EP4662323A2

EP4662323A2 - Muscle targeted capsids

Info

Publication number: EP4662323A2
Application number: EP24754142.8A
Authority: EP
Inventors: Sharif TABEBORDBAR; Saurav SESHADRI; Simon YE
Original assignee: Kate Therapeutics Inc
Current assignee: Kate Therapeutics Inc
Priority date: 2023-02-09
Filing date: 2024-02-09
Publication date: 2025-12-17
Also published as: CN120882875A; JP2026505401A; WO2024168266A2; WO2024168266A3

Abstract

The present invention provides novel capsid variants for viral vectors that target muscle tissues.

Description

Attorney Docket No.: KATE-019/01WO 36391/113 MUSCLE TARGETING CAPSIDS FIELD OF DISCLOSURE This disclosure relates to viral capsids. BACKGROUND Recombinant AAVs (rAAVs) are the most commonly used delivery vehicles for gene therapy and gene editing. Nonetheless, rAAVs that contain natural capsid variants have limited cell tropism. Indeed, rAAVs used today mainly infect the liver after systemic delivery. Further, the transduction efficiency of conventional rAAVs in other cell-types, tissues, and organs by these conventional rAAVs with natural capsid variants is limited. Therefore, AAV-mediated polynucleotide delivery for diseased that affect cells, tissues, and organs other than the liver, such as skeletal muscle, typically requires an injection of a large dose of virus (typically about 2 x 10¹⁴ vg/kg), which often results in liver toxicity. Furthermore, because large doses are required when using conventional rAAVs, manufacturing sufficient amounts of a therapeutic rAAV needed to dose adult patients is extremely challenging. Additionally, due to differences in gene expression and physiology, mouse and primate models respond differently to viral capsids. Transduction efficiency of different virus particles varies between different species, and as a result, preclinical studies in mice often do not accurately reflect results in primates, including humans. As such there exists a need for improved rAAVs for use in the treatment of various genetic diseases. SUMMARY The present invention provides novel capsid protein variants for viral vectors that target muscle tissues. The capsid protein variants comprise an amino acid sequence that results in muscle tropism. For example, capsid proteins variants of the invention may comprise a sequence as set forth in Tables 1-4. Notably, capsid protein variants on the invention comprise deletions, substitutions, and/or insertions relative to wild-type viral vector capsids. In aspects of the invention, the capsid protein comprises an amino acid sequence selected from column 1 of Table 2a or 4a and the amino acid sequence is in hypervariable region VIII (HVR VIII) relative to wild-type AAV9. The capsid protein variant may Attorney Docket No.: KATE-019/01WO 36391/113 comprise substitutions at amino acids 586, 587, and 588 relative to a wild-type AAV9 vector capsid. For example, the substitutions at amino acids 586, 587, and 588 relative to a wild- type AAV9 vector capsid may be an amino acid sequence selected from column 1 of one of Tables 2b or 4b. In aspects of the invention, the capsid protein variant may further comprise an insert. For example, the capsid protein may comprise a 7-mer insert selected from column 2 of one of Tables 2b or 4b. The insert may be in the location after amino acid 588 relative to a wild-type AAV9 vector. In aspects of the invention, the capsid protein comprises an amino acid sequence selected from column 1 of Table 1a or 3a and the amino acid sequence is in hypervariable region IV (HVR IV) relative to wild-type AAV9. The capsid protein variant may comprise substitutions at amino acids 453, 454, and 455 relative to a wild-type AAV9 vector capsid. For example, the substitutions at amino acids 453, 454, and 455 relative to a wild-type AAV9 vector capsid may be an amino acid sequence selected from column 1 of one of Tables 1b or 3b. In aspects of the invention, the capsid protein variant may further comprise an insert. For example, the capsid protein may comprise a 7-mer insert selected from column 2 of one of Tables 1b or 3b. The insert may be in the location after amino acid 455 relative to a wild-type AAV9 vector. Advantageously, viral vectors with capsid protein variants comprising an amino acid sequence as set forth in Tables 1a, 2a, 3a, or 4a exhibit increased muscle tropism as compared to an AAV vector that does not comprise amino acid sequence selected from column 1 of any one of Tables 1a, 2a, 3a, or 4a. Each of Tables 1-4 are described below: Table 1a and 1b below provide a selection of muscle targeting muscle tropic variants first developed in mice in which a ten-mer variant sequence is in hypervariable region IV (HVR IV) relative to wild-type AAV9. Table 2a and 2b below provide a selection of muscle targeting muscle tropic variants first developed in mice in which a ten-mer variant sequence is in hypervariable region VIII (HVR VIII) relative to wild-type AAV9. Table 3a and 3b below provide a selection of muscle targeting muscle tropic variants first developed in NHPs in which a ten-mer variant sequence is in hypervariable region IV (HVR IV) relative to wild-type AAV9. Attorney Docket No.: KATE-019/01WO 36391/113 Table 4a and 4b below provide a selection of muscle targeting muscle tropic variants first developed in NHPs in which a ten-mer variant sequence is in hypervariable region VIII (HVR VIII) relative to wild-type AAV9. As described, for the HVR IV variants, the 3 amino acids upstream are at positions 453, 454, and 455. The 7-mer insert for HVR IV variants starts with "RGD" and is inserted after amino acid 455. For the HVR VIII variants, the 3 amino acids upstream are at positions 586, 587, and 588. The 7-mer insert for HVR VIII variants starts with "RGD" and is inserted after amino acid 588. Table 1a: Mice HVR IV Capsid Variants SEQ SEQ Amino Acid ID ID : 2³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 6⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 3⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 0¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 7⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 4⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 1² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 8⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 5⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 2³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 9⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 6⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 3⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 0¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 7⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 4⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 1² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 8⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 5⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 2³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 9⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 6⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 3⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 0¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 7⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 4⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 1² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 8⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹

Attorney Docket No.: KATE-019/01WO 36391/113 Table 1b: Split Amino Acid Sequences from Table 1a First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 4⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 4⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 5⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 6⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 7⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 8⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 9⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 0¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 1² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ 3 aa Next 7 aa ID

Attorney Docket No.: KATE-019/01WO 36391/113 Table 2a: Mice HVR VIII Capsid Variants SEQ SEQ Amino Acid ID ID : 2³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 6⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 3⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 0¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 7⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 4⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 1² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 8⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 5⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 2³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 9⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 6⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 3⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 0¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 7⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 4⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 1² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 8⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 5⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 2³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 9⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 6⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 3⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 0¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 7⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 4⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 1² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 8⁹ ⁰ ¹

Attorney Docket No.: KATE-019/01WO 36391/113 Table 2b: Split Amino Acid Sequences from Table 2a First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 4⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 4⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 5⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 6⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 7⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 8⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 9⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 0¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 1² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ 3 aa Next 7 aa ID

Attorney Docket No.: KATE-019/01WO 36391/113 Table 3a: NHP HVR IV Capsid Variants SEQ SEQ Amino Acid ID ID : 2³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 8⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 5⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 2³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 9⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 6⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 3⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 0¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 7⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 4⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 1² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 8⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 5⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 2³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 9⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 6⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 3⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 0¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 7⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 4⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 1² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 8⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 5⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 2³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 9⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 6⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 3⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID : 0¹

Attorney Docket No.: KATE-019/01WO 36391/113 Table 3b: Split Amino Acid Sequences from Table 3a First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 4⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 4⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 5⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 6⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 7⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 8⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 9⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 0¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID : 1² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ 3 aa Next 7 aa ID

Attorney Docket No.: KATE-019/01WO 36391/113 Table 4a: NHP HVR VIII Capsid Variants SEQ SEQ Amino Acid ID ID 2³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 7⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 4⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 1² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 8⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 5⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 2³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 9⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 6⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 3⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 0¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 7⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 4⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 1² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 8⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 5⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 2³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 9⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 6⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 3⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 0¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 7⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 4⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 1² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 8⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 5⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 2³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ Attorney Docket No.: KATE-019/01WO 36391/113 SEQ SEQ Amino Acid ID ID 9⁰ ¹

Attorney Docket No.: KATE-019/01WO 36391/113 Table 4b: Split Amino Acid Sequences from Table 4a First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID 4⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID 4⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID 5⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID 6⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID 7⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID 8⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID 9⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID 0¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ First SEQ First SEQ 3 aa Next 7 aa ID 3 aa Next 7 aa ID 3 aa Next 7 aa ID 1² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ⁰ ¹ ² ³ ⁴ ⁵ ⁶ ⁷ Attorney Docket No.: KATE-019/01WO 36391/113 First SEQ 3 aa Next 7 aa ID

Attorney Docket No.: KATE-019/01WO 36391/113 DETAILED DESCRIPTION The present invention provides novel capsid protein variants for viral vectors that target muscle tissues. The capsid protein variants comprise an amino acid sequence that results in muscle tropism. For example, capsid proteins variants of the invention may comprise a sequence as set forth in Tables 1-4. Specifically, each of Tables 1-4 are described below: Table 1a and 1b below provide a selection of muscle targeting muscle tropic variants first developed in mice in which a ten-mer variant sequence is in hypervariable region IV (HVR IV) relative to wild-type AAV9. Table 2a and 2b below provide a selection of muscle targeting muscle tropic variants first developed in mice in which a ten-mer variant sequence is in hypervariable region VIII (HVR VIII) relative to wild-type AAV9. Table 3a and 3b below provide a selection of muscle targeting muscle tropic variants first developed in NHPs in which a ten-mer variant sequence is in hypervariable region IV (HVR IV) relative to wild-type AAV9. Table 4a and 4b below provide a selection of muscle targeting muscle tropic variants first developed in NHPs in which a ten-mer variant sequence is in hypervariable region VIII (HVR VIII) relative to wild-type AAV9. Adeno Associated Virus Vectors AAVs are particularly appropriate viral vectors for delivery of genetic material into mammalian cells. AAVs are not known to cause disease in mammals and cause a very mild immune response. Additionally, AAVs are able to infect cells in multiple stages whether at rest or in a phase of the cell replication cycle. Advantageously, AAV DNA is not regularly inserted into the host’s genome at random sites, reducing the oncogenic properties of this vector. AAVs have been engineered to deliver a variety of treatments, especially for genetic disorders caused by single nucleotide polymorphisms (“SNP”). Genetic diseases that have been studied in conjunction with AAV vectors include Cystic fibrosis, hemophilia, arthritis, macular degeneration, muscular dystrophy, Parkinson’s disease, congestive heart failure, and Alzheimer’s disease. The AAV can be used as a vector to deliver engineered nucleic acid to a Attorney Docket No.: KATE-019/01WO 36391/113 host and utilize the host’s own ribosomes to transcribe that nucleic acid into the desired proteins. See, e.g., West et al., Virology 160:38-47 (1987); U.S. Pat. No.4,797,368; WO 93/24641; Kotin, Human Gene Therapy 5:793-801 (1994); and Muzyczka, J. Clin. Invest. 94:1351 (1994). AAVs have some deficiency in their replication and/or pathogenicity and thus can be safer that adenoviral vectors. In some embodiments, the AAV can integrate into a specific site on chromosome 19 of a human cell with no observable side effects. In some embodiments, the capacity of the AAV vector, system thereof, and/or AAV particles can be up to about 4.7 kb. The AAV vector or system thereof can include one or more engineered capsid polynucleotides described herein. AAVs are small, replication-defective, nonenveloped viruses that infect humans and other primate species and have a linear single-stranded DNA genome. Naturally occurring AAV serotypes exhibit liver tropism. As a result, transfection of non-liver tissue with traditional AAV vectors is impeded by the virus’s natural liver tropism. Moreover, because the liver acts to break down substances delivered to a subject, transfection of non-liver tissue with unmodified AAV vectors requires higher dosing to provide sufficient viral load to overcome the liver and reach non-liver tissue. More than 30 naturally occurring serotypes of AAV are available. Many natural variants in the AAV capsid exist. AAV serotypes include, but are not limited to, AAV serotypes AAV1, AAV2, AAV3, AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV 12, AAV13. AAVs may be engineered using conventional molecular biology techniques, making it possible to optimize these particles, for example, for cell specific delivery, for minimizing immunogenicity, for tuning stability and particle lifetime, for efficient degradation, for accurate delivery to the nucleus. AAV vectors can be specifically targeted to one or more types of cells by choosing the appropriate combination of AAV serotype, promoter, and delivery method. Previous approaches to identify AAV sequences correlated with tropism have relied upon the comparison of highly related extant serotypes with distinct characteristics, random domain swaps between unrelated serotypes, or consideration of higher-order structure, to identify motifs that define liver tropism. For example, mapping determinants of AAV tropism have been carried out by comparing highly related serotypes. One such example is the single-amino acid change (E531K) between AAV1 and AAV6 that improves murine liver transduction in AAV1. See Wu et al. (2006) J. Virol., 80(22):11393-7, incorporated by Attorney Docket No.: KATE-019/01WO 36391/113 reference herein. Another example is a reciprocal domain swap between AAV2 and AAV8 that alters tropism, but fails to define any robust specific tissue-targeting motifs. See Raupp et al. (201) J. Virol., 86(l7):9396-408, incorporated by reference herein. Further, global consideration of structure has only highlighted gross differences between better- or worse- liver-transducers that are more observational than useful in practice. Nam et al (2007) J. Virol., 81(22):12260-71. AAVs exhibiting modified tissue tropism that may be used with the present invention are described in U.S. Patent No.9,695,220, U.S. Patent No.9,719,070; U.S. Patent No. 10,119,125; U.S. Patent No.10,526,584; U.S. Patent Application Publication No.2018- 0369414; U.S. Patent Application Publication No.2020-0123504; U.S. Patent Application Publication No.2020-0318082; PCT International Patent Application Publication No. WO 2015/054653; PCT International Patent Application Publication No. WO 2016/179496; PCT International Patent Application Publication No. WO 2017/100791; and PCT International Patent Application Publication No. WO 2019/217911, the entirety of the contents of each of which are incorporated by reference herein. The AAV vector or system thereof may include one or more regulatory molecules, such as promoters, enhancers, repressors and the like. In some embodiments, the AAV vector or system thereof can include one or more polynucleotides that can encode one or more regulatory proteins. In some embodiments, the one or more regulatory proteins can be selected from Rep78, Rep68, Rep52, Rep40, variants thereof, and combinations thereof. In some embodiments, the muscle specific promoter can drive expression of an engineered AAV capsid polynucleotide. The AAV vector or system thereof can include one or more polynucleotides that can encode one or more capsid proteins, such as the engineered AAV capsid proteins described elsewhere herein. The engineered capsid proteins can be capable of assembling into a protein shell (an engineered capsid) of the AAV virus particle. The engineered capsid can have a cell-, tissue-, and/or organ-specific tropism. The AAV vector or system thereof can be configured to produce AAV particles having a specific serotype. In some embodiments, the serotype can be AAV-1, AAV-2, AAV-3, AAV-4, AAV-5, AAV-6, AAV-8, AAV-9 or any combinations thereof. In some embodiments, the AAV can be AAV1, AAV-2, AAV-5, AAV-9 or any combination thereof. Attorney Docket No.: KATE-019/01WO 36391/113 One can select the AAV of the AAV with regard to the cells to be targeted; e.g., one can select AAV serotypes 1, 2, 5, 9 or a hybrid capsid AAV-1, AAV-2, AAV-5, AAV-9 or any combination thereof for targeting brain and/or neuronal cells; and one can select AAV-4 for targeting cardiac tissue; and one can select AAV-8 for delivery to the liver. Thus, in some embodiments, an AAV vector or system thereof capable of producing AAV particles capable of targeting the brain and/or neuronal cells can be configured to generate AAV particles having serotypes 1, 2, 5 or a hybrid capsid AAV-1, AAV-2, AAV-5 or any combination thereof. In some embodiments, an AAV vector or system thereof capable of producing AAV particles capable of targeting cardiac tissue can be configured to generate an AAV particle having an AAV-4 serotype. In some embodiments, an AAV vector or system thereof capable of producing AAV particles capable of targeting the liver can be configured to generate an AAV having an AAV-8 serotype. See also Srivastava.2017. Curr. Opin. Virol.21:75-80. It will be appreciated that while the different serotypes can provide some level of cell, tissue, and/or organ specificity, each serotype still is multi-tropic and thus can result in tissue-toxicity if using that serotype to target a tissue that the serotype is less efficient in transducing. Thus, in addition to achieving some tissue targeting capacity via selecting an AAV of a particular serotype, it will be appreciated that the tropism of the AAV serotype can be modified by an engineered AAV capsid described herein. As described elsewhere herein, variants of wild-type AAV of any serotype can be generated via a method described herein and determined to have a particular cell-specific tropism, which can be the same or different as that of the reference wild-type AAV serotype. In some embodiments, the cell, tissue, and/or specificity of the wild-type serotype can be enhanced (e.g., made more selective or specific for a particular cell type that the serotype is already biased towards). For example, wild-type AAV-9 is biased towards muscle and brain in humans (see e.g., Srivastava.2017. Curr. Opin. Virol.21:75-80.) By including an engineered AAV capsid and/or capsid protein variant of wild-type AAV-9 as described herein, the tropism for nervous cells might be reduced or eliminated and/or the muscle specificity increased such that the nervous specificity appears reduced in comparison, thus enhancing the specificity for muscle as compared to the wild-type AAV-9. As previously mentioned, inclusion of an engineered capsid and/or capsid protein variant of a wild-type AAV serotype can have a different tropism than the wild-type reference AAV serotype. For example, an engineered AAV capsid Attorney Docket No.: KATE-019/01WO 36391/113 and/or capsid protein variant of AAV-9 can have specificity for a tissue other than muscle or brain in humans. In some embodiments, the AAV vector is a hybrid AAV vector or system thereof. Hybrid AAVs are AAVs that include genomes with elements from one serotype that are packaged into a capsid derived from at least one different serotype. For example, if it is the rAAV2/5 that is to be produced, and if the production method is based on the helper-free, transient transfection method discussed above, the 1st plasmid and the 3rd plasmid (the adeno helper plasmid) will be the same as discussed for rAAV2 production. However, the 2nd plasmid, the pRepCap will be different. In this plasmid, called pRep2/Cap5, the Rep gene is still derived from AAV2, while the Cap gene is derived from AAV5. The production scheme is the same as the above-mentioned approach for AAV2 production. The resulting rAAV is called rAAV2/5, in which the genome is based on recombinant AAV2, while the capsid is based on AAV5. It is assumed the cell or tissue-tropism displayed by this AAV2/5 hybrid virus should be the same as that of AAV5. It will be appreciated that wild-type hybrid AAV particles suffer the same specificity issues as with the non-hybrid wild-type serotypes previously discussed. Advantages achieved by the wild-type based hybrid AAV systems can be combined with the increased and customizable cell-specificity that can be achieved with the engineered AAV capsids can be combined by generating a hybrid AAV that can include an engineered AAV capsid described elsewhere herein. It will be appreciated that hybrid AAVs can contain an engineered AAV capsid containing a genome with elements from a different serotype than the reference wild-type serotype that the engineered AAV capsid is a variant of. For example, a hybrid AAV can be produced that includes an engineered AAV capsid that is a variant of an AAV-9 serotype that is used to package a genome that contains components (e.g., rep elements) from an AAV-2 serotype. As with wild-type based hybrid AAVs previously discussed, the tropism of the resulting AAV particle will be that of the engineered AAV capsid. In some embodiments, the AAV vector or system thereof is configured as a “gutless” vector, similar to that described in connection with a retroviral vector. In some embodiments, the “gutless” AAV vector or system thereof can have the cis-acting viral DNA elements Attorney Docket No.: KATE-019/01WO 36391/113 involved in genome amplification and packaging in linkage with the heterologous sequences of interest (e.g., the engineered AAV capsid polynucleotide(s)). The vectors described herein can be constructed using any suitable process or technique. In some embodiments, one or more suitable recombination and/or cloning methods or techniques can be used to the vector(s) described herein. Suitable recombination and/or cloning techniques and/or methods can include, but not limited to, those described in U.S. Application publication No. US 2004-0171156 A1. Other suitable methods and techniques are described elsewhere herein. Construction of recombinant AAV vectors are described in a number of publications, including U.S. Pat. No.5,173,414; Tratschin et al., Mol. Cell. Biol.5:3251-3260 (1985); Tratschin, et al., Mol. Cell. Biol.4:2072-2081 (1984); Hermonat & Muzyczka, PNAS 81:6466-6470 (1984); and Samulski et al., J. Virol.63:03822-3828 (1989). Any of the techniques and/or methods can be used and/or adapted for constructing an AAV or other vector described herein. AAV vectors are discussed elsewhere herein. In some embodiments, the vector can have one or more insertion sites, such as a restriction endonuclease recognition sequence (also referred to as a “cloning site”). In some embodiments, one or more insertion sites (e.g., about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more insertion sites) are located upstream and/or downstream of one or more sequence elements of one or more vectors. Delivery vehicles, vectors, particles, nanoparticles, formulations and components thereof for expression of one or more elements of a engineered AAV capsid system described herein are as used in the foregoing documents, such as International Patent Application Publications WO WO 2021/050974 and WO 2021/077000 and PCT International Application No. PCT/US2021/042812, the contents of which are incorporated by reference herein. Additional AAV vectors are described in International Patent Application Publication WO 2019/2071632, the contents of which are incorporated by reference herein. Further AAV vectors are described in International Patent Application Publications WO 2020/086881 and WO 2020/235543, the contents of each of which are incorporated by reference herein. Attorney Docket No.: KATE-019/01WO 36391/113 Further AAV vectors are described in International Patent Application Publications WO 2005/033321; WO 2006/110689; WO 2007/127264; WO 2008/027084; WO 2009/073103; WO 2009/073104; WO 2009/105084; WO 2009/134681; WO 2009/136977; WO 2010/051367; WO 2010/138675; WO 2001/038187; WO 2012/112832; WO 2015/054653; WO 2016/179496; WO 2017/100791; WO 2017/019994; WO 2018/209154; WO 2019/067982; WO 2019/195701; WO 2019/217911; WO 2020/041498; WO 2020/210839; U.S. Patent No.7,906,111; U.S. Patent No.9,737,618; U.S. Patent No.10,265,417; U.S. Patent No.10,485,883; U.S. Patent No.10,695,441; U.S. Patent No. 10,722,598; U.S. Patent No.8,999,678; U.S. Patent No.10,301,648; U.S. Patent No. 10,626,415; U.S. Patent No.9,198,984; U.S. Patent No.10,155,931; U.S. Patent No. 8,524,219; U.S. Patent No.9,206,238; U.S. Patent No.8,685,387; U.S. Patent No.9,359,618; U.S. Patent No.8,231,880; U.S. Patent No.8,470,310; U.S. Patent No.9,597,363; U.S. Patent No.8,940,290; U.S. Patent No.9,593,346; U.S. Patent No.10,501,757; U.S. Patent No.10,786,568; U.S. Patent No.10,973,928; U.S. Patent No.10,519,198; U.S. Patent No. 8,846,031; U.S. Patent No.9,617,561; U.S. Patent No.9,884,071; U.S. Patent No. 10,406,173; U.S. Patent No.9,596,220; U.S. Patent No.9,719,010; U.S. Patent No. 10,117,125; U.S. Patent No.10,526,584; U.S. Patent No.10,881,548; U.S. Patent No. 10,738,087; U.S. Patent Publication No.2011-023353; U.S. Patent Publication No.2019- 0015527; U.S. Patent Publication No.2020-155704; U.S. Patent Publication No 2017- 0191079; U.S. Patent Publication No.2019-0218574; U.S. Patent Publication No.2020- 0208176; U.S. Patent Publication No.2020-0325491; U.S. Patent Publication No.2019- 0055523; U.S. Patent Publication No.2020-0385689; U.S. Patent Publication No.2009- 0317417; U.S. Patent Publication No.2016-0051603; U.S. Patent Publication No.2016- 00244783; U.S. Patent Publication No.2017-0183636; U.S. Patent Publication No.2020- 0263201; U.S. Patent Publication No.2020-0101099; U.S. Patent Publication No.2020- 0318082; U.S. Patent Publication No.2018-0369414; U.S. Patent Publication No.2019- 0330278; U.S. Patent Publication No.2020-0231986, the contents of each of which are incorporated by reference herein. Capsid Protein Attorney Docket No.: KATE-019/01WO 36391/113 The capsid protein is the shell or coating of the virus that enables its delivery into the host. Without the protein, the nucleic acids would be destroyed by the host without entering into the host cells and beginning transcription and translation. The capsid protein may be in the natural conformation of a naturally occurring AAV, or it may be modified. In certain example embodiments, the AAV capsid protein is an engineered AAV capsid protein having reduced or eliminated uptake in a non-muscle cell as compared to a corresponding wild-type AAV capsid polypeptide. In some embodiments, the engineered AAV capsid encoding polynucleotide can be included in a polynucleotide that is configured to be an AAV genome donor in an AAV vector system that can be used to generate engineered AAV particles described elsewhere herein. In some embodiments, the engineered AAV capsid encoding polynucleotide can be operably coupled to a poly adenylation tail. In some embodiments, the poly adenylation tail can be an SV40 poly adenylation tail. In some embodiments, the AAV capsid encoding polynucleotide can be operably coupled to a promoter. In some embodiments, the promoter can be a tissue specific promoter. In some embodiments, the tissue specific promoter is specific for muscle (e.g., cardiac, skeletal, and/or smooth muscle), neurons and supporting cells (e.g., astrocytes, glial cells, Schwann cells, etc.), fat, spleen, liver, kidney, immune cells, spinal fluid cells, synovial fluid cells, skin cells, cartilage, tendons, connective tissue, bone, pancreas, adrenal gland, blood cell, bone marrow cells, placenta, endothelial cells, and combinations thereof. In some embodiments, the promoter can be a constitutive promoter. Suitable tissue specific promoters and constitutive promoters are discussed elsewhere herein and are generally known in the art and can be commercially available. Suitable muscle specific promoters include, but are not limited to CK8, MHCK7, Myoglobin promoter (Mb), Desmin promoter, muscle creatine kinase promoter (MCK) and variants thereof, and SPc5-12 synthetic promoter. Described herein are various embodiments of engineered viral capsids, such as adeno- associated virus (AAV) capsids, that can be engineered to confer cell-specific tropism, such as muscle specific tropism, to an engineered viral particle. Engineered viral capsids can be lentiviral, retroviral, adenoviral, or AAV capsids. The engineered capsids can be included in an engineered virus particle (e.g., an engineered lentiviral, retroviral, adenoviral, or AAV virus particle), and can confer cell-specific tropism, reduced immunogenicity, or both to the Attorney Docket No.: KATE-019/01WO 36391/113 engineered viral particle. The engineered viral capsids described herein can include one or more engineered viral capsid proteins described herein. The engineered viral capsids described herein can include one or more engineered viral capsid proteins described herein that can contain a muscle-specific targeting moiety containing or composed of an n-mer motif described elsewhere herein. The engineered viral capsid and/or capsid proteins can be encoded by one or more engineered viral capsid polynucleotides. In some embodiments, the engineered viral capsid polynucleotide is an engineered AAV capsid polynucleotide, engineered lentiviral capsid polynucleotide, engineered retroviral capsid polynucleotide, or engineered adenovirus capsid polynucleotide. In some embodiments, an engineered viral capsid polynucleotide (e.g., an engineered AAV capsid polynucleotide, engineered lentiviral capsid polynucleotide, engineered retroviral capsid polynucleotide, or engineered adenovirus capsid polynucleotide) can include a 3’ polyadenylation signal. The polyadenylation signal can be an SV40 polyadenylation signal. The engineered viral capsids can be variants of wild-type viral capsid. For example, in some embodiments, the engineered AAV capsids can be variants of wild-type AAV capsids. In some embodiments, the wild-type AAV capsids can be composed of VP1, VP2, VP3 capsid proteins or a combination thereof. In other words, the engineered AAV capsids can include one or more variants of a wild-type VP1, wild-type VP2, and/or wild-type VP3 capsid proteins. In some embodiments, the serotype of the reference wild-type AAV capsid can be AAV-1, AAV-2, AAV-3, AAV-4, AAV-5, AAV-6, AAV-8, AAV-9 or any combination thereof. In some embodiments, the serotype of the wild-type AAV capsid can be AAV-9. The engineered AAV capsids can have a different tropism than that of the reference wild-type AAV capsid. The engineered viral capsid can contain 1-60 engineered capsid proteins. In some embodiments, the engineered viral capsids can contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 engineered capsid proteins. In some embodiments, the engineered viral capsid can contain 0- 59 wild-type viral capsid proteins. In some embodiments, the engineered viral capsid can contain 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, Attorney Docket No.: KATE-019/01WO 36391/113 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59 wild-type viral capsid proteins. In some embodiments, the engineered AAV capsid can contain 1-60 engineered capsid proteins. In some embodiments, the engineered AAV capsids can contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 engineered capsid proteins. In some embodiments, the engineered AAV capsid can contain 0-59 wild-type AAV capsid proteins. In some embodiments, the engineered AAV capsid can contain 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59 wild-type AAV capsid proteins. In some embodiments, the engineered viral capsid protein can have an n-mer amino acid motif, where n can be at least 3 amino acids. In some embodiments, n can be 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids. In some embodiments, an engineered AAV capsid can have a 6-mer or 7-mer amino acid motif. In some embodiments, the n-mer amino acid motif can be inserted between two amino acids in the wild-type viral protein (VP) (or capsid protein). In some embodiments, the n-mer motif can be inserted between two amino acids in a variable amino acid region in a viral capsid protein. In some embodiments, the n-mer motif can be inserted between two amino acids in a variable amino acid region in an AAV capsid protein. The core of each wild-type AAV viral protein contains an eight-stranded beta-barrel motif (betaB to betaI) and an alpha-helix (alphaA) that are conserved in autonomous parvovirus capsids (see e.g., DiMattia et al.2012. J. Virol.86(12):6947-6958). Structural variable regions (VRs) occur in the surface loops that connect the beta-strands, which cluster to produce local variations in the capsid surface. AAVs have 12 variable regions (also referred to as hypervariable regions) (see e.g., Weitzman and Linden.2011. “Adeno-Associated Virus Biology.” In Snyder, R.O., Moullier, P. (eds.) Totowa, NJ: Humana Press). In some embodiments, one or more n-mer motifs can be inserted between two amino acids in one or more of the 12 variable regions in the wild- type AVV capsid proteins. In some embodiments, the one or more n-mer motifs can be each be inserted between two amino acids in VR-I, VR-II, VR-III, VR-IV, VR-V, VR-VI, VR- Attorney Docket No.: KATE-019/01WO 36391/113 VII, VR-III, VR-IX, VR-X, VR-XI, VR-XII, or a combination thereof. In some embodiments, the n-mer can be inserted between two amino acids in the VR-III of a capsid protein. In some embodiments, the engineered capsid can have an n-mer inserted between any two contiguous amino acids between amino acids 262 and 269, between any two contiguous amino acids between amino acids 327 and 332, between any two contiguous amino acids between amino acids 382 and 386, between any two contiguous amino acids between amino acids 452 and 460, between any two contiguous amino acids between amino acids 488 and 505, between any two contiguous amino acids between amino acids 545 and 558, between any two contiguous amino acids between amino acids 581 and 593, between any two contiguous amino acids between amino acids 704 and 714 of an AAV9 viral protein. In some embodiments, the engineered capsid can have an n-mer inserted between amino acids 588 and 589 of an AAV9 viral protein. In some embodiments, the engineered capsid can have a 7-mer motif inserted between amino acids 588 and 589 of an AAV9 viral protein. In other embodiments, the motif inserted is a 10-mer motif, with replacement of amino acids 586-88 and an insertion before 589. SEQ ID NO.1 is a reference AAV9 capsid sequence for at least referencing the insertion sites discussed above. It will be appreciated that n-mers can be inserted in analogous positions in AAV viral proteins of other serotypes. In some embodiments as previously discussed, the n-mer(s) can be inserted between any two contiguous amino acids within the AAV viral protein and in some embodiments the insertion is made in a variable region. In some embodiments, the first 1, 2, 3, or 4 amino acids of an n-mer motif can replace 1, 2, 3, or 4 amino acids of a polypeptide into which it is inserted and preceding the insertion site. In some embodiments, the amino acids of the n-mer motif that replace 1 or more amino acids of the polypeptide into which the n-mer motif is inserted come before or immediately before an “RGD” in an n-mer motif. For example, in one or more of the 10-mer inserts, the first three amino acids shown can replace 1-3 amino acids into a polypeptide to which they may be inserted. Using an AAV as another non-limiting example, one or more of the n-mer motifs can be inserted into e.g., and AAV9 capsid prolylpeptide between amino acids 588 and 589 and the insert can replace amino acids 586, 587, and 588 such that the amino acid immediately preceding the n-mer motif after insertion is residue 585. It will be appreciated that this principle can apply in any other insertion context and is not necessarily limited to Attorney Docket No.: KATE-019/01WO 36391/113 insertion between residues 588 and 589 of an AAV9 capsid or equivalent position in another AAV capsid. It will further be appreciated that in some embodiments, no amino acids in the polypeptide into which the n-mer motif is inserted are replaced by the n-mer motif. In some embodiments, the AAV capsids or other viral capsids or compositions can be muscle-specific. In some embodiments, muscle-specificity of the engineered AAV or other viral capsid or other composition is conferred by a muscle specific n-mer motif incorporated in the engineered AAV or other viral capsid or other composition described herein. While not intending to be bound by theory, it is believed that the n-mer motif confers a 3D structure to or within a domain or region of the engineered AAV capsid or other viral capsid or other composition such that the interaction of the viral particle or other composition containing the engineered AAV capsid or other viral capsid or other composition described herein has increased or improved interactions (e.g., increased affinity) with a cell surface receptor and/or other molecule on the surface of a muscle cell. In some embodiments, the cell surface receptor is AAV receptor (AAVR). In some embodiments, the cell surface receptor is a muscle cell specific AAV receptor. In some embodiments, the cell surface receptor or other molecule is a cell surface receptor or other molecule selectively expressed on the surface of a muscle cell. In some embodiments, the cell surface receptor or molecule is an integrin or dimer thereof. In some embodiments, the cell surface receptor or molecule is an Vb6 integrin heterodimer. In some embodiments, a muscle specific engineered viral particle or other composition described herein containing the muscle-specific capsid, n-mer motif, or muscle- specific targeting moiety described herein can have an increased uptake, delivery rate, transduction rate, efficiency, amount, or a combination thereof in a muscle cell as compared to other cells types and/or other virus particles (including but not limited to AAVs) and other compositions that do not contain the muscle-specific n-mer motif of the present invention. First- and second-generation muscle specific AAV capsids were developed using a muscle specific promoter and the resulting capsid libraries were screened in mice and non- human primates as described elsewhere herein and/or in e.g., U.S. Provisional Application Serial Nos.62/899,453, 62/916,207, 63/018,454, 63/242,008, and No.63/345,14. Attorney Docket No.: KATE-019/01WO 36391/113 Incorporation by Reference References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Equivalents Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

Attorney Docket No.: KATE-019/01WO 36391/113 CLAIMS We claim: 1. An adeno-associated virus (AAV) vector comprising: a capsid protein comprising an amino acid sequence selected from column 1 of any one of Tables 1a, 2a, 3a, or 4a. 2. The AAV vector of claim 1, wherein the amino acid sequence is selected from column 1 of Table 2a or 4a and wherein the amino acid sequence is in hypervariable region VIII (HVR VIII) relative to wild-type AAV9. 3. The AAV vector of claim 2, wherein the capsid protein comprises substitutions at amino acids 586, 587, and 588 relative to a wild-type AAV9 vector capsid. 4. The AAV vector of claim 3, wherein the substitutions at amino acids 586, 587, and 588 relative to a wild-type AAV9 vector capsid are substituted with an amino acid sequence selected from column 1 of any one of Tables 2b or 4b. 5. The AAV vector of claim 4, wherein the capsid protein comprises a 7-mer insert selected from column 2 of any one of Tables 2b or 4b. 6. The AAV vector of claim 5, wherein the 7-mer insert is inserted after amino acid 588 relative to a wild-type AAV9 vector. 7. The AAV vector of claim 1, wherein the amino acid sequence is selected from column 1 of Table 1a or 3a and wherein the amino acid sequence is in hypervariable region IV (HVR IV) relative to wild-type AAV9. 8. The AAV vector of claim 7, wherein the capsid protein comprises substitutions at amino acids 453, 454, and 455 relative to a wild-type AAV9 vector capsid. Attorney Docket No.: KATE-019/01WO 36391/113 9. The AAV vector of claim 8, wherein the substitutions at amino acids 453, 454, and 465 relative to a wild-type AAV9 vector capsid are substituted with an amino acid sequence selected from column 1 of any one of Tables 1b or 3b. 10. The AAV vector of claim 9, wherein the capsid protein comprises a 7-mer insert selected from column 2 of any one of Tables 1b or 3b. 11. The AAV vector of claim 10, wherein the 7-mer insert is inserted after amino acid 455 relative to a wild-type AAV9 vector. 12. The AAV vector of claim 1, wherein the vector exhibits increased muscle tropism as compared to an AAV vector that does not comprise amino acid sequence selected from column 1 of any one of Tables 1a, 2a, 3a, or 4a.