEQ ID NO: 90.

4. The method of any one of claims 1 to 3, wherein the anti-TfR1 antibody is a Fab.

5. The method of any one of claims 1 to 4, wherein the molecular payload is configured to modulate expression of a gene associated with the disease or disorder, and / or wherein the molecular payload is configured for inducing exon skipping.

6. The method of any one of claims 1 to 5, wherein the molecular payload comprises an oligonucleotide.

7. The method of claim 6, wherein the oligonucleotide comprises a region of complementarity to any one of SEQ ID NOs: 160-1460, optionally wherein the region of complementarity is at least 15 nucleotides in length.

8. The method of claim 6 or 7, wherein the oligonucleotide comprises at least 12 consecutive nucleotides of a sequence of any one of SEQ ID NOs: 1461-4062, wherein each thymine base (T) may independently and optionally be replaced with a uracil base (U), and each U may independently and optionally be replaced with a T.

9. The method of claim 8, wherein the oligonucleotide comprises a sequence of any one of SEQ ID NOs: 1461-4062, wherein each thymine base (T) may independently and optionally be replaced with a uracil base (U), and each U may independently and optionally be replaced with a T.

10. The method of any one of claims 1 to 9, wherein the complex comprises a structure of formula (J):319 / 350#14837954v1wherein n is any number from 0-10, wherein m is any number from 0-10, optionally wherein n is 3 and / or m is 4, and whereinrepresents an indirect or direct linkage.

11. The method of any one of claims 1 to 10, wherein the complex comprises a structure of formula (E):^-•molecular payload(E),wherein n is any number from 0-10, wherein m is any number from 0-10, optionally wherein n is 3 and / or m is 4.

12. The method of claim 11, wherein LI is a spacer that is a substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, -O-, -N(RA)-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NRA-, -NRAC(=O)-, -NRAC(=O)RA-, -C(=O)RA-, -NRAC(=O)O-, -NRAC(=O)N(RA)-, -OC(=O)-, -OC(=O)O-, -OC(=O)N(RA)-, -S(O)2NRA-, -NRAS(O)2-, or a combination thereof, wherein each RAis independently hydrogen or substituted or unsubstituted alkyl, optionally wherein LI is320 / 350#14837954v1; wherein a labels the site directly linked to the carbamate moiety of formula (I) and b labels the site covalently linked to the molecular payload.

13. The method of any one of claims 1 to 12, wherein the complex comprises a structure of formula (L): [R^ni- R2, in which each instance of R1comprises a structure of the formula (Lb-1):pC-pT-pC-pC-pA-pA-pC-pA-pT-pC-pA-pA-pG-pG-pA-pA-pG-pA-pT-pG-pG-pC-pA-pT-pT-pT-pC-pT-pA-pG-3' I(Lb-1),in which -pN indicates a base position of a phosphorodiamidate morpholino oligomer (PMO); wherein R1is covalently linked to R2at attachment point A, wherein R2comprises the antibody, wherein -p reflects a phosphorodiamidate linkage, and wherein N corresponds to a nucleobase of adenine (A), cytosine (C), guanine (G), or thymine (T), such that the PMO321 / 350#14837954v1comprises a base sequence of CTCCAACATCAAGGAAGATGGCATTTCTAG (SEQ ID NO: 2762).

14. The method of claim 11 or claim 12, wherein LI is:wherein a labels; wherein a labels the site directly linked to the carbamate moiety of formula (I) and b labels the site covalently linked to the molecular payload.

15. The method of claim 11 or claim 12, wherein LI is16. The method of any one of claims 1 to 15, wherein the GCN2 inhibitor is selected from the group consisting of:N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-2,5-dichlorobenzene-l-sulfonamide;N-{3-[(2-aminopyrimidin-5-yl)ethynyl]-2,4-difluorophenyl}-5-chl oro-2-methoxypyridine-3 -carboxamide;N-{3-[6-(2-aminopyrimidin-5-yl)pyridin-3-yl]-2,4-difluorophenyl}-5-chl oro-2-methoxypyridine-3 -sulfonamide;N-[3-(2-aminoquinazolin-7-yl)-2,4-difluorophenyl]-2,5-dichlorobenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-7-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;5-({3-[5-(5-chloro-2-methoxypyridin-3-yl)-l,3,4-oxadiazol-2-yl]-2,6-difluorophenyl}ethynyl)pyrimidin-2-amine;322 / 350#14837954v1N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-2,5-difluorobenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-3,4-dichlorobenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxybenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2-methylphenyl]-2,5-dichlorobenzene-1-sulfonamide; N-[3-(2-aminoquinazolin-6-yl)-2,6-difluorophenyl]-2,5-dichlorobenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2-fluorophenyl]-2,5-dichlorobenzene-l-sulfonamide; N-[3-(2-aminoquinazolin-6-yl)-5-fluorophenyl]-2,5-dichlorobenzene-l-sulfonamide; N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-2,4-dichlorobenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-4-methylphenyl]-2,5-dichlorobenzene-1-sulfonamide; N-[3-(4-aminoquinazolin-6-yl)-2,4-difluorophenyl]-2,5-dichlorobenzene-l-sulfonamide;2,5-dichloro-N-[2,4-difluoro-3-(7-fluoro-lH-benzimidazol-5-yl)phenyl]benzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-4-fluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-aminoquinolin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(3-aminoisoquinolin-7-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-aminopyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3 -sulfonamide;N-[3-(2-aminopyrido[3,2-d]pyrimidin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3 -sulfonamide;N-[3-(6-aminopyrido[2,3-b]pyrazin-2-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3 -sulfonamide;N-[3-(7-aminopyrido[3,4-b]pyrazin-3-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3 -sulfonamide;323 / 350#14837954v1N-[3-(2-aminopteridin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-aminoquinoxalin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(6-amino-9H-purin-8-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-amino-9H-purin-8-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(6-amino-9H-purin-2-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(8-amino-9H-purin-2-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;5-chloro-N-[2,4-difluoro-3-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-2-methoxypyridine-3 -sulfonamide;5-chloro-N-[2,4-difluoro-3-(7H-pyrrolo[3,2-d]pyrimidin-2-yl)phenyl]-2-methoxypyridine-3 -sulfonamide;N-[3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-amino-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3 -sulfonamide;N-[3-(4-amino-7H-pyrrolo[3,2-d]pyrimidin-2-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3 -sulfonamide;N-[3-(6-amino-7H-pyrrolo[3,2-d]pyrimidin-2-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3 -sulfonamide;5-chloro-N-[2,4-difluoro-3-(lH-indazol-6-yl)phenyl]-2-methoxypyridine-3-sulfonamide;5-chloro-N-[2,4-difluoro-3-(lH-pyrrolo[2,3-b]pyridin-6-yl)phenyl]-2-methoxypyridine-3 -sulfonamide;N-[3-(2-amino-lH-pyrrolo[2,3-b]pyridin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3 -sulfonamide;N-[3-(4-aminoquinazolin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;324 / 350#14837954v1N-[3-(3-amino-lH-indazol-6-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;5-chloro-N-[3-(2,4-diaminoquinolin-6-yl)-2,4-difluorophenyl]-2-methoxypyridine-3-sulfonamide;N-[3-(2-aminoquinazolin-8-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-aminoquinazolin-5-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;5-chloro-N-(2,4-difluoro-3-{2-[(2-hydroxyethyl)amino]quinazolin-6-yl}phenyl)-2-methoxypyridine-3 -sulfonamide;5-chloro-N-{2,4-difluoro-3-[2-(methylamino)quinazolin-6-yl]phenyl}-2-methoxypyridine-3 -sulfonamide;N-[3-(lH-benzimidazol-5-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-amino-1H-benzimidazol-5-yl)-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;5-chloro-N-[2,4-difluoro-3-(7-fluoro-lH-benzimidazol-5-yl)phenyl]-2-methoxypyridine-3 -sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2-methylphenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2-fluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-5-fluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,6-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-5-chloro-2,4-difluorobenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]sulfuric diamide;N-[3-(2-aminoquinazolin-6-yl)-4-fluorophenyl]-2,5-dichlorobenzene-l-sulfonamide; N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-5-chloro-2-(trifluoromethyl)benzene-l -sulfonamide;325 / 350#14837954v1N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-3,5-dichlorobenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-2-chloro-5-methylbenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-5-chloro-2-methylbenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-2,3-dichlorobenzene-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-3-chloro-5-(trifluoromethyl)benzene-l -sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]isoquinoline-5-sulfonamide; 5-chloro-N-[2,4-difluoro-3-(2-{[(lr,4r)-4-hydroxycyclohexyl]amino}quinazolin-6-yl)phenyl]-2-methoxypyridine-3-sulfonamide;5-chloro-N-[2,4-difluoro-3-(2-{[(2R)-l-hydroxypropan-2-yl]amino}quinazolin-6-yl)phenyl]-2-methoxypyridine-3-sulfonamide;2.5-dichloro-N-[2,4-difluoro-3-(2-{[(lr,4r)-4-hydroxycyclohexyl]amino}quinazolin-6-yl)phenyl]benzene-l -sulfonamide;2.5-dichloro-N-[2,4-difluoro-3-(2-{[(2R)-l-hydroxypropan-2-yl]amino}quinazolin-6-yl)phenyl]benzene- 1 -sulfonamide;2.5-dichloro-N-[2,4-difluoro-3-(2-{[(lr,4r)-4-hydroxycyclohexyl]amino}quinazolin-6-yl)phenyl]-3-(hydroxymethyl)benzene-l -sulfonamide;2.5-dichloro-N-[2,4-difluoro-3-(2-{[(2R)-l-hydroxypropan-2-yl]amino}quinazolin-6-yl)phenyl]-3-(hydroxymethyl)benzene-l -sulfonamide;6-[l-(5-chloro-2-methoxypyridine-3-sulfonyl)-5-fluoro-lH-indol-4-yl]quinazolin-2-amine;6-[l-(5-chloro-2-methoxypyridine-3-sulfonyl)-lH-indol-4-yl]quinazolin-2-amine; 6-[l-(5-chloro-2-methoxypyridine-3-sulfonyl)-5-fluoro-2,3-dihydro-lH-indol-4-yl]quinazolin-2-amine;6-[l-(5-chloro-2-methoxypyridine-3-sulfonyl)-2,3-dihydro-lH-indol-4-yl]quinazolin-2-amine;6-[l-(2,5-dichlorobenzene-l-sulfonyl)-5-fluoro-lH-indol-4-yl]quinazolin-2-amine; 6-[1-(2,5-dichlorobenzene-1-sulfonyl)-1H-indol-4-yl]quinazolin-2-amine;326 / 350#14837954v1{3-[4-(2-aminoquinazolin-6-yl)-5-fluoro-1H-indole-1-sulfonyl]-2,5-dichlorophenyl}methanol;6-[l-(2,5-dichlorobenzene-l-sulfonyl)-5-fluoro-2,3-dihydro-lH-indol-4-yl]quinazolin-2-amine;6-[l-(2,5-dichlorobenzene-l-sulfonyl)-2,3-dihydro-lH-indol-4-yl]quinazolin-2-amine;{3-[4-(2-aminoquinazolin-6-yl)-5-fluoro-2,3-dihydro-1H-indole-1-sulfonyl]-2,5-dichlorophenyl}methanol;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]cyclohexanesulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]piperidine-4-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-l-methylpiperidine-4-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]piperidine-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]piperazine-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-methylpiperazine-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]oxane-4-sulfonamide;(lr,4r)-N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-hydroxycyclohexane-l-sulfonamide;(ls,4s)-N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-hydroxycyclohexane-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]thiane-4-sulfonamide;(1r,4r)-N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-methoxycyclohexane-1-sulfonamide;(ls,4s)-N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-methoxycyclohexane-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]morpholine-4-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-hydroxypiperidine-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-(hydroxymethyl)piperidine-l-sulfonamide;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]thiomorpholine-4-sulfonamide;327 / 350#14837954v1(lr,4r)-N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-(hydroxymethyl)cyclohexane- 1 -sulfonamide;(ls,4s)-N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-4-(hydroxymethyl)cyclohexane- 1 -sulfonamide;3 - { [3 -(2-aminoquinazolin-6-yl)-2,4-difluoropheny 1] sulfamoyl } cyclohexane- 1 -carboxamide;3 - { [3 -(2-aminoquinazolin-6-yl)-2,4-difluoropheny 1] sulfamoyl } cyclohexane- 1 -carboxylic acid;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]piperidine-3-sulfonamide;3 - { [3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl] sulfamoyl }-N-methylcyclohexane-1 -carboxamide;methyl 3 - { [3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl] sulfamoyl } cyclohexane- 1 -carboxylate;N-[3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl]-6-methylpiperidine-3-sulfonamide;N-(6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pival amide;N-(6-(3((2,5-dichlorophenyl)sulfonamido)2,6-difluorophenyl)quinazolin-2-yl)acetamide;N-(3-(2-aminoquinolin-6-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide; N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2, 5-dichl oro-3 -(hydroxymethyl)benzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-chloro-2,5-dimethylbenzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-fluoro-2-methoxybenzenesulfonamide;N-(3-(2-aminoquinazolin-5-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide; N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,5-difluorobenzenesulfonamide; N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,5-dimethylbenzenesulfonamide; N-(5-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2,6-difluorophenyl)quinazolin-2-yl)pival amide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,4-dimethoxybenzenesulfonamide;328 / 350#14837954v1N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-fluorobenzenesulfonamide; N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-m ethoxy-3 -methylbenzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2-methoxy-5-methylbenzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-dimethoxybenzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-ethyl-2-methoxybenzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-bis(trifluoromethyl)benzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)benzofuran-5-sulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-fluoro-5-(trifluoromethyl)benzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,3-difluorobenzenesulfonamide; N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-methylbenzenesulfonamide; 2.5-dichloro-N-(3,5-difluoro-4-(2-((2-hydroxyethyl)amino)quinazolin-6-yl)pyridin-2-yl)benzenesulfonamide;5-chloro-N-(2,4-difluoro-3-(2-(((ls,4s)-4-hydroxycyclohexyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)pyridine-3-sulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-dichlorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,4-difluorobenzenesulfonamide; N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-5-fluoro-2-methylbenzenesulfonamide;2.5-dichloro-N-(2,4-difluoro-3-(2-((2-hydroxyethyl)amino)quinazolin-6-yl)phenyl)-3-(hydroxymethyl)benzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2-fluoro-5-(trifluoromethyl)benzenesulfonamide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-fluoro-3 -(trifluoromethyl)benzenesulfonamide;329 / 350#14837954v1N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-chloro-2-(trifluoromethyl)benzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)quinoxaline-5-sulfonamide; N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3 -(trifluoromethoxy )benzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)thiophene-3-sulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3-isopropylbenzenesulfonamide; N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)thiophene-2-sulfonamide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-fluoro-3 -methoxybenzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3,5-bis(trifluoromethyl)benzenesulfonamide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3 -(trifluoromethyl)benzenesulfonamide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-chl oro-3 -fluorobenzenesulfonamide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3 -chloro-4-methylbenzenesulfonamide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3 -chloro-4-methoxybenzenesulfonamide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-chl oro-3 -(trifluoromethyl)benzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,4,5-trichlorobenzenesulfonamide;5-chloro-N-(3-(2-((l,3-dihydroxypropan-2-yl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide;(R)-5-chloro-N-(2,4-difluoro-3-(2-((2-hydroxy-l-phenylethyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide;5-chloro-N-(3-(2-(dimethylamino)quinazolin-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3 -sulfonamide;5-chloro-N-(2,4-difluoro-3-(2-(piperidin-l-yl)quinazolin-6-yl)phenyl)-2-methoxypyridine-3 -sulfonamide;330 / 350#14837954v1(S)-5-chloro-N-(2,4-difluoro-3-(2-((l-hydroxypropan-2-yl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3 -chloro-4-fluorobenzenesulfonamide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-3 -fluoro-4-methylbenzenesulfonamide;N-(3 -(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-4-fluoro-3 -methylbenzenesulfonamide;N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-2,3-dihydro-lH-indene-5-sulfonamide;2.5-dichloro-N-(2,4-difluoro-3-(2-(methylamino)quinazolin-6-yl)phenyl)-3-(hydroxymethyl)benzenesulfonamide;(S)-5-chloro-N-(2,4-difluoro-3-(2-((2-hydroxy-l-phenylethyl)amino)quinazolin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide;5-chloro-N-(2,4-difluoro-3-(2-(((lr,4r)-4-hydroxycyclohexyl)amino)quinazolin-6-yl)phenyl)-2-(trifluoromethyl)benzenesulfonamide;5-chloro-N-(2,4-difluoro-3-(2-(((ls,4s)-4-hydroxycyclohexyl)amino)quinazolin-6-yl)phenyl)-2-(trifluoromethyl)benzenesulfonamide;(S)-5-chloro-N-(2,4-difluoro-3-(2-((2-hydroxy-l-phenylethyl)amino)quinazolin-6-yl)phenyl)-2-(trifluoromethyl)benzenesulfonamide;(R)-5-chloro-N-(2,4-difluoro-3-(2-((2-hydroxy-l-phenylethyl)amino)quinazolin-6-yl)phenyl)-2-(trifluoromethyl)benzenesulfonamide;2.5-dichloro-N-(2,4-difluoro-3-(2-((tetrahydrofuran-3-yl)amino)quinazolin-6-yl)phenyl)benzenesulfonamide;and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

17. The method of any one of claims 1 to 15, wherein the GCN2 inhibitor is selected from the compounds listed in Table 9, Table 10, Table 11, or Table 12, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

18. The method of any one of claims 1 to 15, wherein the GCN2 inhibitor is selected from the group consisting of:N-(3-((2-aminopyrimidin-5-yl)ethynyl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3 -sulfonamide;331 / 350#14837954v15-chloro-N-(2, 4-difluoro-3-((2-((trans-4-hydroxycyclohexyl)amino)pyrimidin-5- yl)ethynyl)phenyl)-2-methoxypyridine-3-sulfonamide;2,5-dichloro-N-(2,4-difluoro-3-((2-(((2R)-l-hydroxypropan-2-yl)amino)pyrimidin-5- yl)ethynyl)phenyl)-3-(hydroxymethyl)benzenesulfonamide;and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

19. The method of any one of claims 1 to 15, wherein the GCN2 inhibitor isor a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or wherein the GCN2 inhibitor isHor a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

20. The method of any one of claims 1 to 15, wherein the GCN2 inhibitor is selected from the group consisting of:6-(3-benzenesulfonamido-2,6-difluorophenyl)-7-fluoro-N-methyl-lH-indazole-3- carboxamide;6-[2,6-difluoro-3-[3-(hydroxymethyl)benzenesulfonamido]phenyl]-7-fluoro-N- methyl-lH-indazole-3-carboxamide;6- [2, 6-difluoro-3 - [3 -fluoro-5 -(hy droxymethyl)benzenesulfonamido]phenyl] -7 -fluoro-N-methyl-lH-indazole-3-carboxamide;6-(3-amino-2-fluorophenyl)-7-fluoro-N-methyl-l-[[2- (trimethylsilyl)ethoxy]methyl]indazole-3-carboxamide;332 / 350#14837954v1N-(6-(3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl)-7-fluoro-lH-indazol-3-yl)acetamide;6-[3-[5-chloro-2-(difluoromethoxy)pyridine-3-sulfonamido]-2,6-difluorophenyl]-7-fluoro-N-methyl-lH-indazole-3-carboxamide;6-[3-[5-cyano-2-(difluoromethoxy)pyridine-3-sulfonamido]-2,6-difluorophenyl]-7-fluoro-N-methyl-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N,4-dimethyl-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(2-methylpropyl)-lH-indazole-3-carboxamide;6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2,6-difluorophenyl)-N-ethyl-7-fluoro- lH-indazole-3 -carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(l-methyl-6-oxopiperidin-3-yl)-lH-indazole-3-carboxamide;N-(l-acetylpyrrolidin-3-yl)-6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(2-hydroxypropyl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(l-hydroxypropan-2-yl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(2-oxopyrrolidin-3-yl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(oxan-3-yl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(sec-butyl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(pyrrolidin-3-yl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-propyl-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(pentan-2-yl)-lH-indazole-3-carboxamide;333 / 350#14837954v16-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(4-hydroxybutan-2-yl)-lH-indazole-3-carboxamide;6-[3-(l-benzofuran-4-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-methyl-lH-indazole-3 -carboxamide;6-[3-(lH-l,3-benzodiazole-4-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-methyl-lH-indazole-3-carboxamide;6-[2,6-difluoro-3-(3-methyl-l,3-benzodiazole-4-sulfonamido)phenyl]-7-fluoro-N-methyl-lH-indazole-3-carboxamide;5-chloro-N-[2,4-difluoro-3-[7-fluoro-3-(l,3-oxazol-2-yl)-lH-indazol-6-yl]phenyl]-2-methoxypyridine-3 -sulfonamide;6-[2,6-difluoro-3-(5-fluoro-2-methylpyridine-3-sulfonamido)phenyl]-7-fluoro-N-methyl- lH-indazole-3-carboxamide;6-[2,6-difluoro-3-(5-fluoro-2-methylpyridine-3-sulfonamido)phenyl]-7-fluoro-N-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide;N-[2,4-difluoro-3-[7-fluoro-3-(hydrazinecarbonyl)-lH-indazol-6-yl]phenyl]-l-benzofuran-6-sulfonamide;6-[2,6-difluoro-3-(l-methyl-l,3-benzodiazole-4-sulfonamido)phenyl]-7-fluoro-N-methyl- lH-indazole-3-carboxamide;6-[2,6-difluoro-3-(5-fluoro-2-methoxypyridine-3-sulfonamido)phenyl]-7-fluoro-N-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[3-(5-cyano-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide;6-[3-(5-chloro-2-methylpyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide;5-chloro-N-[2,4-difluoro-3-(7-fluoro-lH-indazol-6-yl)phenyl]-2-methoxypyridine-3-sulfonamide;6-[3-(cyclopentylmethanesulfonamido)-2,6-difluorophenyl]-7-fluoro-N-methyl-lH-indazole-3 -carboxamide;6-[2,6-difluoro-3-(oxane-4-sulfonamido)phenyl]-7-fluoro-N-methyl-lH-indazole-3-carboxamide;334 / 350#14837954v16- [2, 6-difluoro-3 -(6-fluoro- 1 -hydroxy -2, 3 -dihydro- 1 H-indene-4-sulfonamido)phenyl]-7-fluoro-N-methyl-lH-indazole-3-carboxamide;6-[2,6-difluoro-3-(1-methylpiperidine-3-sulfonamido)phenyl]-7-fluoro-N-methyl-1H-indazole-3-carboxamide;6-[2,6-difluoro-3-[(3-hydroxycyclopentyl)methanesulfonamido]phenyl]-7-fluoro-N-methyl-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-cyclopentyl-7-fluoro-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(3-hydroxy cyclohexyl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-cyclopropyl-7-fluoro-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-ethoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(morpholin-4-ylmethyl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-[2-(pyrrolidin-l-yl)ethyl]-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(2-methanesulfonylethyl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-(cyclopropylmethyl)-7-fluoro-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-[2-(morpholin-4-yl)ethyl]-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(2-hydroxy cyclopentyl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(2-hydroxy cyclohexyl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(2-methylbut-3-yn-2-yl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(2,2,2-trifluoroethyl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-[cyano(cyclopropyl)methyl]-7-fluoro-lH-indazole-3-carboxamide;335 / 350#14837954v16-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(prop-2-yn- 1 -yl)- lH-indazole-3 -carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(piperidin-3-ylmethyl)-lH-indazole-3-carboxamide;N-(2-aminocyclohexyl)-6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-lH-indazole-3-carboxamide;N-(l-aminopropan-2-yl)-6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(4-oxocyclohexyl)-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-(3-hydroxy cyclopentyl)-lH-indazole-3-carboxamide;N-(3-aminocyclohexyl)-6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-[2-(2-oxopyrrolidin-l-yl)ethyl]-lH-indazole-3-carboxamide;6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-[(l-methylpyrrolidin-3-yl)methyl]-lH-indazole-3-carboxamide;6-[3-(l,3-dihydro-2-benzofuran-4-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-methyl- lH-indazole-3-carboxamide;6-[3-(2,3-dihydro-l-benzofuran-6-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-methyl- lH-indazole-3-carboxamide;6-[3-(2,3-dihydro-l-benzofuran-6-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-methyl-l-[[2-(trimethylsilyl)ethoxy]methyl]indazole-3-carboxamide;6-[3-(6-cyano-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamido)-2,6-difluorophenyl]-7-fluoro-N-methyl-lH-indazole-3-carboxamide;6- [2, 6-difluoro-3 -(6-fluoro- 1 -hydroxy -2, 3 -dihydro- 1 H-indene-4-sulfonamido)phenyl]-7-fluoro-N-methyl-lH-pyrazolo[4,3-c]pyridine-3-carboxamide; and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.336 / 350#14837954v121. The method of any one of claims 1 to 15, wherein the GCN2 inhibitor is, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

22. The method of any one of claims 1 to 15, wherein the GCN2 inhibitor is HCI-1046.

23. The method of any one of claims 1 to 15, wherein the GCN2 inhibitor is selected from the group consisting of:6-chloro-N-(2,4-difluoro-3 -(8-methoxy-2-(( l-(pyri din-2 -yl)piperidin-4-y 1 )amino)quinazolin-6-yl)pheny 1 )- 1 -hydroxy-2,3 -dihydro- lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((l-(pyridin-3-yl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((l-(pyridin-4-yl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(pyridin-2-yl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)- 1 -hydroxy -2, 3 -dihydro- lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(pyridin-3-yl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)- 1 -hydroxy -2, 3 -dihydro- lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(pyridin-4-yl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)- 1 -hydroxy -2, 3 -dihydro- lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxypropyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxycyclopentyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(l-methoxypropan-2-yl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-hydroxyethyl)piperidin-4-yl)amino)quinazolin- 6-yl)phenyl)- 1 -hydroxy-2,3 -dihydro- lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(tetrahydrofuran-3-yl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;337 / 350#14837954v16-chloro-N-(2,4-difluoro-3-(2-((1-propylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((3- ((methylamino)methyl)cyclopentyl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(3-(2-((3-(dimethylamino)propyl)amino)-8-methoxyquinazolin-6-yl)-2,4-difluorophenyl)- 1 -hydroxy-2,3 -dihydro- lH-indene-4-sulfonamide;6-chloro-N-(3-(2-((2-(dimethylamino)ethyl)amino)-8-methoxyquinazolin-6-yl)-2,4-difluorophenyl)- 1 -hydroxy-2,3 -dihydro- lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)- 1 -hydroxy- 1 -methyl-2, 3 -dihydro- lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)- 1 -oxo-2, 3 -dihydro- 1 H-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)- 1 -hydroxy -2, 3 -dihydro- lH-indene-4-sulfonamide- 1 -d;6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((3-(((2-methoxyethyl)(methyl)amino)methyl)cyclopentyl)amino)quinazolin-6-yl)phenyl)-l -hydroxy-2,3 -dihydro- 1 H-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)- 1 -hydroxy-2,3 -dihydro- lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-2,3-dihydrobenzofuran-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((3-(((2-methoxyethyl)amino)methyl)cyclopentyl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((1-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxy-2-methylpropyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)benzo[D][l,3]dioxole-4-sulfonamide;5-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-2,3-dihydrobenzofuran-7-sulfonamide;338 / 350#14837954v16-chloro-N-(2,4-difluoro-3-(8-methoxy-2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-((tetrahydrofuran-2-yl)methyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin-3-yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((1-isopropylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;6-chloro-N-(3-(2-((1-ethylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((1-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;N-(3-(8-ethyl-2-((4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;N-(2,4-difluoro-3-(2-((4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)phenyl)-6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;N-(2,4-difluoro-3-(2-((1-methylpiperidin-3-yl)amino)quinazolin-6-yl)phenyl)-6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;1-amino-N-(3-(2-aminoquinazolin-6-yl)-2,4-difluorophenyl)-6-chloro-2,3-dihydro-1H-indene-4-sulfonamide;N-(2,4-difluoro-3-(2-((1-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;N-(2,4-difluoro-3-(2-((1-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;N-(2,4-difluoro-3-(2-(piperidin-4-ylamino)quinazolin-6-yl)phenyl)-6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-(piperidin-4-ylamino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;339 / 350#14837954v16-chloro-N-(3-(8-ethyl-2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4-difluorophenyl)- 1 -hydroxy-2,3 -dihydro- lH-indene-4-sulfonamide;3-chloro-N-(3-(8-ethyl-2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-l-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-hydroxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l,5-dihydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-hydroxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l,7-dihydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-(piperidin-4-ylamino)quinazolin-6-yl)phenyl)-l-hydroxy-5-methoxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3 -(2-(piperidin-4-ylamino)quinazolin-6-yl)phenyl)- 1 -hydroxy-7-methoxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-hydroxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l,2-dihydroxy-2,3-dihydro-lH-indene-4-sulfonamide;3-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-l-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-3,3-dimethyl-2,3-dihydro-lH-indene-4-sulfonamide;5-chloro-N-(2,4-difluoro-3-(2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-4-hydroxychromane-8-sulfonamide;N-(3-(2-((4-aminocyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;N-(3-(2-((4-(bis(2-methoxyethyl)amino)cyclohexyl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-6-chloro-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;5-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((4-morpholinocyclohexyl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;340 / 350#14837954v16-chloro-N-(2,4-difluoro-3-(2-((l-(3,3,3-trifluoropropyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2, 4-difluoro-3-(2-(pyridin-4-ylamino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l -methyl- lH-pyrazol-4-yl)amino)quinazolin-6-yl)phenyl)- 1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-(trifluoromethoxy)ethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(8-fluoro-2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(5-fluoro-2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-23-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(5-fluoro-2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)- 1 -hydroxy-23 -dihydro- lH-indene-4-sulfonamide;5-chloro-N-(3-(8-ethyl-2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-3-hydroxy-23-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(2,4-difluoro-3-(8-methoxy-2-((l-methylpiperidin-4-yl)amino)quinazolin- 6-yl)phenyl)-3-hydroxy-23-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(2,4-difluoro-3-(5-fluoro-2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-3-hydroxy-23-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(3-(2-((l-ethylpiperidin-4-yl)amino)-5-fluoroquinazolin-6-yl)-2,4-difluorophenyl)-3-hydroxy-23-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(2,4-difluoro-3-(5-fluoro-2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-3-hydroxy-23-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(2,4-difluoro-3-(2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-3-hydroxy-23-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(2,4-difluoro-3-(5-fluoro-2-((l-isopropylpiperidin-4-yl)amino)quinazolin- 6-yl)phenyl)-3-hydroxy-23-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(3-(8-ethyl-2-((l-isopropylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-3-hydroxy-23-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(3-(2-((l-ethylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4-difluorophenyl)- 3-hydroxy-23-dihydrobenzofuran-7-sulfonamide;341 / 350#14837954v15-chloro-N-(3-(8-ethyl-2-((l-ethylpiperidin-4-yl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(3-(8-ethyl-2-((1-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)-2,4-difluorophenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(2,4-difluoro-3-(8-fluoro-2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(3-(2-((l-ethylpiperidin-4-yl)amino)-8-fluoroquinazolin-6-yl)-2,4-difluorophenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(2,4-difluoro-3-(8-fluoro-2-((l-isopropylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(2,4-difluoro-3-(8-fluoro-2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;5-chloro-N-(3-(2-((l-cyclopropylpiperidin-4-yl)amino)-5-fluoroquinazolin-6-yl)-2,4-difluorophenyl)-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;N-(3-(2-((4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;N-(3-(2-amino-8-ethylquinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;N-(3-(2-amino-8-ethylquinazolin-6-yl)-2,4-difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;N-(3-(2-amino-8-fluoroquinazolin-6-yl)-2,4-difluorophenyl)-5-chloro-3-hydroxy-2,3-dihydrobenzofuran-7-sulfonamide;N-(3-(2-amino-8-fluoroquinazolin-6-yl)-2,4-difluorophenyl)-6-chloro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(7-fluoro-2-((l-(2-methoxyethyl)piperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2,4-difluoro-3-(2-((l-(2-methoxyethyl)piperidin-4-yl)amino)-7-methylquinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;N-[3-(2-amino-5-fluoroquinazolin-6-yl)-2,4-difluorophenyl]-5-chloro-3-hydroxy-2,3-dihydro-l-benzofuran-7-sulfonamide;5-chloro-N-(3-{8-ethyl-5-fluoro-2-[(1-methylpiperidin-4-yl)amino]quinazolin-6-yl}-2,4-difluorophenyl)-3-hydroxy-2,3-dihydro-1-benzofuran-7-sulfonamide;342 / 350#14837954v1N-[3-(2-amino-5-fluoroquinazolin-6-yl)-2, 4-difluorophenyl]-6-chl oro-1 -hydroxy-2, 3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-[2,4-difluoro-3-(2-{ [l-(2 -methoxy ethyl)piperidin-4-yl]amino}-7-methylquinazolin-6-yl)phenyl]-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide, formic acid;6-chloro-N-[2,4-difluoro-3-(7-fluoro-2-{[l-(2-methoxyethyl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(2-fluoro-3-{2-[(l-methylpiperidin-4-yl)amino]quinazolin-6-yl}phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-(4-fluoro-3-(2-((l-methylpiperidin-4-yl)amino)quinazolin-6-yl)phenyl)-l-hydroxy-2,3-dihydro-lH-indene-4-sulfonamide;6-chloro-N-{2,4-difluoro-3-[2-(oxan-4-ylamino)quinazolin-6-yl]phenyl}-l -hydroxy-2,3 -dihydro- 1 H-indene-4-sulfonamide;5-chloro-N-{3-[8-ethyl-2-(piperidin-4-ylamino)quinazolin-6-yl]-2,4-difluorophenyl}-3-hydroxy-2,3-dihydro-l-benzofuran-7-sulfonamide;5-chloro-N-(3-{8-ethyl-2-[(l-ethylpiperidin-4-yl)amino]quinazolin-6-yl}-2-fluorophenyl)-3-hydroxy-2,3-dihydro-l-benzofuran-7-sulfonamide;5-chloro-N-[2-fluoro-3-(5-fluoro-2-{[l-(2-methoxyethyl)piperidin-4-yl]amino}quinazolin-6-yl)phenyl]-3-hydroxy-2,3-dihydro-l-benzofuran-7-sulfonamide;5-chloro-N-(2-fluoro-3-{5-fluoro-2-[(l-methylpiperidin-4-yl)amino]quinazolin-6-yl}phenyl)-3-hydroxy-2,3-dihydro-l-benzofuran-7-sulfonamide;5-chloro-N-{3-[8-ethyl-2-(oxan-4-ylamino)quinazolin-6-yl]-2,4-difluorophenyl}-3-hydroxy-2,3-dihydro-l-benzofuran-7-sulfonamide; and5-chloro-N-{2,4-difluoro-3-[5-fluoro-2-(piperidin-4-ylamino)quinazolin-6-yl]phenyl}-3-hydroxy-2,3-dihydro-l-benzofuran-7-sulfonamide;and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

24. The method of any one of claims 1 to 15, wherein the GCN2 inhibitor is selected from the compounds listed in Table 13, and pharmaceutically acceptable salts, stereoisomers, and tautomer thereof.

25. The method of any one of claims 1 to 15, wherein the GCN2 inhibitor is selected from the group consisting of:343 / 350#14837954v1#14837954v1#14837954v1#14837954v1OH347 / 350#14837954v1stereoisomers, and tautomers thereof.348 / 350#14837954v126. The method of any one of claims 1 to 25, wherein the complex delivers the molecular payload to a muscle cell, optionally wherein the muscle cell is a skeletal muscle cell, a smooth muscle cell, or a cardiac muscle cell.

27. The method of any one of claims 1 to 26, wherein the complex delivers the molecular payload to a cell of the CNS.

28. The method of any one of claims 1 to 27, wherein the payload comprises an oligonucleotide.

29. The method of any one of claims 1 to 28, wherein the molecular payload comprises an oligonucleotide comprising a region of complementarity to a target sequence of an oligonucleotide listed in Table 8, optionally wherein the oligonucleotide comprises a sequence listed in Table 8.

30. The method of any one of claims 1 to 29, wherein the complex is administered to the subject intravenously, optionally wherein the administration is by intravenous infusion.

31. The method of any one of claims 1 to 30, wherein the GCN2 inhibitor is administered to the subject orally.

32. The method of any one of claims 1 to 31, wherein the subject has been diagnosed with or is suspected of having a muscular dystrophy, optionally wherein the muscular dystrophy is Duchenne muscular dystrophy.

33. The method of any one of claims 1 to 32, wherein the subject has a mutation amenable to exon skipping, optionally wherein the mutation amenable to exon skipping is in a dystrophin allele.349 / 350#14837954v1

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