Compositions of CCN3 polypeptides and uses thereof

Abstract

Provided are recombinant polypeptides or polypeptide complexes comprising CCN3 polypeptide or the portion thereof. The recombinant polypeptides or polypeptide complexes described herein are useful in methods for treating or preventing a bone disease or disorder.

Description

WSGR Docket No. 65459-704.601COMPOSITIONS OF CCN3 POLYPEPTIDES AND USES THEREOFCROSS REFERENCE

[0001] This application claims the benefit of the U. S. Provisional Application No. 63 / 760,957, filed February 20, 2025, and U. S. Provisional Application No. 63 / 787,202, filed April 11, 2025, each of which is incorporated herein by reference in its entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 65459-704_601_SL.xml, created on February 10, 2026, which is 443,995 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety.INCORPORATION BY REFERENCE

[0003] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.SUMMARY

[0004] Provided herein, in some embodiments, is a recombinant polypeptide or polypeptide complex comprising a cellular communication network factor 3 (CCN3) polypeptide or a portion thereof and a fragment crystallizable (Fc) region. In some embodiments, the Fc region is covalently linked to the amino terminus of the CCN3 polypeptide or the portion thereof. In some embodiments, the Fc region is covalently linked to the carboxyl terminus of the CCN3 polypeptide or the portion thereof. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to the wildtype CCN3 or a fragment thereof. In some embodiments, the CCN3 polypeptide or the portion thereof comprises a truncation of at least one amino acid of the 19 amino acids at the carboxyl terminus of SEQ ID NO: 53. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence with at least 90% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or the fragment thereof and the truncation of at least one amino acid of the 19 amino acids at the carboxyl terminus of SEQ ID NO: 53. In some embodiments, the truncation comprises at least 2 amino acids. In some embodiments, the truncation comprises at least 3 amino acids. In some embodiments, the truncation comprises at least 4 amino acids. In some embodiments, the truncation comprises at least 5 amino acids. In some embodiments, the truncation comprises at least 6 amino acids. In some embodiments, the truncation comprises at least 7 amino acids. In some embodiments, the truncation comprises at least 8 amino acids. In some embodiments, the truncation comprises at least 9 amino acids. In some embodiments, the truncation comprises at least 10 amino acids.WSGR Docket No. 65459-704.601In some embodiments, the truncation comprises at least 11 amino acids. In some embodiments, the truncation comprises at least 12 amino acids. In some embodiments, the truncation comprises at least 13 amino acids. In some embodiments, the truncation comprises at least 14 amino acids. In some embodiments, the truncation comprises at least 15 amino acids. In some embodiments, the truncation comprises at least 16 amino acids. In some embodiments, the truncation comprises at least 17 amino acids. In some embodiments, the truncation comprises at least 18 amino acids. In some embodiments, the truncation comprises 19 amino acids. In some embodiments, the CCN3 polypeptide or the portion thereof further comprises a deletion of at least one amino acid of the 19 amino acids at the carboxyl terminus of SEQ ID NO: 53. In some embodiments, the deletion comprises a consecutive amino acid sequence. In some embodiments, the deletion comprises at least two nonconsecutive amino acid sequences. In some embodiments, the Fc region is covalently linked to the amino terminus of the CCN3 polypeptide or the portion thereof directly or through a peptide linker. In some embodiments, the Fc region is covalently linked to the carboxyl terminus of the CCN3 polypeptide or the portion thereof directly or through a peptide linker. In some embodiments, the peptide linker comprises a glycine (G) and serine (S) linker comprising (GGGGS)n (SEQ ID NO: 7), wherein n equals 1 to 5. In some embodiments, the peptide linker comprises an amino acid sequence of (EAAAK)n (SEQ ID NO: 5), wherein n equals 1 to 5. In some embodiments, the peptide linker comprises an amino acid sequence of A(EAAAK)nA (SEQ ID NO: 6), wherein n equals 1 to 5. In some embodiments, domains of the recombinant polypeptide or polypeptide complex are arranged, from the amino terminus to the carboxyl terminus, in the following order: (a) the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region; or (b) the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof. In some embodiments, domains of the recombinant polypeptide or polypeptide complex are arranged, from the amino terminus to the carboxyl terminus, in the following order: (a) the CCN3 polypeptide or the portion thereof and the Fc region; or (b) the Fc region and the CCN3 polypeptide or the portion thereof. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises a signal peptide at the amino terminus of the recombinant polypeptide or polypeptide complex. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises a first polypeptide and a second polypeptide, wherein the first polypeptide and the second polypeptide associate to form a homodimer or a heterodimer. In some embodiments, the first polypeptide or the second polypeptide comprises the CCN3 polypeptide or the portion thereof and the Fc region. In some embodiments, (i) the first polypeptide comprises the CCN3 polypeptide or the portion thereof and the Fc region and (ii) the second polypeptide comprises the CCN3 polypeptide or the portion thereof and the Fc region. In some embodiments, the first polypeptide or the second polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof. In some embodiments, (i) the first polypeptide comprises the CCN3 polypeptide or the portion thereof and the Fc region; and (ii) the second polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof. In some embodiments, (a) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region; and (b) domains of the secondWSGR Docket No. 65459-704.601polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region. In some embodiments, (a) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region; and (b) domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region. In some embodiments, (a) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region; and (b) domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region. In some embodiments, (a) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region; and (b) domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region. In some embodiments, (a) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof; and (b) domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof. In some embodiments, (a) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region and the CCN3 polypeptide or the portion thereof; and (b) domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof. In some embodiments, (a) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof; and (b) domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region and the CCN3 polypeptide or the portion thereof. In some embodiments, (a) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region and the CCN3 polypeptide or the portion thereof; and (b) domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region and the CCN3 polypeptide or the portion thereof. In some embodiments, (a) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region; and (b) the second polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof. In some embodiments, (a) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region; and (b) the second polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof. In some embodiments, (a) domains of the first polypeptide are arranged, from the amino terminus to theWSGR Docket No. 65459-704.601carboxyl terminus, in the following order: the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof; and (b) the second polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof. In some embodiments, (a) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region and the CCN3 polypeptide or the portion thereof; and (b) the second polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof. In some embodiments, the Fc region comprises an immunoglobulin (Ig) G, IgM, IgA, IgD, or IgE. In some embodiments, the Fc region comprises an IgG. In some embodiments, the Fc region comprises an IgGl, IgG2, IgG3, or IgG4. In some embodiments, the Fc region comprises an IgGl. In some embodiments, the Fc region comprises an IgG4. In some embodiments, the Fc region comprises a human IgG. In some embodiments, the Fc region comprises a human IgGl. In some embodiments, the Fc region comprises a human IgG4. In some embodiments, the Fc region comprises a first amino acid mutation that reduces or eliminates antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) or binding of the Fc region to a Fc-gamma receptor (FcyR). In some embodiments, the first amino acid mutation comprises a substitution of leucine (L) with alanine (A) at amino acid 234 according to the EU numbering (L234A). In some embodiments, the first amino acid mutation comprises a substitution of leucine (L) with alanine (A) at amino acid 235 according to the EU numbering (L235A). In some embodiments, the first amino acid mutation comprises a substitution of phenylalanine (F) with alanine (A) at amino acid 234 according to the EU numbering (F234A). In some embodiments, the first amino acid mutation comprises a substitution of proline (P) with glycine (G) at amino acid 329 according to the EU numbering (P329G). In some embodiments, the Fc region comprises a deletion of amino acid lysine (K) at amino acid 447 (K447) according to the EU numbering. In some embodiments, the Fc region comprises the first amino acid mutation comprising L234A and L235A. In some embodiments, the Fc region comprises the first amino acid mutation comprising L234A, L235A, and P329G. In some embodiments, the Fc region comprises the first amino acid mutation comprising L234A, L235A, and P329G and the deletion of K447. In some embodiments, the Fc region comprises an IgG4 comprising the first amino acid mutation comprising F234A and L235A. In some embodiments, the Fc region comprises an IgG4 comprising the first amino acid mutation comprising F234A and L235A and the deletion of K447. In some embodiments, (a) the Fc region of the first polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G and the deletion of K447; and (b) tlie Fc region of the second polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G and the deletion of K447. In some embodiments, (a) the Fc region of the first polypeptide comprises the first amino acid mutation comprising F234A and L235A and the deletion of K447; and (b) the Fc region of the second polypeptide comprises the first amino acid mutation comprising F234A and L235A and the deletion of K447. In some embodiments, (a) the Fc region of tire first poly peptide comprises the first amino acid mutation comprising F234A and L235A; and (b) the Fc region of the second polypeptide comprises the first amino acid mutation comprising F234A and L235A. In some embodiments, (a) the Fc region of the first polypeptide comprises the first amino acid mutation comprising L234A and L235A;WSGR Docket No. 65459-704.601and (b) the Fc region of the second polypeptide comprises the first amino acid mutation comprising L234A and L235A. In some embodiments, the Fc region comprises a second amino acid mutation that results in knob-into-hoie amino acid substitution. In some embodiments, the Fc region of first polypeptide comprises tire second amino acid mutation that results in a hole substitution and the Fc region of second polypeptide comprises the second amino acid mutation that results in the knob substitution. In some embodiments, the Fc region of the first polypeptide comprises the second amino acid mutati on that results in a knob substitution and the Fc region of the second poly peptide comprises the second amino acid mutation that results in a hole substitution. In some embodiments, the second amino acid mutation of the Fc region comprises: (a) a substitution of threonine (T) with tryptophan (W) at amino acid residue 366 according to the EU numbering (T366W); (b) a substitution of threonine (T) with serine (S) at amino acid residue 366 according to the EU numbering (T366S); (c) a substitution of leucine (L) with alanine (A) at amino acid residue 368 according to the EU numbering (L368A); or (d) a substitution of tyrosine (Y) with valine (V) at amino acid residue 407 according to the EU numbering (Y407V). In some embodiments, (a) the Fc region of the first polypeptide comprises the second amino acid mutation comprising T366W; and (b) the Fc region of the second polypeptide comprises the second amino acid mutation comprising T366S, L368A and Y407V. In some embodiments, (a) the Fc region of the first polypeptide comprises: (i) the first amino acid mutation comprising L234A, L235A, and P329G; and (ii) the second amino acid mutation comprising T366W; and (b) the Fc region of the second polypeptide comprises: (i) the first amino acid mutation comprising L234A, L235A, and P329G; and (ii) the second amino acid mutation comprising T366S, L368A and Y407V. In some embodiments, (a) the Fc region of the first polypeptide comprises: (i) the first amino acid mutation comprising L234A, L235A, and P329G and the deletion of K447; and (ii) the second amino acid mutation comprising T366W; and (b) the Fc region of the second polypeptide comprises: (i) the first amino acid mutation comprising L234A, L235A, and P329G and the deletion of K447; and (ii) the second amino acid mutation comprising T366S, L368A and Y407V. In some embodiments, the Fc region comprises a third amino acid mutation that stabilizes the hinge region of the Fc region, eliminates or inhibits an exchange of a fragment antigen binding (Fab) region, or both. In some embodiments, the third amino acid mutation comprises a substitution of serine (S) with proline (P) at amino acid 228 according to the EU numbering (S228P). In some embodiments, the Fc region comprises an IgG4 comprising the first amino acid mutation comprising F234A and L235A, the deletion of K447 and the third amino acid mutation comprising S228P. In some embodiments, the Fc region comprises a fourth amino acid mutation that increases the binding of the Fc region to the neonatal Fc receptor (FcRn), increases the half-life of the recombinant polypeptide or polypeptide complex, or both. In some embodiments, the fourth amino acid mutation comprises: (a) a substitution of methionine (M) with leucine (L) at amino acid 428 according to the EU numbering (M428L); (b) a substitution of asparagine (N) with serine (S) at amino acid 434 according to the EU numbering (N434S); (c) a substitution of methionine (M) with tyrosine (Y) at amino acid 252 according to the EU numbering (M252Y); (d) a substitution of serine (S) with threonine (T) at amino acid 254 according to the EU numbering (S254T); or (d) a substitution of threonine (T) withWSGR Docket No. 65459-704.601glutamic acid (E) at amino acid 254 according to the EU numbering (T256E). In some embodiments, the fourth amino acid mutation comprises M428L and N434S. In some embodiments, the fourth amino acid mutation comprises M252Y, S254T, and T256E. In some embodiments, the Fc region comprises the first amino acid mutation comprising L234A, L235A, and P329G, the deletion of K447, and the fourth amino acid mutation comprising M428L and N434S. In some embodiments, the Fc region comprises the first amino acid mutation comprising L234A, L235A, and P329G, the deletion of K447, and the fourth amino acid mutation comprising M252Y, S254T, and T256E. In some embodiments, (a) the Fc region of the first polypeptide comprises: (i) the first amino acid mutation comprising L234A, L235A, and P329G and the deletion of K447; (ii) tlie second amino acid mutation comprising T366W; and (iii) the fourth amino acid mutation comprising M428L and N434S; and (b) the Fc region of the second polypeptide comprises: (i) the first amino acid mutation comprising L234A, L235A, and P329G and the deletion of K447; (ii) the second amino acid mutation comprising T366S, L368A and Y407V; and (iii) the fourth amino acid mutation comprising M428L and N434S.

[0005] Provided herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises: (a) an insulin-like growth factor-binding protein (IGFBP) domain; (b) a von Willebrand factor type C (VWFC) domain; (c) a thrombospondin type-1 (TSP1) domain; or (d) a C-terminal cystine knot-like (CTCK) domain. In some embodiments, wherein the CCN3 polypeptide or the portion thereof consists of one, two, three, or four of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises one of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of one of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises one of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain and lacks the other three of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises two of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of two of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises two of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain and lacks the other two of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises three of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of three of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises three of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain and lacks the other one of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the IGFBP domain, the vWFC domain, the TSP1WSGR Docket No. 65459-704.601domain and the CTCK domain. In some embodiments, (a) the IGFBP domain consists of an amino acid sequence with at least 90% sequence identity to any one SEQ ID NOs: 15-16; (b) the VWFC domain consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 17-20 or 300-301 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain; (c) the TSP1 domain consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 21-25, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP1 domain; or / and (d) the CTCK domain consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 26-29, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain. In some embodiments, (a) the IGFBP domain consists of an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 15-16; (b) the VWFC domain consists of an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 17-20 or 300-301 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain; (c) the TSP1 domain consists of an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 21-25 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP1 domain; or / and (d) the CTCK domain consists of an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 26-29 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxy l terminus of the CTCK domain. In some embodiments, (a) the IGFBP domain consists of an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 15-16; (b) the VWFC domain consists of an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 17-20 or 300-301 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain; (c) the TSP1 domain consists of an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 21-25 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP1 domain; or / and (d) the CTCK domain consists of an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 26-29 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain. In some embodiments, (a) the IGFBP domain consists of the amino acid sequence of any one of SEQ ID NOs: 15-16; (b) the VWFC domain consists of the amino acid sequence of any one of SEQ ID NOs: 17-20 or 300-301 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain; (c) the TSP1 domain consists of the amino acid sequence of any one of SEQ ID NOs: 21-25 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP1 domain; or / and (d) the CTCK domain consists of the amino acid sequence of any one of SEQ ID NOs: 26-29 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain. In some embodiments, (a) the IGFBP domain comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 15-16; (b) the VWFC domain comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 17-20 or 300-301 or a portion thereofWSGR Docket No. 65459-704.601that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain; (c) the TSP1 domain comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 21-25 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP1 domain; or / and (d) the CTCK domain comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 26-29 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain. In some embodiments, (a) the IGFBP domain comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 15-16; (b) the VWFC domain comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 17-20 or 300-301 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain; (c) the TSP1 domain comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 21-25 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP1 domain; or / and (d) the CTCK domain comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 26-29 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain. In some embodiments, (a) the IGFBP domain comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 15-16; (b) the VWFC domain comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 17-20 or 300-301 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain; (c) the TSP1 domain comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 21-25 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP1 domain; or / and (d) the CTCK domain comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 26-29 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain. In some embodiments, (a) the IGFBP domain comprises the amino acid sequence of any one of SEQ ID NOs: 15-16; (b) the VWFC domain comprises the amino acid sequence of any one of SEQ ID NOs: 17-20 or 300-301 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain; (c) the TSP1 domain comprises the amino acid sequence of any one of SEQ ID NOs: 21-25 or aportion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP1 domain; or / and (d) the CTCK domain comprises the amino acid sequence of any one of SEQ ID NOs: 26-29 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 15-54 or 300-301. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 15-54 or 300-301. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 15-54 or 300-301. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the aminoWSGR Docket No. 65459-704.601acid sequence of any one of SEQ ID NOs: 15-54 or 300-301. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 15-54 or 300-301. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 15-54 or 300-301. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 15-54 or 300-301. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence of any one of SEQ ID NOs: 15-54 or 300-301. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to one of SEQ ID NOs: 15-29 or 300-301 and lacks an amino acid sequence with at least 90% sequence identity to any other of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the CCN3 polypeptide or the portion thereof comprises two amino acid sequences that each has at least 90% sequence identity to one of two of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the CCN3 polypeptide or the portion thereof consists of two amino acid sequences that each has at least 90% sequence identity to one of two of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the CCN3 polypeptide or the portion thereof comprises two amino acid sequences that each has at least 90% sequence identity to one of two of SEQ ID NOs: 15-29 or 300-301 and lacks an amino acid sequence with at least 90% sequence identity to any other of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the CCN3 polypeptide or the portion thereof comprises three amino acid sequences that each has at least 90% sequence identity to one of three of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the CCN3 polypeptide or the portion thereof consists of three amino acid sequences that each has at least 90% sequence identity to one of three of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the CCN3 polypeptide or the portion thereof comprises three amino acid sequences that each has at least 90% sequence identity to one of three of SEQ ID NOs: 15-29 or 300-301 and lacks an amino acid sequence with at least 90% sequence identity to any other of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the CCN3 polypeptide or the portion thereof comprises four amino acid sequences that each has at least 90% sequence identity to one of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the CCN3 polypeptide or the portion thereof consists of four amino acid sequences that each has at least 90% sequence identity to one of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments, the peptide linker comprises (GGGGS)s (SEQ ID NO: 339). In some embodiments, the peptide linker comprises AEAAAKA (SEQ ID NO: 332). In some embodiments, the Fc region comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 12. In some embodiments, the Fc region comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 12. In some embodiments, the Fc region comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 12. In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 12. In some embodiments, the Fc region of the first polypeptide comprises the amino acid sequence of SEQ ID NO: 12 and the Fc region of the second polypeptide comprises the amino acid sequence of SEQ ID NO: 12. In some embodiments, the Fc region comprises an amino acidWSGR Docket No. 65459-704.601sequence with at least 90% sequence identity to SEQ ID NO: 13. In some embodiments, the Fc region comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 13. In some embodiments, the Fc region comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 13. In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 13. In some embodiments, the Fc region comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 14. In some embodiments, the Fc region comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 14. In some embodiments, the Fc region comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 14. In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 14. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 13 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 14. In some embodiments, the Fc region of the first polypeptide comprises the amino acid sequence of SEQ ID NO: 13 and the Fc region of the second polypeptide comprises the amino acid sequence of SEQ ID NO: 14. In some embodiments, the Fc region comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 296-299 and 314. In some embodiments, the Fc region comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 296-299 and 314. In some embodiments, the Fc region comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 296-299 and 314. In some embodiments, the Fc region comprises the amino acid sequence of any one of SEQ ID NOs: 296-299 and 314. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 296 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 296. In some embodiments, the Fc region of the first polypeptide comprises the amino acid sequence of SEQ ID NO: 296 and the Fc region of the second polypeptide comprises the amino acid sequence of SEQ ID NO: 296. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 297 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 297. In some embodiments, the Fc region of the first polypeptide comprises the amino acid sequence of SEQ ID NO: 297 and the Fc region of the second polypeptide comprises the amino acid sequence of SEQ ID NO: 297. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 298 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 298. In some embodiments, the Fc region of the first polypeptide comprises the amino acid sequence of SEQ ID NO: 298 and the Fc region of the second polypeptide comprises the amino acid sequence of SEQ ID NO: 298. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 314 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 299. In someWSGR Docket No. 65459-704.601embodiments, the Fc region of the first polypeptide comprises the amino acid sequence of SEQ ID NO: 314 and the Fc region of the second polypeptide comprises the amino acid sequence of SEQ ID NO: 299.

[0006] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, wherein the CCN3 polypeptide or the portion thereof consist of an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence of SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of SEQ ID NO: 52. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 77. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 77. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 77. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the amino acid sequence of SEQ ID NO: 77. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 77 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 77. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0007] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises the IGFBP domain and the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of theIGFBP domain and the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the IGFBP domain and the vWFC domain and lacks the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consist of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 30-32. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence of any one of SEQ ID NOs: 30-32. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 30-32. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 30-32. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 30-32. In some embodiments, the CCN3 polypeptide or the portion thereofWSGR Docket No. 65459-704.601comprises the amino acid sequence of any one of SEQ ID NOs: 30-32. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 57. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 57. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 57. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 57. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 57 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 57. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 61. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 61. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 61. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 61. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 61 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 61. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0008] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises the vWFC domain and the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the vWFC domain and the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the vWFC domain and the TSP1 domain and lacks the IGFBP domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 33-38. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence of any one of SEQ ID NOs: 33-38. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 33-38. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 33-38. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 33-38. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of any one of SEQ ID NOs: 33-38. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 72. In some embodiments, the recombinant polypeptide or polypeptide complex, furtherWSGR Docket No. 65459-704.601comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 72. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 72. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 72. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 72 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 72. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0009] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the TSP1 domain and the CTCK domain and lacks the IGFBP domain and the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 41. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence of SEQ ID NO: 41. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 41. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 41. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 41. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of SEQ ID NO: 41. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 85. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 85. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 85. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 85. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 85 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 85. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 132. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 132. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 132. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acidWSGR Docket No. 65459-704.601sequence of SEQ ID NO: 132. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 132 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 132. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0010] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the TSP1 domain and the CTCK domain and lacks the IGFBP domain and the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 39-44. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence of any one of SEQ ID NOs: 39-44. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 39-44. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 39-44. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 39-44. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of any one of SEQ ID NOs: 39-44. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 62. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 62. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 62. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 62. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 62 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 62. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0011] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises the IGFBP domain and the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the IGFBP domain and the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the IGFBP domain and the vWFC domain and lacks the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 30-32. In some embodiments, the CCN3WSGR Docket No. 65459-704.601polypeptide or the portion thereof consists of the amino acid sequence of any one of SEQ ID NOs: 30-32. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 30-32. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 30-32. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 30-32. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of any one of SEQ ID NOs: 30-32. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 65. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 65. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 65. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 65. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 65 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 65. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 69. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 69. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 69. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 69. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 69 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 69. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0012] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence of SEQ ID NO: SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identityWSGR Docket No. 65459-704.601to SEQ ID NO: SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of SEQ ID NO: SEQ ID NO: 52. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 76. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 76. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 76. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 76. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 76 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 76. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 78. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 78. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 78. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 78. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 78 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 78. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0013] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises the IGFBP domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the IGFBP domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the IGFBP domain and lacks the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 15. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence of SEQ ID NO: 15. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 15. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 15. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 15. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of SEQ ID NO: 15. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 112. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises anWSGR Docket No. 65459-704.601amino acid sequence with at least 95% sequence identity to SEQ ID NO: 112. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 112. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 112. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 112 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 112. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 113. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 113. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 113. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 113. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 113 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 113. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 114. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 114. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 114. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 114. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 114 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 114. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 115. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 115. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 115. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 115. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 115 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 115. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.WSGR Docket No. 65459-704.601

[0014] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the vWFC domain and lacks the IGFBP domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 17. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence of SEQ ID NO: 17. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 17. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 17. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 17. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of SEQ ID NO: 17. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 116. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 116. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 116. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 116. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 116 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 116. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 117. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 117. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 117. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 117. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 117 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 117. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 118. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 118. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 118. In some embodiments, the recombinant polypeptide or polypeptide complex, furtherWSGR Docket No. 65459-704.601comprises the amino acid sequence of SEQ ID NO: 118. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 118 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 118. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 119. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 119. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 119. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 119. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 119 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 119. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0015] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the TSP1 domain and lacks the IGFBP domain, the vWFC domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 23. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence of SEQ ID NO: 23. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 23. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 23. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 23. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of SEQ ID NO: 23. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 120. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 120. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 120. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 120. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 120 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 120. In some embodiments, the recombinant polypeptide or polypeptide complex, furtherWSGR Docket No. 65459-704.601comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 121. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 121. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 121. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 121. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 121 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 121. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 122. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 122. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 122. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 122. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 122 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 122. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 123. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 123. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 123. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 123. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 123 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 123. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0016] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the CTCK domain and lacks the IGFBP domain, the vWFC domain and the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 28. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence of SEQ ID NO: 28. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 28. In someWSGR Docket No. 65459-704.601embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 28. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 28. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of SEQ ID NO: 28. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 128. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 128. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 128. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 128. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 128 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 128. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 129. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 129. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 129. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 129. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 129 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 129. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0017] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the TSP1 domain and the CTCK domain and lacks the IGFBP domain and the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 41. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence of SEQ ID NO: 41. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 41. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 41. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 41. In some embodiments, the CCN3 polypeptide or the portion thereofWSGR Docket No. 65459-704.601comprises the amino acid sequence of SEQ ID NO: 41. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 133. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 133. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 133. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 133. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 133 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 133. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 134. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 134. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 134. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 134. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 134 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 134. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0018] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence of SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of SEQ ID NO: 52. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 161. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 161. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 161. In some embodiments, the recombinant polypeptide or polypeptide complex, furtherWSGR Docket No. 65459-704.601comprises the amino acid sequence of SEQ ID NO: 161. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 161 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 162. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 162. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 162. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 162. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 162 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0019] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises the IGFBP domain and the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the IGFBP domain and the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the IGFBP domain and the vWFC domain and lacks the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 31. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence of SEQ ID NO: 31. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 31. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 31. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 31. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of SEQ ID NO: 31. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 163. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 163. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 163. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 163. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 163 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 14. In someWSGR Docket No. 65459-704.601embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 164. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 164. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 164. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 164. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 164 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0020] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, the CCN3 polypeptide or the portion thereof comprises the vWFC domain and the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the vWFC domain and the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the vWFC domain and the TSP1 domain and lacks the IGFBP domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 34. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence of SEQ ID NO: 34. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 34. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 34. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 34. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of SEQ ID NO: 34. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 165. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 165. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 165. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 165. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 165 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0021] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises the TSP1 domain and the CTCK domain.WSGR Docket No. 65459-704.601In some embodiments, the CCN3 polypeptide or the portion thereof consists of the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the TSP1 domain and the CTCK domain and lacks the IGFBP domain and the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 41. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence with at least 90% sequence identity to SEQ ID NO: 41. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 41. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 41. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 41. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of SEQ ID NO: 41. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 166. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 166. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 166. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 166. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 166 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 167. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 167. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 167. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 167. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 167 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 168. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 168. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 168. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of SEQ ID NO: 168. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the firstWSGR Docket No. 65459-704.601polypeptide comprising the amino acid sequence of SEQ ID NO: 168 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0022] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises the IGFBP domain and the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the IGFBP domain and the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the IGFBP domain and the vWFC domain and lacks the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 31. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence with at least 90% sequence identity to SEQ ID NO: 31. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 31. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 31. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 31. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of SEQ ID NO: 31. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 306, 310 and 324. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 306, 310 and 324. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 306, 310 and 324. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the amino acid sequence of any one of SEQ ID NOs: 306, 310 and 324. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 306 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 306. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 324 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 324. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 310 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 299. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0023] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portionWSGR Docket No. 65459-704.601thereof consist of an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence of SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of SEQ ID NO: 52. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 307, 311 and 325. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 307, 311 and 325. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 307, 311 and 325. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the amino acid sequence of any one of SEQ ID NOs: 307, 311 and 325. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 307 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 307. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 311 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 299. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 325 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 325. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0024] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the TSP1 domain and the CTCK domain and lacks the IGFBP domain and the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 41. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence with at least 90% sequence identity to SEQ ID NO: 41. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 41. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 41. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 41. In some embodiments, theWSGR Docket No. 65459-704.601CCN3 polypeptide or the portion thereof comprises the amino acid sequence of SEQ ID NO: 41. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 308 or 312. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 308 or 312. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 308 or 312. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the amino acid sequence of SEQ ID NO: 308 or 312. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 308 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 308. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 312 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 299. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0025] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the vWFC domain, the TSP1 domain and the CTCK domain and lacks the IGFBP domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 48. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence with at least 90% sequence identity to SEQ ID NO: 48. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 48. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 48. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 48. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of SEQ ID NO: 48. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 309, 313 and 327. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 309, 313 and 327. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 309, 313 and 327. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the amino acid sequence of any one of SEQ ID NOs: 309, 313 and 327. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the firstWSGR Docket No. 65459-704.601polypeptide comprising the amino acid sequence of SEQ ID NO: 309 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 309. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 313 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 299. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 327 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 327. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0026] Provide herein, in some embodiments, is the recombinant polypeptide or polypeptide complex, wherein the CCN3 polypeptide or the portion thereof comprises the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the vWFC domain, the TSP1 domain and the CTCK domain and lacks the IGFBP domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 48. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence with at least 90% sequence identity to SEQ ID NO: 48. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 48. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 48. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 48. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of SEQ ID NO: 48. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 302 -305. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 302 -305. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 302 -305. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the amino acid sequence of any one of SEQ ID NOs: 302 -305. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 302 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 302. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 303 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 303. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 304 and the second polypeptide comprising the amino acidWSGR Docket No. 65459-704.601sequence of SEQ ID NO: 304. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 305 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 305. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0027] In some embodiments, the CCN3 polypeptide or the portion thereof comprises theIGFBP domain, the vWFC domain, and the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof consist of an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 46. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence of SEQ ID NO: 46. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 46. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 46. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 46. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of SEQ ID NO: 46. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 89, 326 and 328. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 89, 326 and 328. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 89, 326 and 328. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the amino acid sequence of any one of SEQ ID NOs: 89, 326 and 328. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 89 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 326 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 326. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 328 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0028] In some embodiments, the CCN3 polypeptide or the portion thereof comprises theIGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence of SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or theWSGR Docket No. 65459-704.601portion thereof comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 52. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of SEQ ID NO: 52. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 157-160. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 157-160. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 157-160. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the amino acid sequence of any one of SEQ ID NOs: 157-160. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises: (a) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 157 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 157; (b) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 158 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 158; (c) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 159 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 159; or (d) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 160 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 160. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0029] In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 55, 56, 58-60, 63-64, 66-68, 70-71, 73-75, 79-84, 86-111, 124-127, 130-131, 135-160, 164, and 169-295. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 55, 56, 58-60, 63-64, 66-68, 70-71, 73-75, 79-84, 86-111, 124-127, 130-131, 135-160, 164, and 169-295. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 55, 56, 58-60, 63-64, 66-68, 70-71, 73-75, 79-84, 86-111, 124-127, 130-131, 135-160, 164, and 169-295. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises the amino acid sequence of any one of SEQ ID NOs: 55, 56, 58-60, 63-64, 66-68, 70-71, 73-75, 79-84, 86-111, 124-127, 130-131, 135-160, 164, and 169-295.

[0030] Further provided herein, in some embodiments, is a recombinant polypeptide or polypeptide complex comprising an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 55-295, 302-313, and 324-328. In some embodiments, the recombinant polypeptide or polypeptide complex comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 55-295, 302-313, and 324-328. In some embodiments, the recombinant polypeptide or polypeptideWSGR Docket No. 65459-704.601complex comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 55-295, 302-313, and 324-328. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the amino acid sequence of any one of SEQ ID NOs: 55-295, 302-313, and 324-328. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus. Provided herein, in some embodiments is a pharmaceutical composition comprising the recombinant polypeptide or polypeptide complex and a pharmaceutically acceptable carrier or excipient. Provided herein, in some embodiments is a nucleic acid sequence encoding the recombinant polypeptide or polypeptide complex. Provided herein, in some embodiments is a vector comprising the nucleic acid sequence encoding the recombinant polypeptide or polypeptide complex. In some embodiments, the vector further comprises a mammalian vector, a yeast vector, a bacterial vector, or a viral vector. Provided herein, in some embodiments is a cell comprising the recombinant polypeptide or polypeptide complex. In some embodiments, the cell comprises the nucleic acid sequence encoding the recombinant polypeptide or polypeptide complex. In some embodiments, the cell comprises the vector comprising the nucleic acid sequence encoding the recombinant polypeptide or polypeptide complex.

[0031] Provided herein, in some embodiments, is a method for treating a bone disease or disorder comprising administering to a subject the recombinant polypeptide or polypeptide complex, thereby treating the bone disease or disorder. In some embodiments, the method for treating a bone disease or disorder comprises administering to a subject the pharmaceutical composition comprising the recombinant polypeptide or polypeptide complex and a pharmaceutically acceptable carrier or excipient., thereby treating the bone disease or disorder. In some embodiments, the method for treating a bone disease or disorder comprises administering to a subject the nucleic acid sequence encoding the recombinant polypeptide or polypeptide complex, thereby treating the bone disease or disorder. In some embodiments, the method for treating a bone disease or disorder comprises administering to a subject the vector comprising the nucleic acid sequence encoding the recombinant polypeptide or polypeptide complex, thereby treating the bone disease or disorder. In some embodiments, the method for treating a bone disease or disorder comprising administering to a subject the cell comprises the recombinant polypeptide or polypeptide complex, the nucleic acid sequence encoding the recombinant polypeptide or polypeptide complex, or the vector comprising the nucleic acid sequence encoding the recombinant polypeptide or polypeptide complex, thereby treating the bone disease or disorder. In some embodiments, the bone disease or disorder comprises bone degeneration, osteoporosis, osteopenia, lactation, traumatic bone injury, pathologic bone injury, periprosthetic bone loss, osteolysis, menopause, obesity, anorexia nervosa, type 1 diabetes, chronic kidney disease, chronic liver disease, celiac disease, inflammatory bowel disease, lupus, rheumatoid arthritis, hyperthyroidism, hyperparathyroidism, cancer, multiple myeloma, a craniofacial disorder, premature ovarian failure, oral and maxillofacial surgery, plastic surgery, reconstructive surgery, ovariectomy, osteogenesis imperfecta, osteoarthritis, osteomalacia, metabolic bone disease, fibrous dysplasia, osteomyelitis, bone fracture, rickets, degenerative disc disease,WSGR Docket No. 65459-704.601osteonecrosis, renal osteodystrophy, Paget's disease, skeletal dysplasia, bone metastases, or otosclerosis. In some embodiments, the subject is human.

[0032] Provided herein, in some embodiments, is a recombinant polypeptide or polypeptide complex comprising a cellular communication network factor 3 (CCN3) polypeptide or a portion thereof and a moiety that increases half-life. In some embodiments, the moiety comprises an albumin, an albuminbinding molecule, a polypeptide or peptide comprising proline, alanine, and serine (PAS), a XTEN polypeptide, a polyethylene glycol (PEG), an elastin-like peptide (ELP), a lipid molecule, a sugar molecule, a glycan molecule, a sialic acid, a transferrin, a GlycoTAIL, or a FlexiTAIL. In some embodiments, the moiety comprises a human serum albumin (HSA) or mouse serum albumin (MSA). In some embodiments, the albumin-binding molecule is linked to the CCN3 polypeptide or the portion thereof through a chemical process or a genetic fusion. In some embodiments, the albumin-binding molecule comprises an antibody or an antigen-binding fragment thereof that binds to albumin. In some embodiments, the antibody or antigen-binding fragment thereof that binds to albumin comprises a single chain variable fragment (scFv), a fragment antigen-binding (Fab) region, a single domain antibody (VHH), a single domain antibody (sdAb), a nanobody, or a minibody. In some embodiments, the albumin-binding molecule comprises a knob domain, a designed ankyrin repeat protein (DARPin), an anticalin, a knottin, an avimer, an affibody, a fynomer, a fibronectin type III (FN3) domain, a linear peptide, a cyclic peptide, or an aptamer. In some embodiments, the lipid molecule is linked to the CCN3 polypeptide or portion thereof through palmitoylation, myristoylation, or prenylation. In some embodiments, the glycan molecule is linked to the CCN3 polypeptide or portion thereof through glycosylation or hyperglycosylation. In some embodiments, the sialic acid is linked to the CCN3 polypeptide or portion thereof through sialylation. In some embodiments, the albumin-binding molecule binds to a human serum albumin (HSA) or mouse serum albumin (MSA). In some embodiments, the CCN3 polypeptide or portion thereof and the moiety are linked to each other, directly or via a linker, through a covalent bond or a nonco valent bond.

[0033] In some embodiments, the CCN3 polypeptide or the portion thereof comprises or consists of one, two, three, or four of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises or consists of one of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises or consists of two of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises or consists of three of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, (a) the IGFBP domain comprises or consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 15-16; (b) the VWFC domain comprises or consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 17-20 and 300-301 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFCWSGR Docket No. 65459-704.601domain; (c) the TSP1 domain comprises or consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 21-25 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP 1 domain; or / and (d) the CTCK domain comprises or consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 26-29 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain. In some embodiments, (a) the IGFBP domain comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 15-16; (b) the VWFC domain comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 17-20 and 300-301 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain; (c) the TSP1 domain comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 21-25 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP 1 domain; or / and (d) the CTCK domain comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 26-29 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain.

[0034] In some embodiments, the CCN3 polypeptide or portion thereof comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 15-54 and 300-301. In some embodiments, the CCN3 polypeptide or portion thereof comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 15-54 and 300-301. In some embodiments, the CCN3 polypeptide or portion thereof comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 15-54 and 300-301. In some embodiments, the CCN3 polypeptide or portion thereof comprises the amino acid sequence of any one of SEQ ID NOs: 15-54 and 300-301. In some embodiments, the CCN3 polypeptide or portion thereof consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 15-54 and 300-301. In some embodiments, the CCN3 polypeptide or portion thereof consists of an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 15-54 and 300-301. In some embodiments, the CCN3 polypeptide or portion thereof consists of an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 15-54 and 300-301. In some embodiments, the CCN3 polypeptide or portion thereof consists of the amino acid sequence of any one of SEQ ID NOs: 15-54 and 300-301.

[0035] In some embodiments, domains of the recombinant polypeptide or polypeptide complex are arranged, from the amino terminus to the carboxyl terminus, in the following order: (a) the CCN3 polypeptide or the portion thereof and the albumin, wherein the CCN3 polypeptide or portion thereof and the albumin are linked to each other, directly or via a linker; or (b) the albumin and the CCN3 polypeptide or the portion thereof, wherein the CCN3 polypeptide or portion thereof and the albumin are linked to each other, directly or via a linker. In some embodiments, the linker comprises: (a) a glycine (G) and serine (S) linker comprising (GGGGS)n (SEQ ID NO: 7), wherein n equals 1 to 5; (b) an amino acid sequence of (EAAAK)n (SEQ ID NO: 5), wherein n equals 1 to 5; or (c) an amino acid sequence of A(EAAAK)nA (SEQ ID NO: 6), wherein n equals 1 to 5. In some embodiments, the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to SEQ IDWSGR Docket No. 65459-704.601NO: 52 or 53. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the amino acid sequence of SEQ ID NO: 52 or 53. In some embodiments, the CCN3 polypeptide or the portion thereof composes an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 52 or 53. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 52 or 53. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 52 or 53. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of SEQ ID NO: 52 or 53. In some embodiments, the albumin comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 322 or 323. In some embodiments, the albumin comprises the amino acid sequence of SEQ ID NO: 322 or 323. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 316- 321. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 316- 321. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 316- 321. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the amino acid sequence of any one of SEQ ID NOs: 316- 321. In some embodiments, the recombinant polypeptide or polypeptide complex further comprises the signal peptide of SEQ ID NO: 9 at the amino terminus.

[0036] Provided herein, in some embodiments, is a pharmaceutical composition comprising the recombinant polypeptide or polypeptide complex and a pharmaceutically acceptable carrier or excipient. Provided herein, in some embodiments, is a nucleic acid sequence encoding the recombinant polypeptide or polypeptide complex. Provided herein, in some embodiments, is a vector comprising the nucleic acid sequence. In some embodiments, the vector further comprises a mammalian vector, a yeast vector, a bacterial vector, or a viral vector. Provided herein, in some embodiments, is a cell comprising the recombinant polypeptide or polypeptide complex. Provided herein, in some embodiments, is a cell comprising the nucleic acid sequence. Provided herein, in some embodiments, is a cell comprising the vector. Provided herein, in some embodiments, is a method for treating a bone disease or disorder comprising administering to a subject the recombinant polypeptide or polypeptide complex, thereby treating the bone disease or disorder. Provided herein, in some embodiments, is a method for treating a bone disease or disorder comprising administering to a subject the pharmaceutical composition, thereby treating the bone disease or disorder. Provided herein, in some embodiments, is a method for treating a bone disease or disorder comprising administering to a subject the nucleic acid sequence, thereby treating the bone disease or disorder. Provided herein, in some embodiments, is a method for treating a bone disease or disorder comprising administering to a subject the vector, thereby treating the bone disease or disorder. Provided herein, in some embodiments, is a method for treating a bone disease or disorder comprising administering to a subject the cell, thereby treating the bone disease or disorder. In some embodiments, the bone disease or disorder comprises bone degeneration, osteoporosis, osteopenia,WSGR Docket No. 65459-704.601lactation, traumatic bone injury, pathologic bone injury, periprosthetic bone loss, osteolysis, menopause, obesity, anorexia nervosa, type 1 diabetes, chronic kidney disease, chronic liver disease, celiac disease, inflammatory bowel disease, lupus, rheumatoid arthritis, hyperthyroidism, hyperparathyroidism, cancer, multiple myeloma, a craniofacial disorder, premature ovarian failure, oral and maxillofacial surgery, plastic surgery, reconstructive surgery, ovariectomy, osteogenesis imperfecta, osteoarthritis, osteomalacia, metabolic bone disease, fibrous dysplasia, osteomyelitis, bone fracture, rickets, degenerative disc disease, osteonecrosis, renal osteodystrophy, Paget's disease, skeletal dysplasia, bone metastases, or otosclerosis. In some embodiments, the subject is human.

[0037] In some embodiments, the administering the recombinant polypeptide or polypeptide complex to the subject results in an increase or decrease in the expression of a biomarker for bone turnover, bone formation, bone resorption, or a combination thereof. In some embodiments, the administering the recombinant polypeptide or polypeptide complex to the subject results in an increase or decrease in the expression of the biomarker in the blood or serum. In some embodiments, the administering the recombinant polypeptide or polypeptide complex to the subject results in an increase or decrease in the protein expression of the biomarker. In some embodiments, the biomarker comprises procollagen type I N-terminal propeptide (P1NP), osteocalcin, C-terminal telopeptide of type I collagen (CTX), or a combination thereof. In some embodiments, the biomarker comprises P INP, osteocalcin, CTX, P INP and osteocalcin, P1NP and CTX, osteocalcin and CTX, or P1NP, osteocalcin and CTX. In some embodiments, the administering the recombinant polypeptide or polypeptide complex to the subject results in the increase in the expression of P1NP, osteocalcin, or both. In some embodiments, the administering the recombinant polypeptide or polypeptide complex to the subject results in the decrease in the expression of CTX. In some embodiments, the increase in the expression of the biomarker starts by day 7 after the administering and lasts until at least day 14 after the administering. In some embodiments, the increase in the expression of the biomarker starts by day 7 after the administering and lasts until at least day 21 after the administering. In some embodiments, the increase in the expression of the biomarker starts by day 7 after the administering and lasts until at least day 28 after the administering. In some embodiments, the decrease in the expression of the biomarker starts within 24 hours after the administering. In some embodiments, the subject is human or a non-human primate. In some embodiments, the subject is cynomolgus monkey.

[0038] In some embodiments, the recombinant polypeptide or polypeptide complex provides a half-life (T1 / 2) of about 12-14 hours, a total area under the concentration-time curve from time zero to infinity (AUC0 Inf) of about 19,000-20,500 ng*h / ml, a clearance of about 0.4 ml / min / kg, and a volume of distribution (Vd) of about 0.5 L / kg when the recombinant polypeptide or polypeptide complex is administered intravenously at a dose of about 0.5 mg / kg, wherein the recombinant polypeptide or polypeptide complex comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 77 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 77. In some embodiments, the recombinant polypeptide or polypeptide complex provides T1 / 2 of about 20-45 hours, AUC0 Infof about 5,500-6,500 ng*h / ml, a maximum concentration (Cmaxof about 60-95 ng / ml, andWSGR Docket No. 65459-704.601bioavailability (F%) of about 30%-31% when the recombinant polypeptide or polypeptide complex is administered subcutaneously at a dose of about 0.5 mg / kg, wherein the recombinant polypeptide or polypeptide complex comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 77 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 77. In some embodiments, the recombinant polypeptide or polypeptide complex provides T1 / 2 of about 40-50 hours, AUC0 Infof about 6,000-8,500 ng*h / ml, a clearance of about 0.1 ml / min / kg, and Vd of about 0.13 L / kg when the recombinant polypeptide or polypeptide complex is administered intravenously at a dose of about 0.5 mg / kg, wherein the recombinant polypeptide or polypeptide complex comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 89 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the recombinant polypeptide or polypeptide complex provides T1 / 2 of about 40-45 hours, AUC0 Infof about 11,000-15,000 ng*h / ml, Cmax of about 150-300 ng / ml, and bioavailability (F%) of about 17%- 18% when the recombinant polypeptide or polypeptide complex is administered subcutaneously at a dose of about 0.5 mg / kg, wherein the recombinant polypeptide or polypeptide complex comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 89 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the recombinant polypeptide or polypeptide complex provides T1 / 2 of about 12-30 hours, AUC0 Infof about 7,000-9,000 ng*h / ml, a clearance of about 0.8-1.2 ml / min / kg, and Vd of about 0.8-1.6 L / kg when the recombinant polypeptide or polypeptide complex is administered intravenously at a dose of about 0.5 mg / kg, wherein the recombinant polypeptide or polypeptide complex comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 303 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 303. In some embodiments, the recombinant polypeptide or polypeptide complex provides T1 / 2 of about 30-90 hours, AUC0 Infof about 1,200-3,000 ng*h / ml, Cmaxof about 15-30 ng / ml, and bioavailability (F%) of about 19%-20% when the recombinant polypeptide or polypeptide complex is administered subcutaneously at a dose of about 0.5 mg / kg, wherein the recombinant polypeptide or polypeptide complex comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 303 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 303. In some embodiments, the recombinant polypeptide or polypeptide complex provides T1 / 2 of about 85-180 hours, AUC0 Infof about 1,900,000-2,400,000 ng*h / ml, a clearance of about 0.005-0.015 ml / min / kg, and Vd of about 0.10-0.15 L / kg when the recombinant polypeptide or polypeptide complex is administered intravenously at a dose of about 0.5 mg / kg, wherein the recombinant polypeptide or polypeptide complex comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 61 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 61. In some embodiments, the recombinant polypeptide or polypeptide complex provides T1 / 2 of about 79.8 hours, AUC0 Infof about 421,020 ng*h / ml, Cmaxof about 2000-3000 ng / ml, and bioavailability (F%) of about 65%-66% when the recombinant polypeptide or polypeptide complex is administered subcutaneously at a dose of about 0.5 mg / kg, wherein the recombinant polypeptide or polypeptide complex comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 61 and the second polypeptide comprising theWSGR Docket No. 65459-704.601amino acid sequence of SEQ ID NO: 61. In some embodiments, the recombinant polypeptide or polypeptide complex provides T1 / 2 of about 0.6 hour, AUC0 Infof about 1,000-1,500 ng*h / ml, a clearance of about 6.5-9 ml / min / kg, and Vd of about 0.45-0.55 L / kg when the recombinant polypeptide or polypeptide complex is administered intravenously at a dose of about 0.5 mg / kg, wherein the recombinant polypeptide or polypeptide complex comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 85 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 85. In some embodiments, the recombinant polypeptide or polypeptide complex provides T1 / 2 of about 14-52 hours, AUC0 Infof about 45,000-55,000 ng*h / ml, a clearance of about 0.16-0.18 ml / min / kg, and Vd of about 0.11-0.13 L / kg when the recombinant polypeptide or polypeptide complex is administered intravenously at a dose of about 0.5 mg / kg, wherein the recombinant polypeptide or polypeptide complex comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 72 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 72. In some embodiments, the recombinant polypeptide or polypeptide complex provides T1 / 2 of about 38-75 hours, AUC0 Infof about 4,000-5,000 ng*h / ml, Cmaxof about 50-110 ng / ml, and bioavailability (F%) of about 7%-8% when the recombinant polypeptide or polypeptide complex is administered subcutaneously at a dose of about 0.5 mg / kg, wherein the recombinant polypeptide or polypeptide complex comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 72 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 72. In some embodiments, the subject is rodent. In some embodiments, the subject is rat.

[0039] In some embodiments, the recombinant polypeptide or polypeptide complex provides Cmaxof about 7,000 ng / ml, AUC0 Infof about 34,800 ng*h / ml, T1 / 2 of about 47 hours, a steady state volume of distribution (Vss) of about 1,300 l / kg, and a clearance of about 29 ml / h / kg, when the recombinant polypeptide or polypeptide complex is administered intravenously at a dose of about 1 mg / kg, wherein the recombinant polypeptide or polypeptide complex comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 307 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 307. In some embodiments, the recombinant polypeptide or polypeptide complex provides Cmaxof about 7,000 ng / ml, AUC0 Infof about 34,800 ng*h / ml, T1 / 2 of about 47 hours, a steady state volume of distribution (Vss) of about 1,300 l / kg, and a clearance of about 29 ml / h / kg, when the recombinant polypeptide or polypeptide complex is administered intravenously at a dose of about 1 mg / kg, wherein the recombinant polypeptide or polypeptide complex comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 325 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 325. In some embodiments, the recombinant polypeptide or polypeptide complex provides C max of about 380 ng / ml, AUC0 Infof about 37,700 ng*h / ml, T1 / 2 of about 104 hours, and bioavailability (F%) of about 100% when the recombinant polypeptide or polypeptide complex is administered subcutaneously at a dose of about 1 mg / kg, wherein the recombinant polypeptide or polypeptide complex comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 307 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 307. In some embodiments, the recombinant polypeptide or polypeptide complex provides Cmaxof aboutWSGR Docket No. 65459-704.601380 ng / ml, AUC0 Infof about 37,700 ng*h / ml, T1 / 2 of about 104 hours, and bioavailability (F%) of about 100% when the recombinant polypeptide or polypeptide complex is administered subcutaneously at a dose of about 1 mg / kg, wherein the recombinant polypeptide or polypeptide complex comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 325 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 325. In some embodiments, the recombinant polypeptide or polypeptide complex provides C max of about 29000 ng / ml, AUC0 Infof about 2,400,000 ng*h / ml to about 2,500,000 ng*h / ml, and T1 / 2 of about 62 hours when the recombinant polypeptide or polypeptide complex is administered subcutaneously at a dose of about 3 mg / kg, wherein the recombinant polypeptide or polypeptide complex comprises the first polypeptide comprising the amino acid sequence of SEQ ID NO: 326 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 326. In some embodiments, the subject is a non-human primate. In some embodiments, the subject is a cynomolgus monkey. In some embodiments, the T1 / 2, AUC0 Inf, clearance, Vd, Cmax, F%, and Vss of the recombinant polypeptide or polypeptide complex is measured in the blood or serum.

[0040] In another aspect, disclosed herein is a recombinant CCN3 peptide consisting of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 15-52, 54, and 300-301. In another aspect, disclosed herein is a recombinant CCN3 peptide consisting of an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 15-52, 54, and 300-301. In another aspect, disclosed herein is a recombinant CCN3 peptide consisting of the amino acid sequence of any one of SEQ ID NOs: 15-52, 54, and 300-301. In another aspect, disclosed herein is a recombinant CCN3 peptide comprising an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 15-52, 54, and 300-301, wherein the recombinant CCN3 peptide comprises an alteration of at least one amino acid with respect to the wild type CCN3 polypeptide of SEQ ID NO: 53. In another aspect, disclosed herein is a recombinant CCN3 peptide comprising an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 15-52, 54, and 300-301, wherein the recombinant CCN3 peptide comprises an alteration of at least one amino acid with respect to the wild type CCN3 polypeptide of SEQ ID NO: 53. In another aspect, disclosed herein is a recombinant CCN3 peptide comprising the amino acid sequence of any one of SEQ ID NOs: 15-52, 54, and 300-301, wherein the recombinant CCN3 peptide comprises an alteration of at least one amino acid with respect to the wild type CCN3 polypeptide of SEQ ID NO: 53. In some embodiments, the alteration of the at least one amino acid comprises a mutation, addition, truncation, deletion, substitution, or a combination thereof, of the at least one amino acid.BRIEF DESCRIPTION OF THE DRAWINGS

[0041] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0042] FIG. 1 illustrates a schematic of C- and N-terminal structures of CCN3-Fc fusions. Numbered circles correspond to CCN3 domains 1 (IGFBP1), 2 (vWFC), 3 (TSP1), and 4 (CTCK). TrianglesWSGR Docket No. 65459-704.601correspond to FLAG epitope tags. Different linkers between the Fc hinge and the CCN3 polypeptides were tested.

[0043] FIGs. 2A-2D illustrate SDS-PAGE gels for CCN3-Fc fusion proteins. Lane 1: MW markers; lane 2: non-reduced; lane 3: reduced. (FIG. 2A) CCN3-3; (FIG. 2B) CCN3-7; (FIG. 2C) CCN3-11; (FIG. 2D) CCN3-15.

[0044] FIGs. 3A-3D illustrate SDS-PAGE gels and anti-FLAG Western blots for CCN3-Fc fusion proteins. (FIG. 3A) and (FIG. 3C) are SDS-PAGE gels for CCN3-5 and CCN3-9, respectively. Lane 1: MW markers; lane 2: non-reduced; lane 3: reduced. (FIG. 3B) and (FIG. 3D) anti-FLAG Western blots on reduced CCN3-5 and CCN3-9 proteins, respectively.

[0045] FIGs. 4A-4C illustrate SDS-PAGE gels and anti-FLAG Western blots for CCN3-Fc fusion proteins. (FIG. 4A) and (FIG. 4B) are SDS-PAGE gels for CCN3-19 and CCN3-20, respectively. Lane 1: MW markers; lane 2: non-reduced; lane 3: reduced. (FIG. 4C) anti-FLAG Western blot on CCN3-20 stained with anti-FLAG antibody. Lane 1: MW markers; lane 2: reduced; lane 3: non-reduced.

[0046] FIGs. 5A-5D illustrate SDS-PAGE gels, SEC traces, and anti-FLAG Western bots for CCN3(d3-4) C-terminal Fc fusion proteins. (FIG. 5A) SDS-PAGE gel for CCN3-6. Lane 1: MW markers; lane 2: non-reduced; lane 3: reduced. (FIG. 5B) SEC profde for CCN3-10 following Protein A purification showing two product peaks. (FIG. 5C) SDS-PAGE gel for CCN3-10. Lane 1: MW markers; lane 2: peak 1 non-reduced; lane 3: peak 1 reduced; lane 4: peak 2 non-reduced; lane 5: peak 2 reduced. (FIG. 5D) Western blot on CCN3-10 peak 1 (reduced) stained with anti-FLAG antibody.

[0047] FIGs. 6A-6D illustrate SEC traces and SDS-PAGE gels for CCN3(d3-4) N-terminal Fc fusion proteins. (FIG. 6A) and (FIG. 6B) are SEC traces for CCN3-14 and CCN3-18, respectively, both showing two product peaks. (FIG. 6C) and (FIG. 6D) are SDS-PAGE gels for CCN3-14 and CCN3-18, respectively. Lane 1: MW markers; lane 2: peak 1 reduced; lane 3: peak 1 non-reduced; lane 4: peak 2 reduced; lane 5: peak 2 non-reduced.

[0048] FIG. 7 illustrates an Alpha Fold model of full length CCN3 protein and C-terminal sequence (bold underlined sequence is domain 4). Arrows show the truncation site after amino acid residue 338.FIG. 7 lists SEQ ID NO: 341.

[0049] FIGs. 8A-8B illustrate reduced SDS-PAGE gel and anti-FLAG Western blot for CCN3 variants.(FIG. 8A) Reduced SDS-PAGE gel for CCN3 variants lacking a linker or with a C-terminal truncation. Lane 1: MW markers; Lane 2: CCN3-25; Lane 3: CCN3-26; Lane 4: CCN3-27; Lane 5: CCN3-28.

[0050] FIGs. 9A-9H illustrate SDS-PAGE gels and anti-FLAG Western blots for CCN3(d3-4) C-terminal Fc fusion proteins. (FIG. 9A), (FIG. 9C), (FIG. 9E), (FIG. 9G) SDS-PAGE gels for CCN3-35, CCN3-62, CCN3-63, and CCN3-64, respectively. Lane 1: MW markers; Lane 2: non-reduced; Lane 3: reduced. (FIG. 9B), (FIG. 9D), (FIG. 9F), (FIG. 9H) anti-FLAG Western blots for CCN3-35 (nonreduced only), CCN3-62, CCN3-63, CCN3-64. Left lane is reduced, right lane is non-reduced.

[0051] FIG. 10 illustrates SDS-PAGE gel for CCN3-72. Lane 1: MW markers; Lane 2: reduced CCN3-72; Lane 3: non-reduced CCN3-72.WSGR Docket No. 65459-704.601

[0052] FIGs. 11A-11H illustrate SDS-PAGE gels and anti -FLAG Wester blots for CCN3 single domain C-terminal Fc fusion proteins. (FIG. 11A), (FIG. 11C), (FIG. HE), (FIG. 11G) SDS-PAGE gels for CCN3(dl)-l, CCN3(d2)-l, CCN3(d3)-l, and CCN3(d4)-6, respectively. Lane 1: MW markers; Lane 2: non-reduced; Lane 3: reduced. (FIG. 11B), (FIG. HD), (FIG. HF), (FIG. 11H) anti-FLAG Western blots for CCN3(dl)-l, CCN3(d2)-l, CCN3(d3)-l, and CCN3(d4)-6, respectively. Lane 1: MW markers; Lane 2: reduced; Lane 3: non-reduced.

[0053] FIG. 12 illustrates a schematic showing the structure of the full-length heterodimeric CCN3 Fc fusions. In this example, CCN3 domains 1-4 are fused at the N-terminus of an Fc that includes a knob mutation, which pairs with an Fc that includes hole mutations. Numbered circles correspond to CCN3 domains 1 (IGFBP1), 2 (vWFC), 3 (TSP1), and 4 (CTCK). Triangles correspond to FLAG epitope tags. The knob and hole mutations in the Fc facilitate heterodimerization.

[0054] FIGs. 13A-13F illustrate SDS-PAGE gels for heterodimeric CCN3 Fc fusion proteins. (FIG. 13A) CCN3-5-mono; (FIG. 13B) CCN3-9-mono; (FIG. 13C) CCN3-20-mono; (FIG. 13D) CCN3-27-mono; (FIG. 13E) CCN3-35-mono; (FIG. 13F) CCN3-62-mono. Lane 1: MW markers; Lane 2: reduced; Lane 3: non-reduced.

[0055] FIG. 14 illustrate SDS-PAGE gels for (A) CCN3-75, (B) CCN3-76, (C) CCN3-79, (D) CCN3-80. Lane 1: MW markers; lane 2: non-reduced; lane 3: reduced.

[0056] FIG. 15 illustrates bone mineral density measurement in weanling rats at 3 skeletal sites, lumbar vertebrae 2-5 (left), distal femur (middle), proximal tibia (right), after 1 week of treatment with vehicle, human CCN3, or CCN3-27. *P<0.05, ***P<0.001, ****P<0.0001.

[0057] FIG. 16 illustrates SDS-PAGE gels for (A) CCN3-83, (B) CCN3-85, (C) CCN3-87, (D) CCN3-88, or Western Blots for (E) CCN3-87 and (F) CCN3-88. Lane 1: MW markers; land 2: reduced; lane 3: non-reduced.

[0058] FIG. 17 illustrates (A) SDS-PAGE gel and (B) anti-FLAG Western blot for CCN3-92. Lane 1: MW markers; land 2: non-reduced; lane 3: reduced.

[0059] FIGs. 18A-18D illustrate ceSDS and SEC profiles for stable pool production of CCN3-Fc sequences: FIG. 18A- CCN3-9, FIG. 18B - CCN3-92, FIG. 18C - CCN3-39, FIG. 18D - CCN3-27.

[0060] FIGs. 19A-19C illustrate Mineralization of MC3T3-E1 cells treated with CCN3-Fc proteins. FIG. 19A- Cells treated with 2.5 nM of various CCN3 proteins, as labeled. hCCN3 refers to commercial recombinant human CCN3 (R& D systems, cat#1640-NV). FIG. 19B Cells treated with different concentrations of CCN3-27. FIG. 19C- Cells treated with different concentrations of CCN3-39. All results are reported as percentage of Alizarin Red staining as compared to Mineralization Media (MM) alone. Trendline at 100% represents mean response for MM used for normalization. Data are presented as mean ± standard error of the mean.

[0061] FIGs. 20A-20F illustrate change in BMD from vehicle control in rats at three anatomical sites measured one week following a single subcutaneous dose of the indicated test article FIGs. 20A-20C: 2 pg / kg of CCN3-27, CCN3-39, CCN3-92, CCN3-9, or CCN3-35; FIGs. 20D-20F: CCN3-27, dose as indicated- 2, 20, 200, and 2000 pg / kg. The dotted vertical line separates two independent studies.WSGR Docket No. 65459-704.601Veh=vehicle; 27=CCN3-27; 39=CCN3-39; 92=CCN3-92; 9=CCN3-9; 35=CCN3-35. Data are presented as mean ± standard deviation with individual data points overlaid (n = 5-6 animals per group). Statistical significance was determined by one-way ANOVA: *P < 0.05, **P < 0.01, ***P < 0.001. Brackets indicate pairwise comparisons between indicated groups.

[0062] FIGs. 21A-21C illustrate Pharmacokinetics of CCN3 proteins. (FIG. 21A) Recombinant His-tagged CCN3 protein dosed SC or IV in adult female rats. (FIG. 21B) CCN3-Fc fusion proteins dosed SC in adult female rats. Concentrations are dose-normalized to 0.5 mg / kg. (FIG. 21C) Serum concentration-time curves of CCN3-27-LS (1 mg / kg) administered to adult female cynomolgus monkeys SC or IV. All data are presented as mean ± standard error of the mean.

[0063] FIGs. 22A-22C illustrate whole body BMD (g / cm2) of adult male C57 / BL6 over 4 weeks of twice-weekly SC dosing of 0.8 mg / kg CCN3-Fc variants (triangles) or vehicle (squares). (FIG. 22A) CCN3-27 vs PBS; (FIG. 22B) CCN3-39 vs PBS; (FIG. 22C) CCN3-9 vs PBS. Data are presented as mean ± standard error of the mean. Statistical significance was determined by Tukey-corrected two-way repeated measures ANOVA: **P < 0.05, ****p < 0.0001 compared to PBS control at the indicated timepoint.

[0064] FIGs. 23A-23C illustrate time course of serum bone turnover biomarkers following a single SC injection of female cynomolgus monkeys (N = 3, ~5 years old) with 1 mg / kg CCN3-27-LS. (FIG. 23A) procollagen type IN-terminal propeptide (P1NP); (FIG. 23B) osteocalcin; (FIG. 23C) C-terminal telopeptide of type I collagen (CTX). Data are presented as change from baseline (ng / mL) as mean ± standard deviation. The dotted horizontal line at y = 0 represents baseline levels.

[0065] FIGs. 24A-24C illustrate time course of serum bone turnover biomarkers following weekly SC injection of female cynomolgus monkeys (N = 3, ~5 years old) with 3 mg / kg CCN3-39-LS. (24A) procollagen type I N-terminal propeptide (P1NP); (24B) osteocalcin; (24C) C-terminal telopeptide of type I collagen (CTx). Data are presented as change from baseline (ng / mL) as mean ± standard deviation. The dotted horizontal line at y = 0 represents baseline levels.

[0066] FIG. 25 illustrates the concentration of serum of CCN-3-39-LS measured overtime following weekly dosing shown by arrows.DETAILED DESCRIPTION

[0067] This disclosure relates generally to recombinant polypeptides or polypeptide complexes. More specifically, the disclosure relates to recombinant polypeptides or polypeptide complexes of Cellular Communication Network Factor 3 (CCN3), and methods of their use and manufacture. CCN3, a member of the CCN family of extracellular matrix proteins, is also known as nephroblastoma overexpressed protein (NOV). Wild-type CCN3 includes the Insulin-like Growth Factor binding (IGFBP) domain, von Willebrand Factor C (vWFC) domain, Thrombospondin Type-1 (TSP1) domain and C-terminal cystine knot-like (CTCK) domain. Disclosed herein are the recombinant polypeptide or the polypeptide complex that comprises CCN3 polypeptide or a portion thereof.WSGR Docket No. 65459-704.601

[0068] While the present disclosure may be embodied in many different forms, disclosed herein are specific illustrative embodiments thereof. It should be emphasized that the present disclosure is not limited to the specific embodiments illustrated. Moreover, any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0069] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. More specifically, as used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a protein” includes a plurality of proteins; reference to “a cell” includes mixtures of cells, and the like. In this disclosure, the use of “or” means “and / or” unless stated otherwise. Furthermore, the use of the term “comprising,” as well as other forms, such as “comprises" and “comprised,” is not limiting. In addition, ranges provided in the specification and appended claims include both end points and all points between the end points.

[0070] Generally, nomenclature used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those well-known and commonly used in the art. The methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. See, e.g., Abbas et al., Cellular and Molecular Immunology, 6thed., W. B. Saunders Company (2010); Sambrook J. & Russell D.Molecular Cloning: A Laboratory Manual, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y. (2000); Ausubel et al., Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Wiley, John & Sons, Inc. (2002); Harlow and Lane Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y. (1998); and Coligan et al., Short Protocols in Protein Science, Wiley, John & Sons, Inc. (2003). The nomenclature used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art.Definitions

[0071] In order to better understand the disclosure, the definitions and explanations of the relevant terms are provided as follows.

[0072] The term “CCN3” refers to human Cellular Communication Network Factor 3 (CCN3), also known as Nephroblastoma Overexpressed (NOV), is a member of the CCN family of matricellular proteins. CCN3 is encoded by the CCN3 gene and plays diverse biological roles, including but not limited to, regulating cell growth and differentiation, skeletal development, tissue repair. The wild-type CCN3 sequence, such as SEQ ID NO: 315, may include a signal peptide, an insulin-like grow th factor¬ binding protein (IGFBP) domain, a von Willebrand factor type C (VWFC) domain, a thrombospondinWSGR Docket No. 65459-704.601type-1 (TSP1) domain, and a C-terminal cystine knot-like (CTCK) domain, a carboxyl terminal sequence, and one or more linker sequences between the domains.

[0073] A “portion” or “fragment” of an amino acid sequence refers to a segment or region of the amino acid sequence that forms part of the amino acid sequence. In one embodiment, a portion or fragment of a CCN3 polypeptide may has one, two, three, or four domains of the CCN3 polypeptide. In one embodiment, a portion or fragment of a CCN3 polypeptide may include a linker or hinge sequence between any two of the domains. In one embodiment, a portion or fragment of a CCN3 polypeptide may include a full or partial length of the carboxyl terminal sequence. In one embodiment, a portion or fragment of a CCN3 polypeptide may include an amino acid sequence having a certain percentage of sequence identity to a wild-type CCN3 sequence.

[0074] A “linker” herein is also referred to as “linker sequence,” “spacer,” “tethering sequence,” or grammatical equivalents thereof. A number of strategies may be used to covalently link molecules together. These include but are not limited to polypeptide linkages between N- and C-termini of proteins or protein domains, linkage via disulfide bonds, and linkage via chemical cross-linking reagents. In one aspect of this embodiment, the linker is a peptide bond, generated by recombinant techniques or peptide synthesis. In one embodiment, the linker is from about 1 to 50 amino acids in length or about 1 to 30 amino acids in length. In one embodiment, linkers of 1 to 20 amino acids in length may be used. Linkers include glycine-serine polymers, including for example (GS)n, (GSGGS)n (SEQ ID NO: 329), (GGGGS)n (SEQ ID NO: 330), and (GGGS)n (SEQ ID NO: 331), where n is an integer of at least one, glycine -alanine polymers, alanine -serine polymers, and other flexible linkers. Exemplary, linkers for linking antibody fragments or single chain variable fragments can include A(EAAAK)nA (SEQ ID NO: 332), (EAAAK)n (SEQ ID NO: 333), AAEPKSS (SEQ ID NO: 334), AAEPKSSDKTHTCPPCP (SEQ ID NO: 335), GGGG (SEQ ID NO: 336), or GGGGDKTHTCPPCP (SEQ ID NO: 337). Alternatively, a variety of non-proteinaceous polymers, including but not limited to polyethylene glycol (PEG), polypropylene glycol, poly oxyalkylenes, or copolymers of polyethylene glycol and polypropylene glycol, may be used as linkers.

[0075] The terms “interdomain region”, “spacer region”, “interdomain linker”, and “flanking region” are used interchangeably to refer to the region between adjacent domains of a wild-type CCN3 polypeptide. The term “interdomain region” may refer to the amino acid residues that connect two adjacent, functional domains of CCN3 polypeptide or portion thereof.

[0076] The term “truncation” may refer to an alteration to a polypeptide sequence resulting in a shortened polypeptide. For example, a truncation may result in an altered polypeptide after the removal of a consecutive amino acid sequence at the N-terminus or C-terminus. For example, in some embodiments, a truncation may refer to the removal of 19 or fewer consecutive amino acids at the C-terminus of the CCN3 polypeptide. In some embodiments, a truncation may improve protein stability or render the protein resistant to cleavage.

[0077] The term “deletion” refers to an alteration to a polypeptide sequence resulting in removal of one or more amino acids that are consecutive or nonconsecutive. A deletion may occur at any position withinWSGR Docket No. 65459-704.601a polypeptide. The remained regions after deletion are then rejoined. Amino acid deletion can be consecutive or non-consecutive. In some embodiments, a deletion of at least one amino acid can be introduced to the N-terminus, C-terminus, or any region between the N-terminus and C-terminus of the CCN3 polypeptide.

[0078] The term “identity,” as used herein, refers to a relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules, as determined by aligning and comparing the sequences. “Percent identity” means the percent of identical residues between the amino acids or nucleotides in the compared molecules and is calculated based on the size of the smallest of the molecules being compared. For these calculations, gaps in alignments (if any) are preferably addressed by a particular mathematical model or computer program (i.e., an “algorithm”). Methods that can be used to calculate the identity of the aligned nucleic acids or polypeptides include those described in Computational Molecular Biology, (Lesk, A. M., ed.), 1988, New York: Oxford University Press;Biocomputing Informatics and Genome Projects, (Smith, D. W., ed.), 1993, New York: Academic Press; Computer Analysis of Sequence Data, Part I, (Griffin, A. M., and Griffin, H. G., eds.), 1994, New Jersey: Humana Press; von Heinje, G., 1987, Sequence Analysis in Molecular Biology, New York: Academic Press; Sequence Analysis Primer, (Gribskov, M. and Devereux, J., eds.), 1991, New York: M. Stockton Press; and Carillo et al, 1988, SIAMJ. Applied Math. 48: 1073.

[0079] Percent (%) sequence identity with respect to a reference polypeptide sequence is the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are known for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Appropriate parameters for aligning sequences are able to be determined, including algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U. S. Copyright Office, Washington D. C., 20559, where it is registered under U. S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, Calif., or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary. In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 times the fraction X / Y, where X is the number of amino acid residues scored as identical matches byWSGR Docket No. 65459-704.601the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0080] The term “constant region” can refer to a light chain or heavy chain constant region of an antibody. Light chain constant regions have two main isotypes kappa and lambda. Heavy chain constant regions may comprise any one of: IgA, IgD, IgG, IgE, or IgM. The IgG may comprise IgGl, IgG2, IgG3, and IgG4 subclasses. Heavy chain constant regions comprise a CHI, hinge, CH2, and / or a CH3 domain. An “Fc Region” as described herein generally refers to the CH2 and the CH3 domains of the heavy chain constant region and optionally the hinge region. An Fc region may include two arms which associate to form a homodimer or a heterodimer.

[0081] The term “knob into hole”, as used herein, refers to engineering the antibody Fc region to create either a “knob” or a “hole” in each heavy chain to promote heterodimerization. A knob can be obtained by replacement of a small amino acid residue with a larger one in the Fc region. A hole can be obtained by replacement of a large amino acid residue with a smaller one in the Fc region. For details of the mutation sites for knobs into holes please see Spiess et al., 2015, supra and Brinkmann et al., 2017, supra; US patent application US2003078385A1.

[0082] The “EU numbering system” or “EU index” is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra).Residues of light and heavy chain constant regions can be numbered according to the EU numbering scheme (Edelman, G. M. et al., Proc. Natl. Acad. USA, 63, 78-85 (1969).). The “EU numbering as in Kabat” or “EU index as in Kabat” refers to the residue numbering of the human IgGl EU antibody. Unless stated otherwise herein, references to residue numbers in the constant domain of antibodies means residue numbering by the EU numbering system.

[0083] The terms “polypeptide” and “protein” are used interchangeably and refers to a polymer of amino acid residues. Polypeptides, including the provided fusions, e.g., linkers and binding peptides, can include amino acid residues including natural and / or non-natural amino acid residues. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. In some aspects, the polypeptides can contain modifications with respect to a native or natural sequence, as long as the protein maintains the desired activity. These modifications can be deliberate, as through site-directed mutagenesis, or can be accidental, such as through mutations of hosts which produce the proteins or errors due to PCR amplification.

[0084] The term “isolated,” as used herein, refers to a state obtained from natural state by artificial means. If a certain “isolated” substance or component is present in nature, it is possible because its natural environment changes, or the substance is isolated from natural environment, or both. For example, a certain un-isolated polynucleotide or polypeptide naturally exists in a certain living animalWSGR Docket No. 65459-704.601body, and the same polynucleotide or polypeptide with a high purity isolated from such a natural state is called isolated polynucleotide or polypeptide.

[0085] The term “vector,” as used herein, refers to a nucleic acid vehicle which can have a polynucleotide inserted therein. When the vector allows for the expression of the protein encoded by the polynucleotide inserted therein, the vector is called an expression vector. The vector can have the carried genetic material elements expressed in a host cell by transformation, transduction, or transfection into the host cell. Vectors are well known by a person skilled in the art, including, but not limited to plasmids, phages, cosmids, artificial chromosome such as yeast artificial chromosome (YAC), bacterial artificial chromosome (BAC) or Pl -derived artificial chromosome (PAC); phage such as X phage or M13 phage and animal virus. The animal viruses that can be used as vectors, include, but are not limited to, retrovirus (including lentivirus), adenovirus, adeno-associated virus, herpes virus (such as herpes simplex virus), pox virus, baculovirus, papillomavirus, papova virus (such as SV40). A vector may comprise multiple elements for controlling expression, including, but not limited to, a promoter sequence, a transcription initiation sequence, an enhancer sequence, a selection element and a reporter gene. In addition, a vector may comprise origin of replication.

[0086] The term “host cell,” as used herein, refers to a cellular system which can be engineered to generate proteins, protein fragments, or peptides of interest. Host cells include, without limitation, bacterial cells, e.g., E. coli, cultured cells, e.g., mammalian cultured cells derived from rodents (rats, mice, guinea pigs, or hamsters) such as CHO, BHK, NSO, SP2 / 0, YB2 / 0; or human tissues or hybridoma cells, yeast cells, and insect cells, and cells comprised within a transgenic animal or cultured tissue. The term encompasses not only the particular subject cell but also the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not be identical to the parent cell, but are still included within the scope of the term “host cell.”

[0087] Amino acid sequence variants of the fusions provided herein can be contemplated and conceived. A variant typically differs from a polypeptide specifically disclosed herein in one or more substitutions, deletions, additions and / or insertions. Such variants can be naturally occurring or can be synthetically generated, for example, by modifying one or more of the above polypeptide sequences of the invention and evaluating one or more biological activities of the polypeptide as described herein and / or using any of a number of known techniques. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., function. For example, a CCN3 polypeptide disclosed herein may possess equivalent or better function to promote bone growth compared with an existing CCN3 molecule. Variants having one or more amino acid substitutions can be provided. Amino acid substitutions can be introduced into a fusion protein of interest and the products screened for a desired activity, e.g., retained / improved function.

[0088] The fusion proteins described herein can be encoded by a nucleic acid. A nucleic acid is a type of polynucleotide comprising two or more nucleotide bases. In certain embodiments, the nucleic acid is a component of a vector that can be used to transfer the polypeptide encoding polynucleotide into a cell. AsWSGR Docket No. 65459-704.601used herein, the term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a genomic integrated vector, or “integrated vector,” which can become integrated into the chromosomal DNA of the host cell. Another type of vector is an “episomal” vector, e.g., a nucleic acid capable of extra-chromosomal replication. Vectors capable of directing the expression of genes to which they are operatively linked are referred to herein as “expression vectors.” Suitable vectors comprise plasmids, bacterial artificial chromosomes, yeast artificial chromosomes, viral vectors and the like. In the expression vectors regulatory elements such as promoters, enhancers, polyadenylation signals for use in controlling transcription can be derived from mammalian, microbial, viral or insect genes. The ability to replicate in a host, usually conferred by an origin of replication, and a selection gene to facilitate recognition of transformants may additionally be incorporated. Vectors derived from viruses, such as lentiviruses, retroviruses, adenoviruses, adeno-associated viruses, and the like, may be employed. Plasmid vectors can be linearized for integration into a chromosomal location. Vectors can comprise sequences that direct site -specific integration into a defined location or restricted set of sites in the genome (e.g., AttP-AttB recombination). Additionally, vectors can comprise sequences derived from transposable elements.

[0089] The nucleic acids encoding the fusion proteins described herein can be used to infect, transfect, transform, or otherwise render a suitable cell transgenic for the nucleic acid, thus enabling the production of antibodies for commercial or therapeutic uses. In certain embodiments, the cell is abacterial cell. In certain embodiments, the cell is an E. coli cell. In certain embodiments, the cell is a Eukaryotic cell. In certain embodiments, the Eukaryotic cell is a mammalian cell. In certain embodiments, the mammalian cell is a cell line useful for producing antibodies is a Chines Hamster Ovary cell (CHO) cell, an NSO murine myeloma cell, or a PER. C6® cell. In certain embodiments, the nucleic acid encoding the antibody is integrated into a genomic locus of a cell useful for producing antibodies. In certain embodiments, described herein is a method of making a fusion protein comprising culturing a cell comprising a nucleic acid encoding a fusion protein under conditions in vitro sufficient to allow production and secretion of said fusion protein.

[0090] As used herein the term “individual,” “patient,” and “subject” are used interchangeably and refer to individuals diagnosed with, suspected of being afflicted with, or at-risk of developing at least one disease for which the described compositions and method are useful for treating. In certain embodiments, the individual is a mammal. In certain embodiments, the mammal is a mouse, rat, rabbit, dog, cat, horse, cow, sheep, pig, goat, llama, alpaca, or yak. In certain embodiments, the individual is a human.

[0091] The term “prevent,” “prevention” or “preventing,” as used herein, with reference to a certain disease condition in a mammal, refers to preventing or delaying the onset of the disease, or preventing the manifestation of clinical or subclinical symptoms thereof.

[0092] The term “treatment,” “treating” or “treated,” as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal, in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, regression of the condition,WSGR Docket No. 65459-704.601amelioration of the condition, and cure of the condition. For cancer, “treating” may refer to dampen or slow the tumor or malignant cell growth, proliferation, or metastasis, or some combination thereof.

[0093] The term “an effective amount,” as used herein, pertains to that amount of an active compound, or a material, composition or dosage form comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio, when administered in accordance with a desired treatment regimen. For instance, the “an effective amount,” when used in connection with treatment of a disease or condition, refers to an antibody or antigenbinding portion thereof in an amount or concentration effective to treat the said disease or condition.

[0094] The term “pharmaceutically acceptable,” as used herein, means that the vehicle, diluent, excipient and / or salts thereof, are chemically and / or physically is compatible with other ingredients in the formulation, and the physiologically compatible with the recipient.

[0095] As used herein, the term “a pharmaceutically acceptable carrier and / or excipient” refers to a carrier and / or excipient pharmacologically and / or physiologically compatible with a subject and an active agent, which is well known in the art (see, e.g., Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995), and includes, but is not limited to pH adjuster, surfactant, adjuvant and ionic strength enhancer. For example, the pH adjuster includes, but is not limited to, phosphate buffer; the surfactant includes, but is not limited to, cationic, anionic, or nonionic surfactant, e.g., Tween-80; the ionic strength enhancer includes, but is not limited to, sodium chloride.

[0096] As used herein, the term “about” used to modify a specific number refers to that number plus or minus 10% of that number. The term “about” modifying a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.Recombinant Polypeptides or Polypeptide Complexes

[0097] Disclosed herein, is a recombinant polypeptide or polypeptide complex comprising a cellular communication network factor 3 (CCN3) polypeptide or a portion thereof. In some embodiments, recombinant polypeptide or polypeptide complex comprises a fragment crystallizable (Fc) region of an antibody. Disclosed herein, is a recombinant polypeptide or polypeptide complex comprising a cellular communication network factor 3 (CCN3) polypeptide or a portion thereof and a fragment crystallizable (Fc) region.

[0098] In some embodiments, the recombinant polypeptide or polypeptide complex disclosed herein has technical advantages, effects, and / or improvements compared with another CCN3 molecule. In some embodiments, the other CCN3 molecule is a wild-type CCN3 polypeptide. In some embodiments, the another CCN3 molecule is a full length wild-type CCN3 polypeptide. In some embodiments, the technical advantages or effects relate to therapeutic activity, stability, immunogenicity, affinity, toxicity, potency, specificity, pharmacokinetics, pharmacodynamics or another property not exhibited by the another CCN3 molecule. In some embodiments, the recombinant polypeptide or polypeptide complex disclosed herein exhibits enhanced therapeutic activity. In some embodiments, the recombinant polypeptide or polypeptide complex disclosed herein exhibits improved or enhanced stability. In someWSGR Docket No. 65459-704.601embodiments, the recombinant polypeptide or polypeptide complex disclosed herein exhibits reduced immunogenicity. In some embodiments, the recombinant polypeptide or polypeptide complex disclosed herein exhibits enhanced or reduced affinity to a target binding partner molecule. In some embodiments, the recombinant polypeptide or polypeptide complex disclosed herein exhibits reduced toxicity. In some embodiments, the recombinant polypeptide or polypeptide complex disclosed herein has improved potency. In some embodiments, the recombinant polypeptide or polypeptide complex disclosed herein has improved specificity. In some embodiments, the recombinant polypeptide or polypeptide complex disclosed herein has improved pharmacokinetics. In some embodiments, the recombinant polypeptide or polypeptide complex disclosed herein has improved pharmacodynamics. In some embodiments, the recombinant polypeptide or polypeptide complex disclosed herein has enhanced or prolonged half-life. In some embodiments, the recombinant polypeptide or polypeptide complex disclosed herein has improved or enhanced resistance to enzymatic cleavage or degradation. In some embodiments, the recombinant polypeptide or polypeptide complex disclosed herein has improved or enhanced resistance to degradation during recombinant protein expression. In some embodiments, the recombinant polypeptide or polypeptide complex disclosed herein is resistant to enzymatic cleavage during recombinant protein expression. In some embodiments, the recombinant polypeptide or polypeptide complex disclosed herein has enhanced expression, solubility, stability, and / or function. In some embodiments, the recombinant polypeptide or polypeptide complex disclosed herein facilitates the recombinant protein expression in bacterial or other heterologous systems. In some embodiments, the recombinant polypeptide or polypeptide complex disclosed herein improves solubility. In some embodiments, the recombinant polypeptide or polypeptide complex disclosed herein facilitates protein production. In some embodiments, the recombinant polypeptide or polypeptide complex disclosed herein enhances protein stability. In some embodiments, the recombinant polypeptide or polypeptide complex disclosed herein is less prone to degradation.

[0099] In one aspect, the recombinant polypeptide or polypeptide complex disclosed herein can be used to treat or prevent a bone disease or disorder in a subject. In another aspect, the recombinant polypeptide or polypeptide complex disclosed herein can be used to promote bone cell growth, promote bone regeneration, or promote bone growth, in a subject. In another aspect, the recombinant polypeptide or polypeptide complex disclosed herein can be used to increase bone mineral density in a subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is human.

[0100] In some embodiments, the Fc region of the recombinant polypeptide or polypeptide complex is covalently linked to the amino terminus of the CCN3 polypeptide or the portion thereof. In some embodiments, the Fc region of the recombinant polypeptide or polypeptide complex is covalently linked to the carboxyl terminus of the CCN3 polypeptide or the portion thereof. In some embodiments, the Fc region of the recombinant polypeptide or polypeptide complex is non-covalently linked to the amino terminus of the CCN3 polypeptide or the portion thereof. In some embodiments, the Fc region of the recombinant polypeptide or polypeptide complex is non-covalently linked to the carboxyl terminus of the CCN3 polypeptide or the portion thereof. In some embodiments, the Fc region can be attached to aWSGR Docket No. 65459-704.601polypeptide via covalent and non-covalent linkages. The methodology of attaching a Fc region to a target polypeptide is known in the art. In some embodiments, covalent linkages can be achieved through genetic fusion, where the Fc region is directly incorporated into the DNA sequence of the target protein. In some embodiments, covalent linkages can also be achieved by chemical crosslinking, such as EDC coupling or the use of maleimide-based reagents. Other methods, such as sortase -mediated ligation and click chemistry can also be employed for covalent linkages. In some embodiments, the Fc region can be genetically fused to the CCN3 polypeptide or the portion thereof at the DNA level, resulting in a single polypeptide chain after expression. In some embodiments, the recombinant polypeptide is expressed as a continuous polypeptide. In some embodiments, non-covalent linkages include affinity tag -based binding with His-tags or biotin-streptavidin systems, and protein-protein interactions, for example, Fc receptor binding or the use of coiled-coil domains. In some embodiments, the Fc region of the recombinant polypeptide or polypeptide complex is non-covalently linked to the amino terminus of the CCN3 polypeptide or the portion thereof.CCN3

[0101] In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising an amino acid sequence with at least 90% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising an amino acid sequence with at least 91% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising an amino acid sequence with at least 92% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising an amino acid sequence with at least 93% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising an amino acid sequence with at least 94% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising an amino acid sequence with at least 95% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising an amino acid sequence with at least 96% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising an amino acid sequence with at leastWSGR Docket No. 65459-704.60197% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising an amino acid sequence with at least 98% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising an amino acid sequence with at least 99% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising the amino acid sequence of the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof.

[0102] In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising a truncation at the amino terminus. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising a truncation at the carboxyl terminus. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising a truncation at the carboxyl terminus of the wildtype CCN3 of SEQ ID NO: 53. In some embodiments, the CCN3 polypeptide or the portion thereof comprises a truncation of at least one amino acid of the 19 amino acids at the carboxyl terminus of SEQ ID NO: 53. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof and a truncation of at least one amino acid of the 19 amino acids at the carboxyl terminus of SEQ ID NO: 53. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof and a truncation of at least one amino acid of the 19 amino acids at the carboxyl terminus of SEQ ID NO: 53. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 91% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof and a truncation of at least one amino acid of the 19 amino acids at the carboxyl terminus of SEQ ID NO: 53. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 92% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof and a truncation of at least one amino acid of the 19 amino acids at the carboxyl terminus of SEQ ID NO: 53. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 93% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof and a truncation of at least one amino acid of the 19 amino acids at the carboxyl terminus of SEQ ID NO: 53. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 94% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof and a truncation of at least one amino acid of the 19 amino acids at the carboxyl terminus of SEQ ID NO: 53. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 95% sequence identity to the wildtype CCN3 ofWSGR Docket No. 65459-704.601SEQ ID NO: 53 or a fragment thereof and a truncation of at least one amino acid of the 19 amino acids at the carboxyl terminus of SEQ ID NO: 53. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 96% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof and a truncation of at least one amino acid of the 19 amino acids at the carboxyl terminus of SEQ ID NO: 53. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 97% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof and a truncation of at least one amino acid of the 19 amino acids at the carboxyl terminus of SEQ ID NO: 53. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 98% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof and a truncation of at least one amino acid of the 19 amino acids at the carboxyl terminus of SEQ ID NO: 53. In some embodiments, the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 99% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof and a truncation of at least one amino acid of the 19 amino acids at the carboxyl terminus of SEQ ID NO: 53. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at least 1 amino acid. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at least 2 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at least 3 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at least 4 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at least 5 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at least 6 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at least 7 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at least 8 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at least 9 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at least 10 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at least 11 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at least 12 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at least 13 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at least 14 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at least 15 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at least 16 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at least 17 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at least 18 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at least 19 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,WSGR Docket No. 65459-704.60112, 13, 14, 15, 16, 17, 18, or 19 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 amino acids. In some embodiments, the truncation at the carboxyl terminus of SEQ ID NO: 53 comprises 19 amino acids.

[0103] In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising a deletion at the carboxyl terminus of the wildtype CCN3 of SEQ ID NO: 53. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising a deletion at the amino terminus of the wildtype CCN3 of SEQ ID NO: 53. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising a deletion between the amino terminus and the carboxyl terminus of the wildtype CCN3 of SEQ ID NO: 53. In some embodiments, the CCN3 polypeptide or the portion thereof comprises a deletion of at least one amino acid of the 19 amino acids at the carboxyl terminus of SEQ ID NO: 53. In some embodiments, the deletion comprises a consecutive amino acid sequence. In some embodiments, the deletion comprises a consecutive amino acid sequence at the carboxyl terminus of the wildtype CCN3 of SEQ ID NO: 53. In some embodiments, the deletion comprises a consecutive amino acid sequence at the amino terminus of the wildtype CCN3 of SEQ ID NO: 53. In some embodiments, the deletion comprises a consecutive amino acid sequence between the amino terminus and the carboxyl terminus of the wildtype CCN3 of SEQ ID NO: 53. In some embodiments, the deletion comprises at least two nonconsecutive amino acid sequences. In some embodiments, the deletion comprises at least two nonconsecutive amino acid sequences at the carboxyl terminus of the wildtype CCN3 of SEQ ID NO: 53. In some embodiments, the deletion comprises at least two nonconsecutive amino acid sequences at the amino terminus of the wildtype CCN3 of SEQ ID NO: 53. In some embodiments, the deletion comprises at least two nonconsecutive amino acid sequences between the amino terminus and the carboxyl terminus of the wildtype CCN3 of SEQ ID NO: 53. In some embodiments, the deletion comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 amino acids at the carboxyl terminus of SEQ ID NO: 53. In some embodiments, the deletion comprises at most 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 amino acids at the carboxyl terminus of SEQ ID NO: 53. In some embodiments, the deletion comprises at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 nonconsecutive amino acid sequence. In some embodiments, the deletion comprises at most 2, 3, 4, 5, 6, 7, 8, 9, or 10 nonconsecutive amino acid sequence. In some embodiments, the comprises the CCN3 polypeptide or the portion thereof comprises proline (P) at amino acid 188 of SEQ ID NO: 315.

[0104] In some embodiments, the CCN3 polypeptide or the portion thereof comprises an insulin-like growth factor-binding protein (IGFBP) domain; a von Willebrand factor type C (vWFC) domain; a thrombospondin type-1 (TSP1) domain; or a C-terminal cystine knot-like (CTCK) domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the IGFBP domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the TSP1 domain. In someWSGR Docket No. 65459-704.601embodiments, the CCN3 polypeptide or the portion thereof comprises the CTCK domain. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof consisting of one, two, three, or four of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of one of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of two of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of three of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises one of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the IGFBP domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the TSBP domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of one of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the IGFBP domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the TSBP domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises one of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain and lacking the other three of the IGFBP domain, the vWFC domain, the TSP1 domain, and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises theIGFBP domain and lacks the vWFC domain, the TSP1 domain, and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the vWFC domain and lacks the IGFBP domain, the TSP1 domain, and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the TSP1 domain and lacks the IGFBP domain, the vWFC domain, and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the C TCK domain and lacks the IGFBP domain, the vWFC domain, and the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises two of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the IGFBP domain and the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the vWFC domain and the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of two of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, theWSGR Docket No. 65459-704.601CCN3 polypeptide or the portion thereof consists of the IGFBP domain and the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of thevWFC domain and the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises two of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain and lacking the other two of the IGFBP domain, the vWFC domain, the TSP1 domain, and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the IGFBP domain the vWFC domain and lacks the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the TSP1 domain and the CTCK domain and lacks the IGFBP domain the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the cWFC domain and the TSP1 domain and lacks the IGFBP domain the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises three of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the IGFBP domain, the vWFC domain, and the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the vWFC domain, the TSP1 domain, and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of three of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the IGFBP domain, the vWFC domain, and the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the vWFC domain, the TSP1 domain, and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises three of the IGFBP domain, the vWFC domain, the TSP1 domain, and the CTCK domain and lacking the other one of the IGFBP domain, the vWFC domain, the TSP1 domain, and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the IGFBP domain, the vWFC domain, and the TSP1 domain and lacks the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the vWFC domain, the TSP1 domain, and the CTCK domain and lacks the IGFBP domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain.

[0105] In some embodiments, the IGFBP domain consists of an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to any one SEQ ID NOs: 15-16; the VWFC domain consists of an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to any one of SEQ ID NOs: 17-20 or 300-301 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain; the TSP1 domain consists of an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99%WSGR Docket No. 65459-704.601sequence identity to any one of SEQ ID NOs: 21-25, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP 1 domain; or / and the CTCK domain consists of an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to any one of SEQ ID NOs: 26-29, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain. In some embodiments, the IGFBP domain consists of an amino acid sequence with at least 90% sequence identity to any one SEQ ID NOs: 15-16; the VWFC domain consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 17-20 or 300-301 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain; the TSP 1 domain consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 21-25, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP1 domain; or / and the CTCK domain consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 26-29, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain. In some embodiments, the IGFBP domain consists of an amino acid sequence with at least 95% sequence identity to any one SEQ ID NOs: 15-16; the VWFC domain consists of an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 17-20 or 300-301 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain; the TSP1 domain consists of an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 21-25, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP 1 domain; or / and the CTCK domain consists of an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 26-29, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain. In some embodiments, the IGFBP domain consists of an amino acid sequence with at least 99% sequence identity to any one SEQ ID NOs: 15-16; the VWFC domain consists of an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 17-20 or 300-301 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain; the TSP1 domain consists of an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 21-25, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP 1 domain; or / and the CTCK domain consists of an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 26-29, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain. In some embodiments, the IGFBP domain consists of the amino acid sequence of any one of SEQ ID NOs: 15-16; the VWFC domain consists of the amino acid sequence of any one of SEQ ID NOs: 17-20 or 300-301 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain; the TSP1 domain consists of the amino acid sequence of any one of SEQ ID NOs: 21-25 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP1WSGR Docket No. 65459-704.601domain; or / and the CTCK domain consists of the amino acid sequence of any one of SEQ ID NOs: 26-29 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain. In some embodiments, the IGFBP domain comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to any one of SEQ ID NOs: 15-16; the VWFC domain comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to any one of SEQ ID NOs: 17-20 or 300-301 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain; the TSP1 domain comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to any one of SEQ ID NOs: 21-25 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP1 domain; or / and the CTCK domain comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to any one of SEQ ID NOs: 26-29 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain. In some embodiments, the IGFBP domain comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 15-16; the VWFC domain comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 17-20 or 300-301 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain; the TSP1 domain comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 21-25 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP1 domain; or / and the CTCK domain comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 26-29 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain. In some embodiments, the IGFBP domain comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 15-16; the VWFC domain comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 17-20 or 300-301 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain; the TSP1 domain comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 21-25 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP1 domain; or / and the CTCK domain comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 26-29 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain. In some embodiments, the IGFBP domain comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 15-16; the VWFC domain comprises an amino acid sequence with at least 99% sequenceWSGR Docket No. 65459-704.601identity to any one of SEQ ID NOs: 17-20 or 300-301 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain; the TSP1 domain comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 21-25 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP1 domain; or / and the CTCK domain comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 26-29 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain. In some embodiments, the IGFBP domain comprises the amino acid sequence of any one of SEQ ID NOs: 15-16; the VWFC domain comprises the amino acid sequence of any one of SEQ ID NOs: 17-20 or 300-301 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain; the TSP1 domain comprises the amino acid sequence of any one of SEQ ID NOs: 21-25 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP1 domain; or / and the CTCK domain comprises the amino acid sequence of any one of SEQ ID NOs: 26-29 or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain.

[0106] In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to any one of SEQ ID NOs: 15-54 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 15-54 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 15-54 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 15-54 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising the amino acid sequence of any one of SEQ ID NOs: 15-54 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof consisting of an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to any one of SEQ ID NOs: 15-54 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide comple x comprises the CCN3 polypeptide or the portion thereof consisting of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 15-54 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof consisting of an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 15-54 or 300-301. In some embodiments,WSGR Docket No. 65459-704.601the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof consisting of an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 15-54 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof consisting of the amino acid sequence of any one of SEQ ID NOs: 15-54 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to one of SEQ ID NOs: 15-29 or 300-301 and lacking an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to any other of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising an amino acid sequence with at least 90% sequence identity to one of SEQ ID NOs: 15-29 or 300-301 and lacking an amino acid sequence with at least 90% sequence identity to any other of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising two amino acid sequences that each has at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to one of two of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising two amino acid sequences that each has at least 90% sequence identity to one of two of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof consisting of two amino acid sequences that each has at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to one of two of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof consisting of two amino acid sequences that each has at least 90% sequence identity to one of two of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising two amino acid sequences that each has at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to one of two of SEQ ID NOs: 15-29 or 300-301 and lacks an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to any other of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising two amino acid sequences that each has at least 90% sequence identity toWSGR Docket No. 65459-704.601one of two of SEQ ID NOs: 15-29 or 300-301 and lacks an amino acid sequence with at least 90% sequence identity to any other of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising three amino acid sequences that each has at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to one of three of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising three amino acid sequences that each has at least 90% sequence identity to one of three of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof consisting of three amino acid sequences that each has at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to one of three of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof consisting of three amino acid sequences that each has at least 90% sequence identity to one of three of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising three amino acid sequences that each has at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to one of three of SEQ ID NOs: 15-29 or 300-301 and lacks an amino acid sequence with at least 90% sequence identity to any other of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising three amino acid sequences that each has at least 90% sequence identity to one of three of SEQ ID NOs: 15-29 or 300-301 and lacks an amino acid sequence with at least 90% sequence identity to any other of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising four amino acid sequences that each has at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to one of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof comprising four amino acid sequences that each has at least 90% sequence identity to one of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof consisting of four amino acid sequences that each has at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to one of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the recombinant polypeptide or polypeptide complex comprises the CCN3 polypeptide or the portion thereof consisting of four amino acid sequences that each has at least 90%WSGR Docket No. 65459-704.601sequence identity to one of SEQ ID NOs: 15-29 or 300-301. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the IGFBP domain and vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain and the vWFC domain, comprises an amino acid sequence with at least 70%, 75%, 80%, 85% 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NOs: 30-32 or a portion thereof that comprises a truncation or deletion at the carboxyl terminus of the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain and the vWFC domain, comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NOs: 30-32 or a portion thereof that comprises a truncation or deletion at the carboxyl terminus of the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain and the vWFC domain, comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NOs: 30-32 or a portion thereof that comprises a truncation or deletion at the carboxyl terminus of the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain and the vWFC domain, comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NOs: 30-32 or a portion thereof that comprises a truncation or deletion at the carboxyl terminus of the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain and the vWFC domain, comprises an amino acid sequence identical to SEQ ID NOs: 30-32 or a portion thereof that comprises a truncation or deletion at the carboxyl terminus of the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof consists of the IGFBP domain and vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain and the vWFC domain, consists of an amino acid sequence with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NOs: 30-32 or a portion thereof that comprises a truncation or deletion at the carboxyl terminus of the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain and the vWFC domain, consists of an amino acid sequence with at least 90% sequence identity to SEQ ID NOs: 30-32 or a portion thereof that comprises a truncation or deletion at the carboxyl terminus of the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain and the vWFC domain, consists of an amino acid sequence with at least 95% sequence identity to SEQ ID NOs: 30-32 or a portion thereof that comprises a truncation or deletion at the carboxyl terminus of the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain and the vWFC domain, consists of an amino acid sequence with at least 99% sequence identity to SEQ ID NOs: 30-32 or a portion thereof that comprises a truncation or deletion at the carboxyl terminus of the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain and the vWFC domain, consists of an amino acid sequence identical to SEQ ID NOs: 30-32 or a portion thereof that comprises a truncation or deletion at the carboxyl terminus of the vWFC domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprises the TSP1 domain and CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the TSP1 domain and the CTCK domain, comprises anWSGR Docket No. 65459-704.601amino acid sequence with at least 70%, 75%, 80%, 85% 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NOs: 39-44 or a portion thereof that comprises a truncation or deletion at the amino terminus of the TSP1 domain and / or a truncation or deletion at the carboxyl terminus of the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the TSP1 domain and the CTCK domain, comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NOs: 39-44 or a portion thereof that comprises a truncation or deletion at the amino terminus of the TSP1 domain and / or a truncation or deletion at the carboxyl terminus of the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the TSP1 domain and the CTCK domain, comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NOs: 39-44 or a portion thereof that comprises a truncation or deletion at the amino terminus of the TSP1 domain and / or a truncation or deletion at the carboxyl terminus of the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the TSP1 domain and the CTCK domain, comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NOs: 39-44 or a portion thereof that comprises a truncation or deletion at the amino terminus of the TSP1 domain and / or a truncation or deletion at the carboxyl terminus of the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the TSP1 domain and the CTCK domain, comprises an amino acid sequence identical to SEQ ID NOs: 39-44 or a portion thereof that comprises a truncation or deletion at the amino terminus of the TSP1 domain and / or a truncation or deletion at the carboxyl terminus of the CTCK domain.

[0107] In some embodiments, the CCN3 polypeptide or the portion thereof consists of the TSP1 domain and CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the TSP1 domain and the CTCK domain, consists of an amino acid sequence with at least 70%, 75%, 80%, 85% 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NOs: 39-44 or a portion thereof that comprises a truncation or deletion at the amino terminus of the TSP1 domain and / or a truncation or deletion at the carboxyl terminus of the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the TSP1 domain and the CTCK domain, consists of an amino acid sequence with at least 90% sequence identity to SEQ ID NOs: 39-44 or a portion thereof that comprises a truncation or deletion at the amino terminus of the TSP1 domain and / or a truncation or deletion at the carboxyl terminus of the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the TSP1 domain and the CTCK domain, consists of an amino acid sequence with at least 95% sequence identity to SEQ ID NOs: 39-44 or a portion thereof that comprises a truncation or deletion at the amino terminus of the TSP1 domain and / or a truncation or deletion at the carboxyl terminus of the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the TSP 1 domain and the CTCK domain, consists of an amino acid sequence with at least 99% sequence identity to SEQ ID NOs: 39-44 or a portion thereof that comprises a truncation or deletion at the amino terminus of the TSP1 domain and / or a truncation or deletion at the carboxyl terminus of the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the TSP 1 domain and the CTCK domain, consists of an amino acid sequence identical toWSGR Docket No. 65459-704.601SEQ ID NOs: 39-44 or a portion thereof that comprises a truncation or deletion at the amino terminus of the TSP1 domain and / or a truncation or deletion at the carboxyl terminus of the CTCK domain.

[0108] In some embodiments, the CCN3 polypeptide or the portion thereof comprises the vWFC domain and the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the vWFC domain and the TSP1 domain, comprises an amino acid sequence with at least 70%, 75%, 80%, 85% 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NOs: 33-38 or a portion thereof that comprises a truncation or deletion at the amino terminus of the vWFC domain and / or a truncation or deletion at tire carboxyl terminus of the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the vWFC domain and the TSP1 domain, comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NOs: 33-38 or a portion thereof that comprises a truncation or deletion at the amino terminus of the vWFC domain and / or a truncation or deletion at the carboxyl terminus of the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the vWFC domain and the TSP1 domain, comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NOs: 33-38 or a portion thereof that comprises a truncation or deletion at the amino terminus of the vWFC domain and / or a truncation or deletion at the carboxyl terminus of the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the vWFC domain and the TSP1 domain, comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NOs: 33-38 or a portion thereof that comprises a truncation or deletion at the amino terminus of the vWFC domain and / or a truncation or deletion at the carboxyl terminus of the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the vWFC domain and the TSP1 domain, comprises an amino acid sequence identical to SEQ ID NOs: 33-38 or a portion thereof that comprises a truncation or deletion at the amino terminus of the vWFC domain and / or a truncation or deletion at the carboxyl terminus of the TSP1 domain.

[0109] In some embodiments, the CCN3 polypeptide or the portion thereof consists of the vWFC domain and the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the vWFC domain and the TSP1 domain, consists of an amino acid sequence with at least 70%, 75%, 80%, 85% 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NOs: 33-38 or a portion thereof that comprises a truncation or deletion at the amino terminus of the vWFC domain and / or a truncation or deletion at the carboxyl terminus of the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the vWFC domain and the TSP1 domain, consists of an amino acid sequence with at least 90% sequence identity to SEQ ID NOs: 33-38 or a portion thereof that comprises a truncation or deletion at the amino terminus of the vWFC domain and / or a truncation or deletion at the carboxyl terminus of the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the vWFC domain and the TSP1 domain, consists of an amino acid sequence with at least 95% sequence identity to SEQ ID NOs: 33-38 or a portion thereof that comprises a truncation or deletion at the amino terminus of the vWFC domain and / or a truncation or deletion at the carboxyl terminus of the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the vWFC domain and the TSP1 domain, consists of an amino acidWSGR Docket No. 65459-704.601sequence with at least 99% sequence identity to SEQ ID NOs: 33-38 or a portion thereof that comprises a truncation or deletion at the amino terminus of the vWFC domain and / or a truncation or deletion at the carboxyl terminus of the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the vWFC domain and the TSP1 domain, consists of an amino acid sequence identical to SEQ ID NOs: 33-38 or a portion thereof that comprises a truncation or deletion at the amino terminus of the vWFC domain and / or a truncation or deletion at the carboxyl terminus of the TSP1 domain.

[0110] In some embodiments, the CCN3 polypeptide or the portion thereof comprises the IGFBP domain, the vWFC domain, and TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain, the vWFC domain, and the TSP1 domain, comprises an amino acid sequence with at least 70%, 75%, 80%, 85% 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NOs: 45-47 or a portion thereof that comprises a truncation or deletion at the carboxyl terminus of the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain, the vWFC domain, and the TSP1 domain comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NOs: 45-47 or a portion thereof that comprises a truncation or deletion at the carboxyl terminus of the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain, the vWFC domain, and the TSP1 domain, comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NOs: 45-47 or a portion thereof that comprises a truncation or deletion at the carboxyl terminus of the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain, the vWFC domain, and the TSP1 domain, comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NOs: 45-47 or a portion thereof that comprises a truncation or deletion at the carboxyl terminus of the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain, the vWFC domain, and the TSP1 domain, comprises an amino acid sequence identical to SEQ ID NOs: 45-47 or a portion thereof that comprises a truncation or deletion at the carboxyl terminus of the TSP1 domain.

[0111] In some embodiments, the CCN3 polypeptide or the portion thereof consists of the IGFBP domain, the vWFC domain, and TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain, the vWFC domain, and the TSP1 domain, consists of an amino acid sequence with at least 70%, 75%, 80%, 85% 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NOs: 45-47 or a portion thereof that comprises a truncation or deletion at the carboxyl terminus of the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain, the vWFC domain, and the TSP1 domain, consists of an amino acid sequence with at least 90% sequence identity to SEQ ID NOs: 45-47 or a portion thereof that comprises a truncation or deletion at the carboxyl terminus of the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain, the vWFC domain, and the TSP1 domain, consists of an amino acid sequence with at least 95% sequence identity to SEQ ID NOs: 45-47 or a portion thereof that comprises a truncation or deletion at the carboxyl terminus of the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising theWSGR Docket No. 65459-704.601IGFBP domain, the vWFC domain, and the TSP1 domain, consists of an amino acid sequence with at least 99% sequence identity to SEQ ID NOs: 45-47 or a portion thereof that comprises a truncation or deletion at the carboxyl terminus of the TSP1 domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain, the vWFC domain, and the TSP1 domain, consists of an amino acid sequence identical to SEQ ID NOs: 45-47 or a portion thereof that comprises a truncation or deletion at the carboxyl terminus of the TSP1 domain.

[0112] In some embodiments, the CCN3 polypeptide or the portion thereof comprises the vWFC domain, TSP1 domain, and CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the vWFC domain, the TSP1 domain, and the CTCK domain comprises an amino acid sequence with at least 70%, 75%, 80%, 85% 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 48-51 or a portion thereof that comprises a truncation or deletion at the amino terminus of the vWFC domain and / or a truncation or deletion at the carboxyl terminus of the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the vWFC domain, the TSP1 domain, and the CTCK domain, comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 48-51 or a portion thereof that comprises a truncation or deletion at the amino terminus of the vWFC domain and / or a truncation or deletion at the carboxyl terminus of the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the vWFC domain, the TSP1 domain, and the CTCK domain, comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 48-51 or a portion thereof that comprises a truncation or deletion at the amino terminus of the vWFC domain and / or a truncation or deletion at the carboxyl terminus of the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the vWFC domain, the TSP1 domain, and the CTCK domain, comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 48-51 or a portion thereof that comprises a truncation or deletion at the amino terminus of the vWFC domain and / or a truncation or deletion at the carboxyl terminus of the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the vWFC domain, the TSP1 domain, and the CTCK domain, comprises an amino acid sequence identical to any one of SEQ ID NOs: 48-51 or a portion thereof that comprises a truncation or deletion at the amino terminus of the vWFC domain and / or a truncation or deletion at the carboxyl terminus of the CTCK domain.

[0113] In some embodiments, the CCN3 polypeptide or the portion thereof consists of the vWFC domain, TSP1 domain, and CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the vWFC domain, the TSP1 domain, and the CTCK domain, consists of an amino acid sequence with at least 70%, 75%, 80%, 85% 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 48-51 or a portion thereof that comprises a truncation or deletion at the amino terminus of the vWFC domain and / or a truncation or deletion at the carboxyl terminus of the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the vWFC domain, the TSP1 domain, and the CTCK domain, consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 48-51 or a portion thereof thatWSGR Docket No. 65459-704.601comprises a truncation or deletion at the amino terminus of the vWFC domain and / or a truncation or deletion at the carboxyl terminus of the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the vWFC domain, the TSP1 domain, and the CTCK domain, consists of an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 48-51 or a portion thereof that comprises a truncation or deletion at the amino terminus of the vWFC domain and / or a truncation or deletion at the carboxyl terminus of the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the vWFC domain, the TSP1 domain, and the CTCK domain, consists of an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 48-51 or a portion thereof that comprises a truncation or deletion at the amino terminus of the vWFC domain and / or a truncation or deletion at the carboxyl terminus of the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the vWFC domain, the TSP1 domain, and the CTCK domain, consists of an amino acid sequence identical to any one of SEQ ID NOs: 48-51 or a portion thereof that comprises a truncation or deletion at the amino terminus of the vWFC domain and / or a truncation or deletion at the carboxyl terminus of the CTCK domain.

[0114] In some embodiments, the CCN3 polypeptide or the portion thereof comprises four of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain, the vWFC domain, the TSP1 domain, and the CTCK domain, comprises an amino acid sequence with at least 70%, 75%, 80%, 85% 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 52-54. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain, the vWFC domain, the TSP1 domain, and the CTCK domain, comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 52-54. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain, the vWFC domain, the TSP1 domain, and the CTCK domain, comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 52-54. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain, the vWFC domain, the TSP1 domain, and the CTCK domain, comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 52-54. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain, the vWFC domain, the TSP1 domain, and the CTCK domain, comprises an amino acid sequence identical to any one of SEQ ID NOs: 52-54.

[0115] In some embodiments, the CCN3 polypeptide or the portion thereof consists of theIGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain, the vWFC domain, the TSP1 domain, and the CTCK domain, consists of an amino acid sequence with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 52-54. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain, the vWFC domain, the TSP1 domain, and the CTCK domain, consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 52-54. In some embodiments,WSGR Docket No. 65459-704.601the CCN3 polypeptide or the portion thereof comprising the IGFBP domain, the vWFC domain, the TSP1 domain, and the CTCK domain, consists of an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 52-54. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain, the vWFC domain, the TSP1 domain, and the CTCK domain, consists of an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 52-54. In some embodiments, the CCN3 polypeptide or the portion thereof comprising the IGFBP domain, the vWFC domain, the TSP1 domain, and the CTCK domain, consists of an amino acid sequence identical to any one of SEQ ID NOs: 52-54.Linker and Signal Peptide

[0116] In some embodiments, the Fc region is covalently linked to the amino terminus of the CCN3 polypeptide or the portion thereof directly or through a linker. In some embodiments, the linker comprises a peptide linker. In some embodiments, the Fc region is covalently linked to the amino terminus of the CCN3 polypeptide or the portion thereof directly or through a peptide linker. In some embodiments, the Fc region is covalently linked to the amino terminus of the CCN3 polypeptide or the portion thereof directly. In some embodiments, the Fc region is covalently linked to the amino terminus of the CCN3 polypeptide or the portion thereof through a peptide linker. In some embodiments, the Fc region is covalently linked to the amino terminus of the CCN3 polypeptide or the portion thereof through a linker. In some embodiments, the Fc region is covalently linked to the carboxyl terminus of the CCN3 polypeptide or the portion thereof directly or through a linker. In some embodiments, the linker comprises a peptide linker. In some embodiments, the Fc region is covalently linked to the carboxyl terminus of the CCN3 polypeptide or the portion thereof directly or through a peptide linker. In some embodiments, the Fc region is covalently linked to the carboxyl terminus of the CCN3 polypeptide or the portion thereof directly. In some embodiments, the Fc region is covalently linked to the carboxyl terminus of the CCN3 polypeptide or the portion thereof through a peptide linker. In some embodiments, the Fc region is covalently linked to the carboxyl terminus of the CCN3 polypeptide or the portion thereof through a linker.

[0117] In some embodiments, the peptide linker comprises a glycine (G) and serine (S) linker comprising (GGGGS)n (SEQ ID NO: 7), wherein n equals 1 to 5. In some embodiments, the peptide linker comprises a glycine (G) and serine (S) linker comprising (GGGGS)n (SEQ ID NO: 330), wherein n equals 1. In some embodiments, the peptide linker comprises a glycine (G) and serine (S) linker comprising (GGGGS)n (SEQ ID NO: 342), wherein n equals 2. In some embodiments, the peptide linker comprises a glycine (G) and serine (S) linker comprising (GGGGS)n (SEQ ID NO: 339), wherein n equals 3. In some embodiments, the peptide linker comprises a glycine (G) and serine (S) linker comprising (GGGGS)n (SEQ ID NO: 343), wherein n equals 4. In some embodiments, the peptide linker comprises a glycine (G) and serine (S) linker comprising (GGGGS)n (SEQ ID NO: 344), wherein n equals 5. In some embodiments, the peptide linker comprises an amino acid sequence of (EAAAK)n (SEQ ID NO: 5), wherein n equals 1 to 5. In some embodiments, the peptide linker comprises an amino acid sequence of (EAAAK)n (SEQ ID NO: 333), wherein n equals 1. In some embodiments, the peptideWSGR Docket No. 65459-704.601linker comprises an amino acid sequence of (EAAAK)n (SEQ ID NO: 345), wherein n equals 2. In some embodiments, the peptide linker comprises an amino acid sequence of (EAAAK)n (SEQ ID NO: 346), wherein n equals 3. In some embodiments, the peptide linker comprises an amino acid sequence of (EAAAK)n (SEQ ID NO: 347), wherein n equals 4. In some embodiments, the peptide linker comprises an amino acid sequence of (EAAAK)n (SEQ ID NO: 348), wherein n equals 5. In some embodiments, the peptide linker comprises an amino acid sequence of A(EAAAK)nA (SEQ ID NO: 6), wherein n equals 1 to 5. In some embodiments, the peptide linker comprises an amino acid sequence of A(EAAAK)nA (SEQ ID NO: 332), wherein n equals 1. In some embodiments, the peptide linker comprises an amino acid sequence of A(EAAAK)nA (SEQ ID NO: 349), wherein n equals 2. In some embodiments, the peptide linker comprises an amino acid sequence of A(EAAAK)nA (SEQ ID NO: 350), wherein n equals 3. In some embodiments, the peptide linker comprises an amino acid sequence of A(EAAAK)nA (SEQ ID NO: 351), wherein n equals 4. In some embodiments, the peptide linker comprises an amino acid sequence of A(EAAAK)nA (SEQ ID NO: 352), wherein n equals 5. In some embodiments, domains of the recombinant polypeptide or polypeptide complex are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region; or the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof. In some embodiments, domains of the recombinant polypeptide or polypeptide complex are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region. In some embodiments, domains of the recombinant polypeptide or polypeptide complex are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof. In some embodiments, domains of the recombinant polypeptide or polypeptide complex are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region; or the Fc region and the CCN3 polypeptide or the portion thereof. In some embodiments, domains of the recombinant polypeptide or polypeptide complex are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region. In some embodiments, domains of the recombinant polypeptide or polypeptide complex are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region and the CCN3 polypeptide or the portion thereof. In some embodiments, the recombinant polypeptide or polypeptide complex further comprising a signal peptide at the amino terminus of the recombinant polypeptide or polypeptide complex. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 9.Homodimer and Heterodimer

[0118] In some embodiments, the recombinant polypeptide or polypeptide complex comprises a first polypeptide and a second polypeptide, wherein the first polypeptide and the second polypeptide associate to form a homodimer or heterodimer. In some embodiments, the recombinant polypeptide or polypeptide complex comprises a first polypeptide and a second polypeptide, wherein the first polypeptide and the second polypeptide associate to form a homodimer. In some embodiments, the recombinant polypeptideWSGR Docket No. 65459-704.601or polypeptide complex comprises a first polypeptide and a second polypeptide, wherein the first polypeptide and the second polypeptide associate to form a heterodimer. In some embodiments, the first polypeptide or second polypeptide comprises the CCN3 polypeptide or the portion thereof and the Fc region. In some embodiments, the first polypeptide comprises the CCN3 polypeptide or the portion thereof and the Fc region. In some embodiments, the second polypeptide comprises the CCN3 polypeptide or the portion thereof and the Fc region. In some embodiments, the first polypeptide comprises the CCN3 polypeptide or the portion thereof and the Fc region and the second polypeptide comprises the CCN3 polypeptide or the portion thereof and the Fc region. In some embodiments, the first polypeptide or second polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof. In some embodiments, the first polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof. In some embodiments, the second polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof. In some embodiments, the first polypeptide comprises the CCN3 polypeptide or the portion thereof and the Fc region and the second polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof. In some embodiments, the first polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof and the second polypeptide comprises the CCN3 polypeptide or the portion thereof and the Fc region. In some embodiments, the first polypeptide and the second polypeptide of the recombinant polypeptide or the polypeptide complex form a knob-into-hole within the Fc regions. In some embodiments, the first polypeptide comprising a first CCN3 polypeptide or portion thereof and the Fc region that has the hole structure and the second polypeptide comprising a second CCN3 polypeptide or portion thereof and the Fc region that has the knob structure. In some embodiments, the first polypeptide comprising a first CCN3 polypeptide or portion thereof and the Fc region that has the knob structure and the second polypeptide comprising a second CCN3 polypeptide or portion thereof and the Fc region that has the hole structure. In some embodiments, the knob is positioned into the hole to form a heterodimer or a homodimer.

[0119] In some embodiments, domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region; and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region. In some embodiments, domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region; and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region. In some embodiments, domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region; and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region. In some embodiments, domains of the first polypeptide are arranged, from theWSGR Docket No. 65459-704.601amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region; and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region. In some embodiment, domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof; and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof. In some embodiments, domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region and the CCN3 polypeptide or the portion thereof; and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof. In some embodiments, domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof; and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region and the CCN3 polypeptide or the portion thereof. In some embodiments, domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region and the CCN3 polypeptide or the portion thereof; and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region and the CCN3 polypeptide or the portion thereof. In some embodiments, domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region; and the second polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof. In some embodiments, domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region; and the second polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof. In some embodiments, domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof; and the second polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof. In some embodiments, domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region and the CCN3 polypeptide or the portion thereof; and the second polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof. In some embodiments, domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region; and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof. In some embodiments, domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or theWSGR Docket No. 65459-704.601portion thereof, the peptide linker, and the Fc region; and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region and the CCN3 polypeptide or the portion thereof. In some embodiments, domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region and the CCN3 polypeptide or the portion thereof; and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region. In some embodiments, domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region; and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof. In some embodiments, domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof; and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region. In some embodiments, domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region; and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region and the CCN3 polypeptide or the portion thereof. In some embodiments, a linker can be a flexible linker or a rigid linker. In some embodiments, the recombinant polypeptide or polypeptide complex disclosed herein is in a homodimeric, heterodimeric, or monomeric form.Fc region

[0120] In some embodiments, the Fc region of the recombinant polypeptide or polypeptide complex comprises an immunoglobulin (Ig) G, IgM, IgA, IgD, or IgE. In some embodiments, the Fc region comprises an immunoglobulin (Ig) G, IgM, IgA, IgD, or IgE. In some embodiments, the Fc region comprises an IgG. In some embodiments, the Fc region comprises an IgGl, IgG2, IgG3, or IgG4. In some embodiments, the Fc region comprises an IgGl. In some embodiments, the Fc region comprises an IgG4. In some embodiments, the Fc region comprises a human IgG. In some embodiments, the Fc region comprises a human IgGl. In some embodiments, the Fc region comprises a human IgG4.

[0121] In some embodiments, the Fc region comprises one or more amino acid changes (e.g., insertions, deletions or substitutions) as compared to wild-type Fc region. In some embodiments, the Fc region comprises a human Fc region sequence (e.g., a human IgGl, IgG2, IgG3 or IgG4 Fc region) comprising an amino acid modification (e.g., a substitution) at one or more amino acid positions. In some embodiments, the Fc region comprises a “knob into hole” structure to promote heterodimerization. In some embodiments, the Fc region comprises an amino acid modification to change the binding interaction between Fc and the neonatal Fc receptor (FcRn). In some embodiments, the Fc region comprises an amino acid modification to change the binding interaction between Fc and Fc-gamma receptors (FcyR) or complement component Iq (Clq).WSGR Docket No. 65459-704.601

[0122] Accordingly, in some embodiments, the Fc region may comprise one or more amino acid modification (e.g., Leu234Ala / Leu235Ala, i.e. LALA, F234A / L235A, i.e. FALA, or P329G) that alters the antibody-dependent cellular cytotoxicity (ADCC) or other effector functions. In some embodiments, the Fc region may comprise one or more amino acid modification (e.g.,, AK447) that improves protein homogeneity. In certain embodiments, the Fc modification comprise a FALA mutation, i.e., mutations of F234A and L235A, according to the EU numbering. In certain embodiments, LALA and FALA mutations decrease or eliminate Fc binding to FcyRs, and / or reduce ADCC activity. In certain embodiments, the Fc modification comprises a lysine (K) deletion at amino acid position 447 (AK447) according to the EU numbering to improve protein homogeneity. In certain embodiments, the Fc modification comprises substitution of proline (P) at position 329 according to the EU numbering with Glycine (G) to modify FcyR or Clq binding and immune effector functions. In certain embodiments, the Fc modification comprises YTE (M252Y / S254T7T256E) and LS (M428L / N434S) in the Fc regions to increase half-life and / or prolong duration of protection. In certain embodiments, the Fc modification comprises S228P to prevent in vivo and in vitro IgG4 fragment antigen-binding region (Fab)-arm exchange.

[0123] In some embodiments, the Fc region of the recombinant polypeptide or polypeptide complex comprises a first amino acid mutation that reduces or eliminates antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) or binding of the Fc region to a Fc-gamma receptor (FcyR). In some embodiments, the first amino acid mutation comprises a substitution of leucine (L) with alanine (A) at amino acid 234 according to the EU numbering (L234A). In some embodiments, the first amino acid mutation comprises a substitution of leucine (L) with alanine (A) at amino acid 235 according to the EU numbering (L235A). In some embodiments, the first amino acid mutation comprises a substitution of phenylalanine (F) with alanine (A) at amino acid 234 according to the EU numbering (F234A). In some embodiments, the first amino acid mutation comprises a substitution of proline (P) with glycine (G) at amino acid 329 according to the EU numbering (P329G). In some embodiments, the Fc region comprises a deletion of amino acid lysine (K) at amino acid 447 (K447) according to the EU numbering. In some embodiments, the Fc region comprises a human IgGl comprising the deletion of K447. In some embodiments, the Fc region comprises a human IgGl comprising K447. In some embodiments, the Fc region comprises the first amino acid mutation comprising L234A and L235A. In some embodiments, the Fc region comprises the first amino acid mutation comprising L234A, L235A, and P329G. In some embodiments, the Fc region comprises the first amino acid mutation comprising L234A, L235A, and P329G and the deletion of K447. In some embodiments, the Fc region comprises an IgG4 comprising the first amino acid mutation comprising F234A and L235A. In some embodiments, the Fc region comprises an IgG4 comprising the first amino acid mutation comprising F234A and L235A and the deletion of K447.

[0124] In some embodiments, the recombinant polypeptide or polypeptide complex comprises a homodimer. In some embodiments, the Fc region of the first polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G and the deletion of K447; and the Fc region of theWSGR Docket No. 65459-704.601second polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G and the deletion of K447. In some embodiments, the Fc region of the first polypeptide comprises the first amino acid mutation comprising F234A and L235A and the deletion of K447; and the Fc region of the second polypeptide comprises the first amino acid mutation comprising F234A and L235A and the deletion of K447. In some embodiments, the Fc region of the first polypeptide comprises the first amino acid mutation comprising F234A and L235A; and the Fc region of the second polypeptide comprises the first amino acid mutation comprising F234A and L235A. In some embodiments, the Fc region of the first polypeptide comprises the first amino acid mutation comprising L234A and L235A; and the Fc region of the second polypeptide comprises the first amino acid mutation comprising L234A and L235A.

[0125] In some embodiments, the recombinant polypeptide or polypeptide complex comprises a heterodimer. In some embodiments, the Fc region comprises a second amino acid mutation that results in knob-into-hole amino acid substitution. In some embodiments, the Fc region of first polypeptide comprises the second amino acid mutation that results in a hole substitution and the Fc region of second polypeptide comprises the second amino acid mutation that results in the knob substitution. In some embodiments, the Fc region of the first polypeptide composes the second amino acid mutation that results in a knob substitution and the Fc region of the second polypeptide comprises the second amino acid mutation that results in a hole substitution.

[0126] In some embodiments, the second amino acid mutation of the Fc region comprises: a substitution of threonine (T) with tryptophan (W) at amino acid residue 366 according to the EU numbering (T366W); a substitution of threonine (T) with serine (S) at amino acid residue 366 according to the EU numbering (T366S); a substitution of leucine (L) with alanine (A) at amino acid residue 368 according to the EU numbering (L368A); or a substitution of tyrosine (Y) with valine (V) at amino acid residue 407 according to the EU numbering (Y407V). In some embodiments, the Fc region of the first polypeptide comprises the second amino acid mutation comprising T366W; and the Fc region of the second polypeptide comprises the second amino acid mutation comprising T366S, L368A and Y407V. In some embodiments, the Fc region of the first polypeptide comprises the second amino acid mutation comprising T366S, L368A and Y407V; and the Fc region of the second polypeptide comprises the second ammo acid mutation comprising T366W.

[0127] In some embodiments, the Fc region of the first polypeptide comprises the first amino acid mutation comprising L234A and L235A and the second amino acid mutation comprising T366W; and the Fc region of the second polypeptide comprises the first amino acid mutation comprising L234A and L235A; and the second ammo acid mutation comprising T366S, L368A and Y407V. In some embodiments, the Fc region of the first polypeptide comprises the first amino acid mutation comprising F234A and L235A and the second amino acid mutation comprising T366W; and the Fc region of the second polypeptide comprises the first amino acid mutation comprising F234A and L235A; and the second ammo acid mutation comprising T366S, L368A and Y407V. In some embodiments, the Fc region of the first polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G; and the second amino acid mutation comprising T366W; and the Fc region of the second polypeptideWSGR Docket No. 65459-704.601comprises the first amino acid mutation comprising L234A, L235A, and P329G; and the second amino acid mutation comprising T366S, L368A and Y407V. In some embodiments, the Fc region of the first polypeptide comprises: the first amino acid mutation comprising L234A, L235A, and P329G and the deletion of K447; and the second amino acid mutation comprising T366W; and the Fc region of the second polypeptide comprises: the first amino acid mutation comprising L234A, L235A, and P329G and the deletion of K447; and the second amino acid mutation comprising T366S, L368A and Y407V.

[0128] In some embodiments, Fc region of the recombinant polypeptide or polypeptide complex comprises a third amino acid mutation that stabilizes the hinge region of the Fc region, eliminates or inhibits an exchange of a fragment antigen binding (Fab) region, or both. In some embodiments, the third amino acid mutation comprises a substitution of serine (S) with proline (P) at amino acid 228 according to the EU numbering (S228P).

[0129] In some embodiments, the Fc region of the recombinant polypeptide or polypeptide complex comprises an IgG4 comprising the first amino acid mutation comprising F234A and L235A, the deletion of K447 and the third amino acid mutation comprising S228P. In some embodiments, the Fc region of the first polypeptide comprises an IgG4 comprising the first amino acid mutation comprising F234A and L235A, the deletion of K447 and the third amino acid mutation comprising S228P; and the Fc region of the second polypeptide comprises an IgG4 comprising the first amino acid mutation comprising F234A and L235A, the deletion of K447 and the third amino acid mutation comprising S228P. In some embodiments, the Fc region of the first polypeptide comprises an IgG4 comprising the first amino acid mutation comprising F234A and L235A, the deletion of K447, the second amino acid mutation comprising T366W and the third amino acid mutation comprising S228P; and the Fc region of the second polypeptide comprises an IgG4 comprising the first amino acid mutation comprising F234A and L235A, the deletion of K447, the second amino acid mutation comprising T366S, L368A and Y407V and the third amino acid mutation comprising S228P. In some embodiments, Fc region of the recombinant polypeptide or polypeptide complex comprises a fourth amino acid mutation that increases the binding of the Fc region to the neonatal Fc receptor (FcRn), increases the half-life of the recombinant polypeptide or polypeptide complex, or both. In some embodiments, the fourth amino acid mutation comprises: a substitution of methionine (M) with leucine (L) at amino acid 428 according to the EU numbering (M428L); a substitution of asparagine (N) with serine (S) at amino acid 434 according to the EU numbering (N434S); a substitution of methionine (M) with tyrosine (Y) at amino acid 252 according to the EU numbering (M252Y); a substitution of serine (S) with threonine (T) at amino acid 254 according to the EU numbering (S254T); a substitution of threonine (T) with glutamic acid (E) at amino acid 254 according to the EU numbering (T256E), or a combination thereof. In some embodiments, the fourth amino acid mutation comprises M428L and N434S. In some embodiments, the fourth amino acid mutation comprises M252Y, S254T, and T256E. In some embodiments, the Fc region of the recombinant polypeptide or polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G, the deletion of K447, and the fourth amino acid mutation comprising M428L and N434S. In some embodiments, the Fc region of the recombinant polypeptide or polypeptide comprises the firstWSGR Docket No. 65459-704.601amino acid mutation comprising L234A, L235A, and P329G, the deletion of K447, and the fourth amino acid mutation comprising M252Y, S254T, and T256E.

[0130] In some embodiments, the Fc region of the recombinant polypeptid e or polypeptide comprises the first amino acid mutation, the third amino acid mutation, and the fourth amino acid mutation. In some embodiments, the Fc region of the recombinant polypeptide or polypeptide comprises the first amino acid mutation, the second amino acid mutation, and the third amino acid mutation. In some embodiments, the Fc region of the recombinant polypeptide or polypeptide comprises the first amino acid mutation, the second amino acid mutation, and the fourth amino acid mutation. In some embodiments, the Fc region of the recombinant polypeptide or polypeptide comprises the first amino acid mutation, the second amino acid mutation, the third amino acid mutation, and the fourth amino acid mutation.

[0131] In some embodiments, the Fc region of the first polypeptide of the recombinant polypeptide or polypeptide comprises the first amino acid mutation comprising L234A and L235A and the fourth amino acid mutation comprising M428L and N434S; and the Fc region of the second polypeptide comprises the first amino acid mutation comprising L234A and L235A and the fourth amino acid mutation comprising M428L and N434S. In some embodiments, the Fc region of the first polypeptide of the recombinant polypeptide or polypeptide comprises the first amino acid mutation comprising L234A and L235A and the fourth amino acid mutation comprising M252Y, S254T, and T256E; and the Fc region of the second polypeptide comprises the first amino acid mutation comprising L234A and L235A and the fourth amino acid mutation comprising M252Y, S254T, and T256E. In some embodiments, the Fc region of the first polypeptide of the recombinant polypeptide or polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G, and the fourth amino acid mutation comprising M428L and N434S; and the Fc region of the second polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G, and the fourth amino acid mutation comprising M428L and N434S. In some embodiments, the Fc region of the first polypeptide of the recombinant polypeptide or polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G, and the fourth amino acid mutation comprising M252Y, S254T, and T256E; and the Fc region of the second polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G, and the fourth amino acid mutation comprising M252Y, S254T, and T256E. In some embodiments, the Fc region of the first polypeptide of the recombinant polypeptide or polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G, the deletion of K447, and the fourth amino acid mutation comprising M428L and N434S; and the Fc region of the second polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G, the deletion of K447, and the fourth amino acid mutation comprising M428L and N434S. In some embodiments, the Fc region of the first polypeptide of the recombinant polypeptide or polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G, the deletion of K447, and the fourth amino acid mutation comprising M252Y, S254T, and T256E; and the Fc region of the second polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G, the deletion of K447, and the fourth amino acid mutation comprising M252Y, S254T, and T256E. In some embodiments, the Fc region of the first polypeptide ofWSGR Docket No. 65459-704.601the recombinant polypeptide or polypeptide comprises the first amino acid mutation comprising L234A and L235A, the second amino acid mutation comprising T366W, and the fourth amino acid mutation comprising M428L and N434S; and the Fc region of the second polypeptide comprises the first amino acid mutation comprising L234A and L235A, the second amino acid mutation comprising T366S, L368A and Y407V, and the fourth amino acid mutation comprising M428L and N434S. In some embodiments, the Fc region of the first polypeptide of the recombinant polypeptide or polypeptide comprises the first amino acid mutation comprising L234A and L235A, the second amino acid mutation comprising T366W, and the fourth amino acid mutation comprising M252Y, S254T, and T256E; and the Fc region of the second polypeptide comprises the first amino acid mutation comprising L234A and L235A, the second amino acid mutation comprising T366S, L368A and Y407V, and the fourth amino acid mutation comprising M252Y, S254T, and T256E. In some embodiments, the Fc region of the first polypeptide of the recombinant polypeptide or polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G, the second amino acid mutation comprising T366W, and the fourth amino acid mutation comprising M428L and N434S; and the Fc region of the second polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G, the second amino acid mutation comprising T366S, L368A and Y407V, and the fourth amino acid mutation comprising M428L and N434S. In some embodiments, the Fc region of the first polypeptide of the recombinant polypeptide or polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G, the second amino acid mutation comprising T366W, and the fourth amino acid mutation comprising M252Y, S254T, and T256E; and the Fc region of the second polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G, the second amino acid mutation comprising T366S, L368A and Y407V, and the fourth amino acid mutation comprising M252Y, S254T, and T256E. In some embodiments, the Fc region of the first polypeptide of the recombinant polypeptide or polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G, the deletion of K447, the second amino acid mutation comprising T366W, and the fourth amino acid mutation comprising M428L and N434S; and the Fc region of the second polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G, the deletion of K447, the second amino acid mutation comprising T366S, L368A and Y407V, and the fourth amino acid mutation comprising M428L and N434S.

[0132] In some embodiments, the Fc region comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to any one of SEQ ID NOs: 12, 13, 14, 296, 297, 298, 299, and 314. In some embodiments, the Fc region comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to SEQ ID NO: 12. In some embodiments, the Fc region comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 12. In some embodiments, the Fc region comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 12. In some embodiments, the Fc region comprises an amino acid sequence with at least 99% sequence identityWSGR Docket No. 65459-704.601to SEQ ID NO: 12. in some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 12. In some embodiments, wherein the Fc region of the first polypeptide comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to SEQ ID NO: 12 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to SEQ ID NO: 12. In some embodiments, wherein the Fc region of the first polypeptide comprises the amino acid sequence of SEQ ID NO: 12 and the Fc region of the second polypeptide comprises the amino acid sequence of SEQ ID NO: 12. In some embodiments, the Fc region comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to SEQ ID NO: 13. In some embodiments, the Fc region comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 13. In some embodiments, the Fc region comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 13. In some embodiments, the Fc region comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 13. In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 13. In some embodiments, the Fc region comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to SEQ ID NO: 14. In some embodiments, the Fc region comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 14. In some embodiments, the Fc region comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 14. In some embodiments, the Fc region comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 14. In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 14. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to SEQ ID NO: 13 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to SEQ ID NO: 14. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 13 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 14. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 13 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 14. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 99% sequence identity toWSGR Docket No. 65459-704.601SEQ ID NO: 13 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 14. In some embodiments, the Fc region of the first polypeptide comprises the amino acid sequence of SEQ ID NO: 13 and the Fc region of the second polypeptide comprises the amino acid sequence of SEQ ID NO: 14.

[0133] In some embodiments, the Fc region comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to any one of SEQ ID NOs: 296-299 or SEQ ID NO: 314. In some embodiments, the Fc region comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 296-299 or SEQ ID NO: 314. In some embodiments, the Fc region comprises an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 296-299 or SEQ ID NO: 314. In some embodiments, the Fc region comprises an amino acid sequence with at least 99% sequence identity to any one of SEQ ID NOs: 296-299 or SEQ ID NO: 314. In some embodiments, the Fc region comprises the amino acid sequence of any one of SEQ ID NOs: 296-299 or SEQ ID NO: 314. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to SEQ ID NO: 296 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to SEQ ID NO: 296. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 296 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 296. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 296 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 296. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 296 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 296. In some embodiments, the Fc region of the first polypeptide comprises the amino acid sequence of SEQ ID NO: 296 and the Fc region of the second polypeptide comprises the amino acid sequence of SEQ ID NO: 296. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to SEQ ID NO: 297 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to SEQ ID NO: 297. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 90%WSGR Docket No. 65459-704.601sequence identity to SEQ ID NO: 297 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 297. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 297 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 297. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 297 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 297. In some embodiments, the Fc region of the first polypeptide comprises the amino acid sequence of SEQ ID NO: 297 and the Fc region of the second polypeptide comprises the amino acid sequence of SEQ ID NO: 297. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to SEQ ID NO: 298 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to SEQ ID NO: 298. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 298 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 298. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 298 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 298. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 298 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 298. In some embodiments, the Fc region of the first polypeptide comprises the amino acid sequence of SEQ ID NO: 298 and the Fc region of the second polypeptide comprises the amino acid sequence of SEQ ID NO: 298. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to SEQ ID NO: 314 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% sequence identity to SEQ ID NO: 299. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 314 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 299. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 314 and the Fc region of the second polypeptide comprises an amino acid sequence with atWSGR Docket No. 65459-704.601least 95% sequence identity to SEQ ID NO: 299. In some embodiments, the Fc region of the first polypeptide comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 314 and the Fc region of the second polypeptide comprises an amino acid sequence with at least 99% sequence identity to SEQ ID NO: 299. In some embodiments, the Fc region of the first polypeptide comprises the amino acid sequence of SEQ ID NO: 314 and the Fc region of the second polypeptide comprises the amino acid sequence of SEQ ID NO: 299.Domain Arrangement

[0134] Provided herein, in some embodiments, are the recombinant polypeptide or polypeptide complex comprising a CCN3 polypeptide or a portion thereof and a fragment crystallizable (Fc) region.

[0135] The position of the Fc region within the fusion protein can vary. It can be placed at either the amino terminus or carboxyl terminus of the fusion protein. In some embodiments, the Fc region is placed at the N-terminus of the recombinant polypeptide or polypeptide complex, resulting in domains of the recombinant polypeptide or polypeptide complex being arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region. In some embodiments, the Fc region is placed at the C-terminus of the recombinant polypeptide or polypeptide complex, resulting in domains of the recombinant polypeptide or polypeptide complex being arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof. In some embodiments, the recombinant polypeptide or polypeptide complex is engineered without a linker connecting the CCN3 polypeptide or the portion thereof and the Fc region. Accordingly, domains of the recombinant polypeptide or polypeptide complex are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region; or the Fc region and the CCN3 polypeptide or the portion thereof. In some embodiments, the recombinant polypeptide or polypeptide complex, further comprises a signal peptide at the amino terminus of the recombinant polypeptide or polypeptide complex. Exemplary signal peptides used for the secretion of a recombinant polypeptide or polypeptide complex include, but are not limited to human IgG heavy chain signal peptide, IL-2 signal peptide, and tissue plasminogen activator signal peptide. In some embodiments, the native CCN3 signal peptide is used for recombinant polypeptide or polypeptide complex. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 9.

[0136] The Fc region of the first and second polypeptides can be modified, comprising mutations, and / or deletions. For example, a “knob-into-hole” mutations can be introduced to the Fc region to force selective heterodimerization. In some embodiments, the recombinant polypeptide or polypeptide complex comprises a first polypeptide and a second polypeptide, wherein the first polypeptide and the second polypeptide associate to form a homodimer. In some embodiments, the recombinant polypeptide or polypeptide complex comprises a first polypeptide and a second polypeptide, wherein the first polypeptide and the second polypeptide associate to form a heterodimer. The two identical polypeptides form a symmetric Fc-fusion protein. In some embodiments, the first polypeptide comprises the CCN3 polypeptide or the portion thereof and the Fc region and the second polypeptide comprises the CCN3WSGR Docket No. 65459-704.601polypeptide or the portion thereof and the Fc region. The two Fc regions can be covalently linked but fused to distinct CCN3 polypeptides or the portions thereof, resulting in an asymmetric Fc-fusion protein. In some embodiments, the first polypeptide comprises the Fc region and the CCN3 polypeptide or the portion thereof, while the second polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof. In some embodiments, the first polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof, while the second polypeptide comprises the Fc region and the CCN3 polypeptide or the portion thereof. For example, the first polypeptide and the second polypeptide of the recombinant polypeptide or the polypeptide complex form a knob-into-hole within the Fc regions. The first polypeptide comprising a first CCN3 polypeptide or portion thereof has the “hole” structure, while the second polypeptide comprising a second CCN3 polypeptide or portion thereof has the “knob” structure. Alternatively, the first polypeptide comprising a first CCN3 polypeptide or portion thereof has the “knob” structure, while the second polypeptide comprising a second CCN3 polypeptide or portion thereof has the “hole” structure. In another example, the first polypeptide comprising the CCN3 polypeptide or portion thereof has the “hole” structure, while the second polypeptide lacking the CCN3 polypeptide or portion thereof has the “knob” structure. Alternatively, the first polypeptide comprising the CCN3 polypeptide or portion thereof has the “knob” structure, while the second polypeptide lacking the CCN3 polypeptide or portion thereof has the “hole” structure. Domains of a polypeptide may be arranged, from the amino terminus to the carboxyl terminus, in the following order: the fused polypeptide or the portion thereof, the peptide linker, and the Fc region. Alternatively, domains of a polypeptide can be arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region, the peptide linker, and the fused polypeptide or the portion thereof. In the absence of a linker between, domains of a polypeptide can be arranged, from the amino terminus to the carboxyl terminus, in the following order: the fused polypeptide or the portion thereof and the Fc region. Alternatively, domains of a polypeptide can be arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region and the fused polypeptide or the portion thereof. The two polypeptide chains of a recombinant polypeptide may be configured such that one chain includes a linker while the other does not. As a result, the recombinant polypeptide or the polypeptide complex can yield distinct structural variants based on the presence or absence of a linker, as well as the orientation of the Fc region relative to the fused polypeptide or the portion thereof. The following embodiments provided herein illustrate various structural variants. In some embodiments, domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region; and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region. In some embodiments, domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region; and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region. In some embodiments, domainsWSGR Docket No. 65459-704.601of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region; and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in th...

Claims

WSGR Docket No. 65459-704.601CLAIMS WHAT IS CLAIMED IS:

1. A recombinant polypeptide or polypeptide complex comprising a cellular communication network factor 3 (CCN3) polypeptide or a portion thereof and a fragment crystallizable (Fc) region.

2. The recombinant polypeptide or polypeptide complex of claim 1, wherein the Fc region is covalently linked to the amino terminus or carboxyl terminus of the CCN3 polypeptide or the portion thereof directly or through a peptide linker.

3. The recombinant polypeptide or polypeptide complex of claim 2, wherein the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to the wildtype CCN3 of SEQ ID NO: 53 or a fragment thereof.

4. The recombinant polypeptide or polypeptide complex of claim 3, wherein the CCN3 polypeptide or the portion thereof comprises a truncation of at least one amino acid of the 19 amino acids at the carboxyl terminus of SEQ ID NO: 53.

5. The recombinant polypeptide or polypeptide complex of claim 4, wherein the truncation comprises 1-19 amino acids.

6. The recombinant polypeptide or polypeptide complex of claim 4, wherein the truncation comprises 5-10 amino acids.

7. The recombinant polypeptide or polypeptide complex of claim 4, wherein the truncation comprises 10-19 amino acids.

8. The recombinant polypeptide or polypeptide complex of claim 4, wherein the truncation comprises 19 amino acids.

9. The recombinant polypeptide or polypeptide complex of claim 3, wherein the CCN3 polypeptide or the portion thereof further comprises a deletion of at least one amino acid of the 19 amino acids at the carboxyl terminus of SEQ ID NO: 53.

10. The recombinant polypeptide or polypeptide complex of claim 9, wherein the deletion comprises a consecutive amino acid sequence or at least two nonconsecutive amino acid sequences.

11. The recombinant polypeptide or polypeptide complex of claim 2, wherein the peptide linker comprises:WSGR Docket No. 65459-704.601(a) a glycine (G) and serine (S) linker comprising (GGGGS)n (SEQ ID NO: 7), wherein n equals 1 to 5;(b) an amino acid sequence of (EAAAK)n (SEQ ID NO: 5), wherein n equals 1 to 5; or (c) an amino acid sequence of A(EAAAK)nA (SEQ ID NO: 6), wherein n equals 1 to 5.

12. The recombinant polypeptide or polypeptide complex of claim 2, wherein domains of the recombinant polypeptide or polypeptide complex are arranged, from the amino terminus to the carboxyl terminus, in the following order:(a) the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region; (b) the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof. (c) the CCN3 polypeptide or the portion thereof and the Fc region; or(d) the Fc region and the CCN3 polypeptide or the portion thereof.

13. The recombinant polypeptide or polypeptide complex of claim 1, further comprising a signal peptide at the amino terminus of the recombinant polypeptide or polypeptide complex.

14. The recombinant polypeptide or polypeptide complex of claim 2, further comprising a first polypeptide and a second polypeptide, wherein the first polypeptide and the second polypeptide associate to form a homodimer or a heterodimer.

15. The recombinant polypeptide or polypeptide complex of claim 14, wherein:(a) the first polypeptide or the second polypeptide comprises the CCN3 polypeptide or the portion thereof and the Fc region;(b) the first polypeptide comprises the CCN3 polypeptide or the portion thereof and the Fc region and the second polypeptide comprises the CCN3 polypeptide or the portion thereof and the Fc region;(c) the first polypeptide or the second polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof; or(d) the first polypeptide comprises the CCN3 polypeptide or the portion thereof and the Fc region and the second polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof.

16. The recombinant polypeptide or polypeptide complex of claim 15, wherein:(a) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region;(b) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the FcWSGR Docket No. 65459-704.601region and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region;(c) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region;(d) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region;(e) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof;(f) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region and the CCN3 polypeptide or the portion thereof and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof;(g) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region and the CCN3 polypeptide or the portion thereof;(h) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region and the CCN3 polypeptide or the portion thereof and domains of the second polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region and the CCN3 polypeptide or the portion thereof;(i) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof, the peptide linker, and the Fc region and the second polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof;WSGR Docket No. 65459-704.601(j) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the CCN3 polypeptide or the portion thereof and the Fc region and the second polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof;(k) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region, the peptide linker, and the CCN3 polypeptide or the portion thereof and the second polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof; or(l) domains of the first polypeptide are arranged, from the amino terminus to the carboxyl terminus, in the following order: the Fc region and the CCN3 polypeptide or the portion thereof and the second polypeptide comprises the Fc region and lacks the CCN3 polypeptide or the portion thereof.

17. The recombinant polypeptide or polypeptide complex of claim 16, wherein the Fc region comprises an immunoglobulin (Ig) G, IgM, IgA, IgD, or IgE.

18. The recombinant polypeptide or polypeptide complex of claim 17, wherein the Fc region comprises an IgGl, IgG2, IgG3, or IgG4.

19. The recombinant polypeptide or polypeptide complex of claim 17, wherein the Fc region comprises an IgGl.

20. The recombinant polypeptide or polypeptide complex of claim 17, wherein the Fc region comprises a human IgG.

21. The recombinant polypeptide or polypeptide complex of claim 18, wherein the Fc region comprises a first amino acid mutation comprising L234A, L235A, or P329G according to the EU numbering.

22. The recombinant polypeptide or polypeptide complex of claim 21, wherein the Fc region comprises the first amino acid mutation comprising: (a) L234A, L235A, and P329G; or (b) L234A, L235A, P329G, and the deletion of K447.

23. The recombinant polypeptide or polypeptide complex of claim 21, wherein:(a) the Fc region of the first polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G and the deletion of K447; and(b) the Fc region of the second polypeptide comprises the first amino acid mutation comprising L234A, L235A, and P329G and the deletion of K447.

24. The recombinant polypeptide or polypeptide complex of claim 21, wherein the Fc region further comprises a second amino acid mutation that results in knob-into-hole amino acid substitution.WSGR Docket No. 65459-704.60125. The recombinant polypeptide or polypeptide complex of claim 24, wherein the second amino acid mutation of the Fc region comprises:(a) a substitution of threonine (T) with tryptophan (W) at amino acid residue 366 according to the EU numbering (T366W);(b) a substitution of threonine (T) with serine (S) at amino acid residue 366 according to the EU numbering (T366S);(c) a substitution of leucine (L) with alanine (A) at amino acid residue 368 according to the EU numbering (L368A); or(d) a substitution of tyrosine (Y) with valine (V) at amino acid residue 407 according to the EU numbering (Y407V).

26. The recombinant polypeptide or polypeptide complex of claim 25, wherein:(a) the Fc region of the first polypeptide comprises:(i) the first amino acid mutation comprising L234A, L235A, and P329G; and (ii) the second amino acid mutation comprising T366W; and(b) the Fc region of the second polypeptide comprises:(i) the first amino acid mutation comprising L234A, L235A, and P329G; and (ii) the second amino acid mutation comprising T366S, L368A and Y407V.

27. The recombinant polypeptide or polypeptide complex of claim 25, wherein:(a) the Fc region of the first polypeptide comprises:(i) the first amino acid mutation comprising L234A, L235A, and P329G and the deletion of K447; and(ii) the second amino acid mutation comprising T366W; and(b) the Fc region of the second polypeptide comprises:(i) the first amino acid mutation comprising L234A, L235A, and P329G and the deletion of K447; and(ii) the second amino acid mutation comprising T366S, L368A and Y407V.

28. The recombinant polypeptide or polypeptide complex of claim 18, wherein the Fc region comprises a third amino acid mutation that stabilizes the hinge region of the Fc region, eliminates or inhibits an exchange of a fragment antigen binding (Fab) region, or both.

29. The recombinant polypeptide or polypeptide complex of claim 28, wherein the third amino acid mutation comprises a substitution of serine (S) with proline (P) at amino acid 228 according to the EU numbering (S228P).

30. The recombinant polypeptide or polypeptide complex of claim 18, wherein the Fc region comprises an IgG4 comprising the F234A, L235A, and S228P mutations, and the deletion ofWSGR Docket No. 65459-704.60131. The recombinant polypeptide or polypeptide complex of claim 18, wherein the Fc region comprises a fourth amino acid mutation that increases the binding of the Fc region to the neonatal Fc receptor (FcRn), increases the half-life of the recombinant polypeptide or polypeptide complex, or both.

32. The recombinant polypeptide or polypeptide complex of claim 31, wherein the fourth amino acid mutation comprises:(a) a substitution of methionine (M) with leucine (L) at amino acid 428 according to the EU numbering (M428L);(b) a substitution of asparagine (N) with serine (S) at amino acid 434 according to the EU numbering (N434S);(c) a substitution of methionine (M) with tyrosine (Y) at amino acid 252 according to the EU numbering (M252Y);(d) a substitution of serine (S) with threonine (T) at amino acid 254 according to the EU numbering (S254T); or(e) a substitution of threonine (T) with glutamic acid (E) at amino acid 254 according to the EU numbering (T256E).

33. The recombinant polypeptide or polypeptide complex of claim 32, wherein:(a) the Fc region of the first polypeptide comprises:(i) the first amino acid mutation comprising L234A, L235A, and P329G and the deletion of K447;(ii) the second amino acid mutation comprising T366W; and(iii) the fourth amino acid mutation comprising M428L and N434S; and(b) the Fc region of the second polypeptide comprises:(i) the first amino acid mutation comprising L234A, L235A, and P329G and the deletion of K447;(ii) the second amino acid mutation comprising T366S, L368A and Y407V; and (iii) the fourth amino acid mutation comprising M428L and N434S.

34. The recombinant polypeptide or polypeptide complex of claim 1, wherein the CCN3 polypeptide or the portion thereof comprises:(a) an insulin-like growth factor-binding protein (IGFBP) domain;(b) a von Willebrand factor type C (VWFC) domain;(c) a thrombospondin type- 1 (TSP1) domain; or(d) a C-terminal cystine knot-like (CTCK) domain.

35. The recombinant polypeptide or polypeptide complex of claim 34, wherein the CCN3 polypeptide or the portion thereof comprises one, two, three, or four of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain.WSGR Docket No. 65459-704.60136. The recombinant polypeptide or polypeptide complex of claim 34, wherein the CCN3 polypeptide or the portion thereof consists of one of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain.

37. The recombinant polypeptide or polypeptide complex of claim 34, wherein the CCN3 polypeptide or the portion thereof comprises one of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain and lacks the other three of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain.

38. The recombinant polypeptide or polypeptide complex of claim 34, wherein the CCN3 polypeptide or the portion thereof consists of two of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain.

39. The recombinant polypeptide or polypeptide complex of claim 34, wherein the CCN3 polypeptide or the portion thereof comprises two of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain and lacks the other two of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain.

40. The recombinant polypeptide or polypeptide complex of claim 34, wherein the CCN3 polypeptide or the portion thereof consists of three of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain.

41. The recombinant polypeptide or polypeptide complex of claim 34, wherein the CCN3 polypeptide or the portion thereof comprises three of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain and lacks the other one of the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain.

42. The recombinant polypeptide or polypeptide complex of claim 34, wherein the CCN3 polypeptide or the portion thereof comprises the IGFBP domain, the vWFC domain, the TSP1 domain and the CTCK domain.

43. The recombinant polypeptide or polypeptide complex of claim 34, wherein:(a) the IGFBP domain consists of an amino acid sequence with at least 90% sequence identity to any one SEQ ID NOs: 15-16;(b) the VWFC domain consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 17-20 and 300-301, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain;(c) the TSP1 domain consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 21-25, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP1 domain; or / andWSGR Docket No. 65459-704.601(d) the CTCK domain consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 26-29, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain.

44. The recombinant polypeptide or polypeptide complex of claim 34, wherein:(a) the IGFBP domain consists of the amino acid sequence of any one of SEQ ID NOs: 15- 16;(b) the VWFC domain consists of the amino acid sequence of any one of SEQ ID NOs: 17- 20 and 300-301, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain;(c) the TSP1 domain consists of the amino acid sequence of any one of SEQ ID NOs: 21-25, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP1 domain; or / and(d) the CTCK domain consists of the amino acid sequence of any one of SEQ ID NOs: 26- 29, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain.

45. The recombinant polypeptide or polypeptide complex of claim 34, wherein:(a) the IGFBP domain comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 15-16;(b) the VWFC domain comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 17-20 and 300-301, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain;(c) the TSP1 domain comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 21-25, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP1 domain; or / and (d) the CTCK domain comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 26-29, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain.

46. The recombinant polypeptide or polypeptide complex of claim 34, wherein:(a) the IGFBP domain comprises the amino acid sequence of any one of SEQ ID NOs: 15- 16;(b) the VWFC domain comprises the amino acid sequence of any one of SEQ ID NOs: 17- 20 and 300-301, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the VWFC domain;WSGR Docket No. 65459-704.601(c) the TSP1 domain comprises the amino acid sequence of any one of SEQ ID NOs: 21-25, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the TSP1 domain; or / and(d) the CTCK domain comprises the amino acid sequence of any one of SEQ ID NOs: 26- 29, or a portion thereof that comprises a truncation or deletion at the amino terminus or carboxyl terminus of the CTCK domain.

47. The recombinant polypeptide or polypeptide complex of claim 1, wherein the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 15-54 and 300-301.

48. The recombinant polypeptide or polypeptide complex of claim 1, wherein the CCN3 polypeptide or the portion thereof comprises the amino acid sequence of any one of SEQ ID NOs: 15-54 and 300-301.

49. The recombinant polypeptide or polypeptide complex of claim 1, wherein the CCN3 polypeptide or the portion thereof consists of an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 15-54 and 300-301.

50. The recombinant polypeptide or polypeptide complex of claim 1, wherein the CCN3 polypeptide or the portion thereof consists of the amino acid sequence of any one of SEQ ID NOs: 15-54 and 300-301.

51. The recombinant polypeptide or polypeptide complex of claim 1, wherein the CCN3 polypeptide or the portion thereof comprises an amino acid sequence with at least 90% sequence identity to one of SEQ ID NOs: 15-29 and 300-301 and lacks an amino acid sequence with at least 90% sequence identity to any other of SEQ ID NOs: 15-29 and 300-301.

52. The recombinant polypeptide or polypeptide complex of claim 1, wherein the CCN3 polypeptide or the portion thereof comprises two amino acid sequences that each has at least 90% sequence identity to one of two of SEQ ID NOs: 15-29 and 300-301 and lacks an amino acid sequence with at least 90% sequence identity to any other of SEQ ID NOs: 15-29 and 300-301.

53. The recombinant polypeptide or polypeptide complex of claim 1, wherein the CCN3 polypeptide or the portion thereof comprises three amino acid sequences that each has at least 90% sequence identity to one of three of SEQ ID NOs: 15-29 and 300-301 and lacks an amino acid sequence with at least 90% sequence identity to any other of SEQ ID NOs: 15-29 and 300-301.

54. The recombinant polypeptide or polypeptide complex of claim 1, wherein the CCN3 polypeptide or the portion thereof comprises four amino acid sequences that each has at least 90% sequence identity to one of SEQ ID NOs: 15-29 and 300-301.WSGR Docket No. 65459-704.60155. The recombinant polypeptide or polypeptide complex of claim 13, wherein the signal peptide comprises the amino acid sequence of SEQ ID NO: 9.

56. The recombinant polypeptide or polypeptide complex of claim 1, wherein the Fc region comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ IDs NO: 12-14, 296-299 and 314.

57. The recombinant polypeptide or polypeptide complex of claim 1, wherein the Fc region comprises the amino acid sequence of any one of SEQ IDs NO: 12-14, 296-299 and 314.

58. The recombinant polypeptide or polypeptide complex of claim 14, further comprising an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 76-78.

59. The recombinant polypeptide or polypeptide complex of claim 14, further comprising:(a) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 76 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 76;(b) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 77 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 77; or(c) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 78 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 78.

60. The recombinant polypeptide or polypeptide complex of claim 14, further comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 161 or 162.

61. The recombinant polypeptide or polypeptide complex of claim 14, further comprising:(a) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 161 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 14; or(b) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 162 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 14.

62. The recombinant polypeptide or polypeptide complex of claim 14, further comprising an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 307, 311 and 325.

63. The recombinant polypeptide or polypeptide complex of claim 14, further comprising:(a) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 307 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 307;(b) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 311 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 299; or (c) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 325 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 325.WSGR Docket No. 65459-704.60164. The recombinant polypeptide or polypeptide complex of claim 14, further comprising an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 309, 313 and 327.

65. The recombinant polypeptide or polypeptide complex of claim 14, further comprising:(a) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 309 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 309;(b) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 327 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 327; or (c) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 313 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 299.

66. The recombinant polypeptide or polypeptide complex of claim 14, further comprising an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 302 -305.

67. The recombinant polypeptide or polypeptide complex of claim 14, further comprising:(a) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 302 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 302;(b) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 303 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 303;(c) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 304 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 304; or (d) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 305 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 305.

68. The recombinant polypeptide or polypeptide complex of claim 14, further comprising an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 89, 326 and 328.

69. The recombinant polypeptide or polypeptide complex of claim 14, further comprising:(a) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 89 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 89;(b) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 326 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 326; or (c) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 328 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 14.

70. The recombinant polypeptide or polypeptide complex of claim 14, further comprising an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 157-160.

71. The recombinant polypeptide or polypeptide complex of claim 14, further comprising:(a) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 157 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 157;WSGR Docket No. 65459-704.601(b) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 158 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 158;(c) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 159 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 159; or (d) the first polypeptide comprising the amino acid sequence of SEQ ID NO: 160 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 160.

72. The recombinant polypeptide or polypeptide complex of claim 1, further comprising an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 55, 56, 58-60, 63- 64, 66-68, 70-71, 73-75, 79-84, 86-111, 124-127, 130-131, 135-160, 164, and 169-295.

73. A recombinant polypeptide or polypeptide complex comprising an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 55-295, 302-313 and 324-328.

74. A recombinant polypeptide or polypeptide complex comprising the amino acid sequence of any one of SEQ ID NOs: 55-295, 302-313 and 324-328.

75. A pharmaceutical composition comprising the recombinant polypeptide or polypeptide complex of claim 1 and a pharmaceutically acceptable carrier or excipient.

76. A nucleic acid sequence encoding the recombinant polypeptide or polypeptide complex of claim 1.

77. A vector comprising the nucleic acid sequence of claim 76.

78. The vector of claim 77, further comprising a mammalian vector, a yeast vector, a bacterial vector, or a viral vector.

79. A cell comprising the recombinant polypeptide or polypeptide complex of claim 1.

80. A cell comprising the nucleic acid sequence of claim 76.

81. A cell comprising the vector of claim 77.

82. A method for treating a bone disease or disorder comprising administering to a subject the recombinant polypeptide or polypeptide complex of claim 1, thereby treating the bone disease or disorder.

83. A method for treating a bone disease or disorder comprising administering to a subject the pharmaceutical composition of claim 75, thereby treating the bone disease or disorder.

84. A method for treating a bone disease or disorder comprising administering to a subject the nucleic acid sequence of claim 76, thereby treating the bone disease or disorder.WSGR Docket No. 65459-704.60185. A method for treating a bone disease or disorder comprising administering to a subject the vector of claim 77, thereby treating the bone disease or disorder.

86. A method for treating a bone disease or disorder comprising administering to a subject the cell of claim 79, thereby treating the bone disease or disorder.

87. The method of claim 82, wherein the bone disease or disorder comprises bone degeneration, osteoporosis, osteopenia, lactation, traumatic bone injury, pathologic bone injury, periprosthetic bone loss, osteolysis, menopause, obesity, anorexia nervosa, type 1 diabetes, chronic kidney disease, chronic liver disease, celiac disease, inflammatory bowel disease, lupus, rheumatoid arthritis, hyperthyroidism, hyperparathyroidism, cancer, multiple myeloma, a craniofacial disorder, premature ovarian failure, oral and maxillofacial surgery, plastic surgery, reconstructive surgery, ovariectomy, osteogenesis imperfecta, osteoarthritis, osteomalacia, metabolic bone disease, fibrous dysplasia, osteomyelitis, bone fracture, rickets, degenerative disc disease, osteonecrosis, renal osteodystrophy, Paget's disease, skeletal dysplasia, bone metastases, or otosclerosis.

88. The method of claim 82, wherein the subject is human.

89. The method of claim 82, wherein the administering the recombinant polypeptide or polypeptide complex to the subject results in an increase or decrease in the expression of a biomarker for bone turnover, bone formation, bone resorption, or a combination thereof.

90. The method of claim 89, wherein the biomarker comprises procollagen type I N-terminal propeptide (P INP), osteocalcin, C-terminal telopeptide of type I collagen (CTx), or a combination thereof.

91. The method of claim 89, wherein the administering the recombinant polypeptide or polypeptide complex to the subject results in the increase in the expression of P1NP, osteocalcin, or both.

92. The method of claim 89, wherein the administering the recombinant polypeptide or polypeptide complex to the subject results in the decrease in the expression of CTx.

93. A recombinant polypeptide or polypeptide complex comprising a cellular communication network factor 3 (CCN3) polypeptide or a portion thereof and a moiety that increases half-life.

94. The recombinant polypeptide or polypeptide complex of claim 93, wherein the moiety comprises an albumin, an albumin-binding molecule, a polypeptide or peptide comprising proline, alanine, and serine (PAS), a XTEN polypeptide, a polyethylene glycol (PEG), an elastin-like peptide (ELP), a lipid molecule, a sugar molecule, a glycan molecule, a sialic acid, a transferrin, a GlycoTAIL, or a FlexiTAIL.WSGR Docket No. 65459-704.60195. The recombinant polypeptide or polypeptide complex of claim 93, wherein the CCN3 polypeptide or portion thereof comprises an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 15-54 and 300-301.

96. The recombinant polypeptide or polypeptide complex of claim 94, wherein the albumin comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 322 or 323.

97. The recombinant polypeptide or polypeptide complex of claim 93, further comprising an amino acid sequence with at least 90% sequence identity to any one of SEQ ID NOs: 316- 321.

98. The recombinant polypeptide or polypeptide complex of claim 93, further comprising the amino acid sequence of any one of SEQ ID NOs: 316- 321.

99. A method for treating a bone disease or disorder comprising administering to a subject the recombinant polypeptide or polypeptide complex of claim 93, thereby treating the bone disease or disorder.

100. The method of claim 99, wherein the bone disease or disorder comprises bone degeneration, osteoporosis, osteopenia, lactation, traumatic bone injury, pathologic bone injury, periprosthetic bone loss, osteolysis, menopause, obesity, anorexia nervosa, type 1 diabetes, chronic kidney disease, chronic liver disease, celiac disease, inflammatory bowel disease, lupus, rheumatoid arthritis, hyperthyroidism, hyperparathyroidism, cancer, multiple myeloma, a craniofacial disorder, premature ovarian failure, oral and maxillofacial surgery, plastic surgery, reconstructive surgery, ovariectomy, osteogenesis imperfecta, osteoarthritis, osteomalacia, metabolic bone disease, fibrous dysplasia, osteomyelitis, bone fracture, rickets, degenerative disc disease, osteonecrosis, renal osteodystrophy, Paget's disease, skeletal dysplasia, bone metastases, or otosclerosis.

101. The method of claim 99, wherein the subject is human.

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