Wnt surrogate agents and methods for lacrimal gland regeneration

Abstract

Methods and compositions for regenerating lacrimal gland cells for treatment of dry eye disorders are provided. In particular, the present disclosure provides methods and compositions for modulating WNT signaling by administering engineered WNT signaling agonist in a subject to modulate regeneration of tear-producing acinar cells to treat aqueous-deficient type dry eye diseases.

Description

[0001] Agent’s File Ref. SRZN-029 / 01WO 328202-2197 WNT SURROGATE AGENTS AND METHODS FOR LACRIMAL GLAND REGENERATION CROSS REFERENCE TO RELATED APPLICATION This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 469,496, filed May 29, 2023, which is incorporated herein by reference in its entirety. SEQUENCE LISTING The Sequence Listing XML associated with this application is provided in XML file format and is hereby incorporated by reference into the specification. The name of the XML file containing the Sequence Listing XML is SRZN_029_01WO_ST26.xml. The XML file is 75,154 bytes, and created on May 24, 2024, and is being submitted electronically via USPTO Patent Center. FIELD OF THE INVENTION The disclosure provides methods and compositions for regenerating lacrimal gland cells for treatment of dry eye disorders are provided. In particular, the disclosure provides methods and compositions for modulating WNT signaling by administering engineered WNT signaling agonist in a subject to modulate regeneration of tear-producing acinar cells to treat aqueous-deficient type dry eye diseases. BACKGROUND OF THE INVENTION The lacrimal gland is an exocrine gland positioned under the outer lateral portion of the upper eyelid in most vertebrates. The lacrimal gland produces a tear film, which is secreted by lacrimal ducts, and is associated with ocular health (See Yao & Zhang at 939). The film keeps the cornea surface and inner eyelids moistened and protects the corneal and conjunctival epithelia from physical damage, as well as from immune reactions (See id.). Lacrimal gland disorders and damage can cause significant ocular disease pathologies, especially dry eye disease (Dartt, OCULAR DISEASE at 105). Dry eye disease is characterized by increased osmolarity of the tear film, and inflammation of the ocular surface (See id.). Inadequate production of tears can lead to irritation, pain, and potentially damage to the ocular surface. In addition, dry eye can lead to ocular irritation and discomfort, as well as severe ocular surface diseases (e.g., ocular infections, corneal ulcerations, and ocular surface Agent’s File Ref. SRZN-029 / 01WO 328202-2197 keratinization). These severe diseases can be induced by an atrophied or injured lacrimal gland (See Tetsuya Kawakita). There are two major classes of dry eye diseases: aqueous-deficient and evaporative. In turn, aqueous deficiency is subclassed into Sjögren’s syndrome (autoimmune) dry eye and non-Sjögren’s syndrome (non-autoimmune) dry eye. In cases of aqueous-deficient dry eye, the lacrimal gland is frequently inflamed, leading to atrophy and death of the tear fluid-producing acinar cells. Following loss of acinar cells, tear production problems worsen, leading to a reinforcing vicious inflammation-atrophy cycle. Accordingly, the lacrimal gland is a target in aqueous-deficient dry eye diseases. Presently, both aqueous-deficient and evaporative dry eye diseases are treated by topical administration on the ocular surface of artificial tears and / or anti-inflammatory agents. (See id. at 106.) Only a few treatments target the lacrimal gland itself, by systemic administration of anti-inflammatory agents, so-called secretagogue agents, immunosuppressive agents, and sex hormones (See id.). None of these treatment approaches deal directly with atrophy and / or damage to the lacrimal gland, including the tear-producing acinar cells. Consequently, there is a great unmet need for agents and methods for regeneration of acinar cells, restoring endogenous tear production, and breaking the cycle of inflammation and atrophy. BRIEF SUMMARY The present description provides an engineered multivalent bispecific WNT signaling modulator, wherein the WNT signaling modulator comprises a) at least one first antigen binding domain that binds to at least one of Lrp6 and / or Lrp5; and b) at least one- second antigen binding domains bind to at least one FZD receptor. In some embodiments, the engineered WNT signaling modulator is a tetravalent bispecific molecule. In particular embodiments, the engineered WNT signaling modulator of comprises: a) two light chains, each comprising a polypeptide sequence having at least 95% identity to SEQ ID NO:3; and b) two heavy chains, each comprising a polypeptide sequence having at least 95% identity to SEQ ID NO: 4, or 5, or 6. In some embodiments of the engineered WNT signaling modulator, each of the two light chains comprises a VHH domain comprising one or more or more of the following amino acid residue substitutions: N29Q and / or VHH3-H4 DDD substituted with DED. Agent’s File Ref. SRZN-029 / 01WO 328202-2197 In some embodiments of the engineered WNT signaling modulator, each heavy chain comprises amino acid residues: a CDRH1 of SEQ ID NO: 20, a CDRH2 of SEQ ID NO: 21, and a CDRH3 of SEQ ID NO: 22. In another embodiments, the engineered WNT signaling modulator comprises amino acid modifications comprising: L234A, L235A, and P329G amino acid substitutions, as numbered according to the EU index. In some embodiments, the heavy chain of SEQ ID NO: 5 comprises Fc region mutation with at least one of the three amino acid modifications selected from the group consisting of: I253A, H310A, and H435A, as numbered according to the EU index. In another embodiments, the heavy chain of SEQ ID NO: 6 comprises Fc region mutation with at least one of the three amino acid modifications selected from the group consisting of: I253A, H310A and H435Q, as numbered according to the EU index. In some embodiments, the engineered WNT signaling modulator is a trivalent bispecific molecule. In particular embodiments, the engineered WNT signaling modulator comprises: a) a first antigen binding domain that bind to one of Lrp6 and / or Lrp5; and b) two second antigen binding domains that each bind to one or more or two or more FZD receptors. In certain embodiments, the engineered Wnt signaling molecule binds to two or more FZD receptors. In some embodiments of the engineered WNT signaling modulator, the anti-LRP 5 / 6 is an N-terminal ‘Hole’ appended, comprising a polypeptides sequence having 95% identity to the combination of SEQ ID NOs: 8, 7, and 9. In another embodiments of the engineered WNT signaling modulator, the anti- LRP 5 / 6 is a C-terminal ‘Hole’ appended, comprising a polypeptides sequence having 95% identity to the combination of SEQ ID NOs: 13, 7, and 9. In particular embodiments of the engineered WNT signaling modulator, the anti- LRP 5 / 6 is an N-terminal ‘Knob’ appended, comprising a polypeptides sequence having 95% identity to the combination of SEQ ID NOs: 11, 7, and 12. In some embodiments of the engineered WNT signaling modulator, the anti-LRP 5 / 6 is a C-terminal ‘Knob’ appended, comprising a polypeptides sequence having 95% identity to the combination of SEQ ID NOs: 10, 7, and 12. In some embodiments, the description provides a nucleic acid comprising a sequence encoding the engineered multivalent bispecific WNT signaling modulator, or a polypeptide chain thereof, wherein the nucleic acid(s) is / are DNA, cDNA, RNA, mRNA, modified mRNA, or a DNA / RNA hybrid. In some embodiments, the description provides a vector comprising the nucleic acid wherein the vector is an expression vector comprising a Agent’s File Ref. SRZN-029 / 01WO 328202-2197 promoter operatively linked to the nucleic acid. In another embodiments, the description provides a pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or carrier, and: the engineered WNT signaling modulator, or the nucleic acid and / or the vector. In some embodiments, the disclosure provides a method of regenerating lacrimal gland cells in a subject, comprising administering a WNT signaling modulator to the subject, wherein the subject is a mammal animal or human patient. In another embodiments, the lacrimal gland cells are acinar cells, progenitor cells, ductal cells, myoepithelial cells, or immune cells. In particular embodiments the engineered WNT signaling modulator is a WNT agonist. In some embodiments, the engineered WNT signaling agonist is administered to i) one or more of the subject’s eyes, optionally intra-lacrimal gland or via ocular drops; ii) locally administering, optionally to the eye, ear, nose (optionally intranasally), skin (optionally trans dermally or epicutaneously), mucosa, skin, or vagina, or by inhalation; or iii) parenterally administering, optionally by injection (optionally intravenous, intramuscular, subcutaneous, intradermal, intrathecal, intra-arterial, intraarticular, intraosseous, or intraperitoneal administration) or by inhalation; or, buccally, or rectally. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 provides the amino acid sequences of a tetravalent bispecific WNT signaling agonist, 1SH1-03 (SEQ ID NOs: 1 and 2), which comprises two heavy chains and two light chains of an anti-FZD antibody, 1SH1, wherein an anti-LRP5 / 6 VHH3 domain is fused to the N-terminus of each anti-FZD antibody light chain via the linker sequence, GGSGS (SEQ ID NO:26), and its associated IgG-like antibody structure, wherein the two heavy chains are joined via disulfide bonds, and each light chain is joined to a heavy chain via a disulfide bond. The VL sequence of the anti-FZD antibody is: DVVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSK RASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQIPPTFGQGTKVEIK (SEQ ID NO: 27), and the CDRs are indicated in bold italic underlined. The VH sequence of the anti-FZD antibody is: EVQLVESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYYSGS TYYNPSLKSRVTISVDTSKNQFSLKLNSVTAADTAVYYCARHAGFYGLADYFDYWG QGTLVTVSS (SEQ ID NO: 28), and the CDRs are indicated in bold italic underlined. The VHH domain sequence is: DVQLVESGGGLVQPGGSLRLSCTSSANINSIETLGWYRQAPGKQRELIANMRGGGY Agent’s File Ref. SRZN-029 / 01WO 328202-2197 MKYAGSLKGRFTMSTESAKNTMYLQMNSLKPEDTAVYYCYVKLRDDDYVYRGQGT QVTVSS (SEQ ID NO: 29), and the CDRs are indicated in bold italic underlined. The linker sequence is: GGSGS (SEQ ID NO: 26). The FC sequence is: DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPI EKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK (SEQ ID NO: 30). FIG. 2 shows various amino acids substitution made to 1SH1-03 molecule to eliminate liable amino acids, including the substitution of N29 with Q (N29Q) in CDR1 of the VHH3 and the substitution of D102 with E (D102E; DDD to DED) in CDR3 of the VHH3, and the substitution of V124 with I (V124I) in the 1SH1 light chain, and the substitutions of V5 with Q (V5Q) and N85 with S (N85S) in the 1SH1 heavy chain. Light chain numbering is provided in the context of the fusion of the VHH3 and 1SH1 light chain for V124I, and in the context of only the 1SH1 light chain domain for N33G and N36T. Thus, V124I corresponds to V2I in the context of the 1SH1 light chain domain. FIG. 3 provides the amino acid sequences of the humanized tetravalent bispecific WNT signaling agonist, 1SH1-03 (SEQ ID NOs: 3 and 4), comprising the modifications noted above to the parental 1SH1-03 molecule. The construct has the same general structure as the parental construct. The VHH domain sequence is: EVQLVESGGGLVQPGGSLRLSCASSANIQSIETLGWYRQAPGKQRELIANMRGGGY MKYADSLKGRFTMSTDNSKNTMYLQMNSLRAEDTAVYYCYVKLRDEDYVYRGQG TQVTVSS (SEQ ID NO: 31). The VL sequence is: DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSGGYTYLDWYLQKPGQSPQLLIYLGSKR ASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQIPPTFGQGTKVEIKR (SEQ ID NO: 32). The VH sequence is: EVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYYSGS TYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHAGFYGLADYFDYWG QGTLVTVSS (SEQ ID NO: 33). The linker sequence is: GGGGS (SEQ ID NO: 34). The FC sequence is: DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAK GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 35). Agent’s File Ref. SRZN-029 / 01WO 328202-2197 FIG. 4 shows the amino acid sequences of humanized tetravalent bispecific WNT signaling agonist, 1SH1-03 (SEQ ID NOs: 3 and 5), with additional mutations in the Fc domain to decrease the serum half-life, including I253A, H310A, and H435A amino acid substitutions. The VHH domain sequence is: EVQLVESGGGLVQPGGSLRLSCASSANIQSIETLGWYRQAPGKQRELIANMRGGGY MKYADSLKGRFTMSTDNSKNTMYLQMNSLRAEDTAVYYCYVKLRDEDYVYRGQG TQVTVSS (SEQ ID NO: 31). The VL domain sequence is: DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSGGYTYLDWYLQKPGQSPQLLIYLGSKR ASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQIPPTFGQGTKVEIKR (SEQ ID NO: 32). The VH sequence is: EVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYYSGS TYYNPSLKSRVTISVDTSKNQFSLKLSSVADTAVYYCARHAGFYGLADYFDYWGQG TLVTVSS (SEQ ID NO: 36). The FC sequence is: APEAAGGPSVFLFPPKPKDTLMASRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLAQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYT LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPGK (SEQ ID NO: 37). The linker sequence is: GGGGS (SEQ ID NO: 34). FIG. 5 provides the amino acid sequences of humanized tetravalent bispecific WNT signaling agonist, 1SH1-03 (SEQ ID NOs.: 3 and 6), with additional mutations in the Fc domain to decrease the serum half-life, I253A, H310A, and H435Q. The VHH sequence is: EVQLVESGGGLVQPGGSLRLSCASSANIQSIETLGWYRQAPGKQRELIANMRGGGY MKYADSLKGRFTMSTDNSKNTMYLQMNSLRAEDTAVYYCYVKLRDEDYVYRGQG TQVTVSS (SEQ ID NO: 31). The VL sequence is: DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSGGYTYLDWYLQKPGQSPQLLIYLGSKR ASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQIPPTFGQGTKVEIKR (SEQ ID NO: 32). The VH sequence is: EVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYYSGS TYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHAGFYGLADYFDYWG QGTLVTVSS (SEQ ID NO: 38). The FC sequence is: DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMASRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLAQDWLNGKEYKCKVSNKALGAPIEKTISKAK GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPVLDSD Agent’s File Ref. SRZN-029 / 01WO 328202-2197 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNQYTQKSLSLSPGK (SEQ ID NO: 39). The linker sequence is: GGGGS (SEQ ID NO: 34). FIGs. 6A-6D illustrate constructs of four trivalent bispecific WNT signaling agonist variants of hp1SH1-03, each comprising two heavy chains and two light chains of an anti-FZD antibody, 1SH1, and an anti-LRP5 / 6 VHH3 domain appended to the N-terminus of either the knob – heavy chain (FIG. 6C) or hole-heavy chain (FIG. 6A) or to the C-terminus of either the knob – heavy chain (FIG. 6D) or hole-heavy chain (FIG. 6B). FIG. 7 depicts the response of the WNT reporter cell line HEK293-GFP-RA (TCF-GFP reporter assay) to positive control (R2M3-26), parental 1SH1-03, and humanized polished (hp) 1SH1-03 with and without FcRn mutations AAA and AAQ in the presence of 20 nM RSPO. FIG. 8 shows response of the WNT reporter cell line HEK293-GFP-RA (TCF- GFP reporter assay) to positive control (R2M3-26), parental 1SH1-03, humanized polished (hp) 1SH1-03, and trivalent bispecific N-term and C-term hole appended molecules. FIG. 9 shows WNT target gene, Axin2, expression 24h after treatment of primary mouse lacrimal gland cells ex vivo (explant assay). Treatments included negative control (R2M3-null), parental 1SH1-03, and the different versions of humanized polished (hp) 1SH1- 03 at the concentrations indicated on the X-axis in nM. FIG. 10 shows WNT target gene Axin2 expression 24h after local injection of the indicated WNT signaling agonist constructs in the IL-1a model. All treatment groups were treated with a single dose of 10 ug injection. Data was normalized to the anti-GFP control group. FIG. 11 depicts WNT target gene Axin2 expression 24h after local treatment in the duct ligation damage model. All treatment groups were treated with a single dose of 10 ug injection. Data was normalized to the R2M3-null negative control group. FIG. 12 shows tear volume measurements using phenol red thread in the IL-1a model. Treatments included three different doses of hp1SH1-03 (10 ug, 2 ug and 0.4 ug) as compared to parental 1SH1-03 and the negative control, R2M3-null. At day 3, the lines from top to bottom correspond to: hp1SH1-032 ug, 1SH1-0310 ug, hp1SH1-0310 ug, R2M3null 10 ug, and hp1SH1-030.4 ug. FIG. 13 shows tear volume measurements using phenol red thread in the IL-1a model. Data represents an average of twelve animals. Treatments included two different doses of hp1SH1-03 and hp1SH1-03-AAA (10 ug and 2 ug) as compared to parental 1SH1- 03 and the negative control, R2M3-null. At day 3, the lines from top to bottom correspond to: Agent’s File Ref. SRZN-029 / 01WO 328202-2197 hp1SH1-03_AAA 2 ug, hp1SH1-03_AAA 10ug, 1SH1-0310 ug, hp1SH1-032 ug, hp1SH1- 0310 ug, and R2M3null 10 ug. FIG. 14 describes tear volume measurements using phenol red thread in the mouse duct ligation model of dry eye. Treatments included two different doses of hp1SH1-03 and hp1SH1-03-AAA (10 and 2 ug) and compared to parental 1SH1-03 and negative control R2M3-null. The lines from top to bottom at day 14 correspond to: hp1SH1-03_AAA 10 ug X2, hp1SH1-03_AAA 2 ug, hp1SH1-032 ug, 1SH1-0310 ug, hp1SH1-03_AAA 10 ug, hp1SH1-0310 ug, R2M3null 10 ug X2, and R2M3null 10 ug. FIG. 15 shows proliferation of cornea endothelial cells from human skirt material after 14 days of treatment. FIGs. 16A-16D illustrate WNT target gene expression (AXIN2 (FIG. 16A), LEF1 (FIG. 16B), RNF43 (FIG. 16C)) and proliferation marker (CCND1 (FIG. 16D)) after 24h treatment in human endothelial cell . FIG. 17 shows the proliferation of cornea endothelial cells from human skirt material after 14 days of treatment with humanized polished (hp) 1SH1-03 (hp1SH1- 03_AAA) alone or in combination with engineered FGF TTHX1114. FIG. 18 describes cornea WNT target gene Axin2 expression 24h after treatment of non-injured mouse eyes through intracameral injection with the indicated amounts of hp1SH1-03_AAA. FIG. 19 shows cornea WNT target gene Axin2 expression 24h after treatment of cryoinjured mouse eyes through intracameral injection with the indicated amounts of hp1SH1-03_AAA. FIG. 20 illustrates the measurement of central corneal thickness (CCT) following corneal freeze (cryoinjury) and treatment over the course of 8 days. FIG. 21 shows the measurement of central corneal thickness (CCT) following corneal freeze (cryoinjury) and treatment over the course of 7 days. FIG. 22 describes pharmacokinetic measurement of serum drug concentration following IV injection (3mpk) of hp1SH1-03 with or without FcRn mutation AAA. Agent’s File Ref. SRZN-029 / 01WO 328202-2197 DETAILED DESCRIPTION I. Definitions As used herein, including the appended claims, the singular forms of words such as “a,” “an,” and “the,” include their corresponding plural references unless the context clearly dictates otherwise. All references cited herein are incorporated by reference to the same extent as if each individual publication, patent application, or patent, was specifically and individually indicated to be incorporated by reference. The terms “Engineered WNT signaling modulator”, “Engineered WNT signaling agonist”, “WNT surrogate molecule”, and “WNT mimetic” are used interchangeably. “Activity” of a molecule may describe or refer to the binding of the molecule to a ligand or to a receptor, to catalytic activity, to the ability to stimulate gene expression, to antigenic activity, to the modulation of activities of other molecules, and the like. “Activity” of a molecule may also refer to activity in modulating or maintaining cell-to-cell interactions, e.g., adhesion, or activity in maintaining a structure of a cell, e.g., cell membranes or cytoskeleton. “Activity” may also mean specific activity, e.g., [catalytic activity] / [mg protein], or [immunological activity] / [mg protein], or the like. The terms “administering” or “introducing” or “providing”, as used herein, refer to delivery of a composition to a cell, to cells, tissues and / or organs of a subject, or to a subject. Such administering or introducing may take place in vivo, in vitro or ex vivo. As used herein, the term “antibody” means an isolated or recombinant binding agent that comprises the necessary variable region sequences to specifically bind an antigenic epitope. Therefore, an antibody is any form of antibody or fragment thereof that exhibits the desired biological activity, e.g., binding the specific target antigen. Thus, it is used in the broadest sense and specifically covers monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, nanobodies, diabodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments including, but not limited to, scFv, Fab, Fab2, Fab’2, diabody, VHH, single domain antibody, so long as they exhibit the desired biological activity. “Antibody fragments” comprise a portion of an intact antibody, for example, the antigen-binding or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies (e.g., Zapata et al., Agent’s File Ref. SRZN-029 / 01WO 328202-2197 Protein Eng. 8(10): 1057-1062 (1995)); single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single antigen-binding site, and a residual “Fc” fragment, a designation reflecting the ability to crystallize readily. Pepsin treatment yields an F(ab')2 fragment that has two antigen combining sites and is still capable of cross-linking antigen. The term “antigen” refers to a molecule or a portion of a molecule capable of being bound by a selective binding agent, such as an antibody, and 30 additionally capable of being used in an animal to produce antibodies capable of binding to an epitope of that antigen. In certain embodiments, a binding agent (e.g., a WNT surrogate molecule or binding region thereof, or a WNT antagonist) is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and / or macromolecules. The term “antigen-binding fragment” as used herein refers to a polypeptide fragment that contains at least one complementarity-determining region (CDR) of an immunoglobulin heavy and / or light chain, or of a VHH / sdAb (single domain antibody) or Nanobody® (Nab), that binds to the antigen of interest, in particular to one or more Fzd receptors, or to LRP5 and / or LRP6. In this regard, an antigen-binding fragment of the herein described antibodies may comprise 1, 2, 3, 4, 5, or all 6 CDRs of a VH and VL from antibodies that bind one or more Fzd receptors or LRP5 and / or LRP6. As used herein, the terms “biological activity” and “biologically active” refer to the activity attributed to a particular biological element in a cell. For example, the “biological activity” of a WNT agonist, or fragment or variant thereof refers to the ability to mimic or enhance WNT signals. As another example, the biological activity of a polypeptide or functional fragment or variant thereof refers to the ability of the polypeptide or functional fragment or variant thereof to carry out its native functions of, e.g., binding, enzymatic activity, etc. In some embodiments, a functional fragment or variant retains at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% of an activity of the corresponding native protein or nucleic acid. As a third example, the biological activity of a gene regulatory element, e.g., promoter, enhancer, Kozak sequence, and the like, refers to the ability of the regulatory element or functional fragment or variant thereof to regulate, i.e., promote, enhance, or activate the translation of, respectively, the expression of the gene to which it is operably linked. Agent’s File Ref. SRZN-029 / 01WO 328202-2197 The term “bifunctional antibody,” as used herein, refers to an antibody that comprises a first arm having a specificity for one antigenic site and a second arm having a specificity for a different antigenic site, i.e., the bifunctional antibodies have a dual specificity. “Bispecific antibody” refers to a full-length antibody that is generated by but not limited to quadroma technology (see Milstein et al., Nature, 305(5934): 537-540 (1983)), by chemical conjugation of two different monoclonal antibodies (see Staerz et al., Nature, 314(6012): 628-631 (1985)), or by knob-into-hole or similar approaches, which introduce mutations in the Fc region (see Holliger et al., Proc. Natl. Acad. Sci. USA, 90(14): 6444–6448 (1993)), resulting in multiple different immunoglobulin species of which only one is the functional bispecific antibody. A bispecific antibody binds one antigen (or epitope) on one of its two binding arms (one pair of HC / LC or VHH), and binds a different antigen (or epitope) on its second arm (a different pair of HC / LC or VHH). By this definition, a bispecific antibody has two distinct antigen-binding arms (in both specificity and CDR sequences) and is monovalent for each antigen to which it binds. By “comprising,” it is meant that the recited elements are required in, for example, the composition, method, kit, etc., but other elements may be included to form the, for example, composition, method, kit etc. within the scope of the claim. For example, an expression cassette “comprising” a gene encoding a therapeutic polypeptide operably linked to a promoter is an expression cassette that may include other elements in addition to the gene and promoter, e.g., poly-adenylation sequence, enhancer elements, other genes, linker domains, etc. By “consisting essentially of,” it is meant a limitation of the scope of the, for example, composition, method, kit, etc., described to the specified materials or steps that do not materially affect the basic and novel characteristic(s) of the, for example, composition, method, kit, etc. For example, an expression cassette “consisting essentially of” a gene encoding a therapeutic polypeptide operably linked to a promoter and a polyadenylation sequence may include additional sequences, e.g., linker sequences, so long as they do not materially affect the transcription or translation of the gene. As another example, a variant, or mutant, polypeptide fragment “consisting essentially of” a recited sequence has the amino acid sequence of the recited sequence plus or minus about 10 amino acid residues at the boundaries of the sequence based upon the full length naïve polypeptide from which it was derived, e.g., 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 residue less than the recited bounding amino acid Agent’s File Ref. SRZN-029 / 01WO 328202-2197 residue, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 residues more than the recited bounding amino acid residue. By “consisting of,” it is meant the exclusion from the composition, method, or kit of any element, step, or ingredient not specified in the claim. For example, a polypeptide or polypeptide domain “consisting of” a recited sequence contains only the recited sequence. A “control element” or “control sequence” is a nucleotide sequence involved in an interaction of molecules that contributes to the functional regulation of a polynucleotide, including replication, duplication, transcription, splicing, translation, or degradation of the polynucleotide. The regulation may affect the frequency, speed, or specificity of the process, and may be enhancing or inhibitory in nature. Control elements known in the art include, for example, transcriptional regulatory sequences such as promoters and enhancers. A promoter is a DNA region capable under certain conditions of binding RNA polymerase and initiating transcription of a coding region usually located downstream (in the 3' direction) from the promoter. An “expression vector” is a vector, e.g., plasmid, minicircle, viral vector, liposome, and the like as discussed herein or as known in the art, comprising a region which encodes a gene product of interest, and is used for effecting the expression of the gene product in an intended target cell. An expression vector also comprises control elements, e.g., promoters, enhancers, untranslated regions (UTRs), miRNA targeting sequences, etc., operatively linked to the encoding region to facilitate expression of the gene product in the target. The combination of control elements and a gene or genes to which they are operably linked for expression is sometimes referred to as an “expression cassette,” a large number of which are known and available in the art or can be readily constructed from components that are available in the art. As used herein, the term “FR set” refers to the four flanking amino acid sequences which frame the CDRs of a CDR set of a heavy or light chain V region. Some FR residues may contact bound antigen; however, FRs are primarily responsible for folding the V region into the antigen-binding site, particularly the FR residues directly adjacent to the CDRs. Within FRs, certain amino residues and certain structural features are very highly conserved. In this regard, all V region sequences contain an internal disulfide loop of around 90 amino acid residues. When the V regions fold into a binding-site, the CDRs are displayed as projecting loop motifs which form an antigen-binding surface. It is generally recognized that there are conserved structural regions of FRs which influence the folded shape of the CDR loops into certain “canonical” structures—regardless of the precise CDR amino acid Agent’s File Ref. SRZN-029 / 01WO 328202-2197 sequence. Further, certain FR residues are known to participate in non-covalent interdomain contacts which stabilize the interaction of the antibody heavy and light chains. As used herein, the term “HC” refers to the heavy chain and the term “LC” refers to the light chain. The terms “individual,” “host,” “subject,” and “patient” are used interchangeably herein, and refer to a mammal, including, but not limited to, human and non-human primates, including simians and humans; mammalian sport animals (e.g., horses); mammalian farm animals (e.g., sheep, goats, etc.); mammalian pets (dogs, cats, etc.); and rodents (e.g., mice, rats, etc.). “Humanized” antibodies or fragments thereof refers to antibodies or fragments thereof from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. The process of "humanization" is usually applied to monoclonal antibodies developed for administration to humans. A “monoclonal antibody” refers to a homogeneous antibody population wherein the monoclonal antibody is comprised of amino acids (naturally occurring and non-naturally occurring) that are involved in the selective binding of an epitope. Monoclonal antibodies are highly specific, being directed against a single epitope. The term “monoclonal antibody” encompasses not only intact monoclonal antibodies and full-length monoclonal antibodies, but also fragments thereof (such as Fab, Fab', F(ab')2, Fv), single chain (scFv), single domain antibodies (sdAbs, also known as Nanobodies), variants thereof, fusion proteins comprising an antigen-binding fragment of a monoclonal antibody, humanized monoclonal antibodies, chimeric monoclonal antibodies, and any other modified configuration of the immunoglobulin molecule that comprises an antigen- binding fragment (epitope recognition site) of the required specificity and the ability to bind to an epitope, including WNT surrogate molecules disclosed herein. It is not intended to be limited as regards the source of the antibody or the manner in which it is made (e.g., by hybridoma, phage selection, recombinant expression, transgenic animals, etc.). The term includes whole immunoglobulins as well as the fragments etc. described above under the definition of “antibody”. The term “native” or “wild-type” as used herein refers to a nucleotide sequence, e.g., gene, or gene product, e.g., RNA or protein, that is present in a wild-type cell, tissue, organ, or organism. The term “variant” as used herein refers to a mutant of a reference polynucleotide or polypeptide sequence, for example, a native polynucleotide or polypeptide sequence, i.e., having less than 100% sequence identity with the reference polynucleotide or Agent’s File Ref. SRZN-029 / 01WO 328202-2197 polypeptide sequence. Put another way, a variant comprises at least one amino acid difference (e.g., amino acid substitution, amino acid insertion, amino acid deletion) relative to a reference polynucleotide sequence, e.g., a native polynucleotide or polypeptide sequence. For example, a variant may be a polynucleotide having a sequence identity of 50% or more, 60% or more, or 70% or more with a full-length native polynucleotide sequence, e.g., an identity of 75% or 80% or more, such as 85%, 90%, or 95% or more, for example, 98% or 99% identity with the full-length native polynucleotide sequence. As another example, a variant may be a polypeptide having a sequence identity of 70% or more with a full-length native polypeptide sequence, e.g., an identity of 75% or 80% or more, such as 85%, 90%, or 95% or more, for example, 98% or 99% identity with the full-length native polypeptide sequence. Variants may also include variant fragments of a reference, e.g., native, sequence sharing a sequence identity of 70% or more with a fragment of the reference, e.g., native, sequence, e.g., an identity of 75% or 80% or more, such as 85%, 90%, or 95% or more, for example, 98% or 99% identity with the native sequence. “Operatively linked” or “operably linked” refers to a juxtaposition of genetic elements, wherein the elements are in a relationship permitting them to operate in the expected manner. For instance, a promoter is operatively linked to a coding region if the promoter helps initiate transcription of the coding sequence. There may be intervening residues between the promoter and coding region so long as this functional relationship is maintained. As used herein, the terms “polypeptide,” “peptide,” and “protein” refer to polymers of amino acids of any length. The terms also encompass an amino acid polymer that has been modified; for example, to include disulfide bond formation, glycosylation, lipidation, phosphorylation, or conjugation with a labeling component. The term “polynucleotide” refers to a polymeric form of nucleotides of any length, including deoxyribonucleotides or ribonucleotides, or analogs thereof. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs, and may be interrupted by non-nucleotide components. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The term polynucleotide, as used herein, refers interchangeably to double-stranded and single-stranded molecules. Unless otherwise specified or required, any embodiment of the invention described herein that is a polynucleotide encompasses both the double-stranded form and each of two complementary single-stranded forms known or predicted to make up the double-stranded form. Agent’s File Ref. SRZN-029 / 01WO 328202-2197 A polynucleotide or polypeptide has a certain percent “sequence identity” to another polynucleotide or polypeptide, meaning that, when aligned, that percentage of bases or amino acids are the same when comparing the two sequences. The terms “identical” or “identity” when used in the context of two or more nucleic acids or polypeptide sequences, refer to the number or percentage of residues that are the same in a sequence of interest and a reference sequence. The percentage can be calculated by optimally aligning the sequence of interest to the reference sequence; comparing the two sequences over the entire length of the reference sequence; determining the number of positions at which the identical amino acid residue or nucleic acid base occurs in both sequences to yield the number of matched positions; dividing the number of matched positions by the total number of positions in the reference sequence adjusted by adding the number of gap positions introduced into the reference sequence in generating the alignment; and multiplying the result by 100 to yield the percentage of sequence identity. When comparing DNA and RNA, thymine (T) and uracil (U) can be considered equivalent Sequence “identity” may be determined by using the stand- alone executable BLAST engine program for blasting two sequences (bl2seq), which can be retrieved from the National Center for Biotechnology Information (NCBI) ftp site or over the worldwide web at ncbi.nlm.nih.gov / BLAST / , using the default parameters (Tatusova and Madden, FEMS Microbiol Lett., 1999, 174, 247-250; which is incorporated herein by reference in its entirety). A “promoter” as used herein encompasses a DNA sequence that directs the binding of RNA polymerase and thereby promotes RNA synthesis, i.e., a minimal sequence sufficient to direct transcription. Promoters and corresponding protein or polypeptide expression may be ubiquitous, meaning strongly active in a wide range of cells, tissues and species or cell-type specific, tissue-specific, or species specific. Promoters may be “constitutive,” meaning continually active, or “inducible,” meaning the promoter can be activated or deactivated by the presence or absence of biotic or abiotic factors. Also included in the nucleic acid constructs or vectors of the invention are enhancer sequences that may or may not be contiguous with the promoter sequence. Enhancer sequences influence promoter- dependent gene expression and may be located in the 5' or 3' regions of the native gene. “Recombinant,” as applied to a polynucleotide means that the polynucleotide is the product of various combinations of cloning, restriction or ligation steps, and other procedures that result in a construct that is distinct from a polynucleotide found in nature. As used herein “Sjögren’s syndrome” or “Sjogren’s syndrome” is a chronic autoimmune disease affecting the lacrimal and salivary glands, defined according to Agent’s File Ref. SRZN-029 / 01WO 328202-2197 customary international diagnostic criteria such as described in Vitali et al (2002) Ann.Rheum. Dis. 61:554. Sjögren’s syndrome is one of two major subclasses of aqueous- deficient dry eye diseases, distinguished from non-Sjögren’s syndrome type. As used herein, “SWAP™” (Surrozen WNT-signal activating proteins) refers to WNT mimetic compounds comprising engineered bi-specific full-length immunoglobulin-G (IgG) antibodies that, like WNT proteins, directly activate the canonical WNT-signaling pathway in a target tissue, e.g., lacrimal gland tissue. As used herein, “SWEETS™” (Surrozen WNT-signal enhancer engineered for tissue specificity) refers to antibody-based R-spondin mimetic compounds, e.g., as described in US20200048324. The terms “treatment”, “treating” and the like are used herein to generally mean obtaining a desired pharmacologic and / or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof, e.g., reducing the likelihood that the disease or symptom thereof occurs in the subject, and / or may be therapeutic in terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease. “Treatment” as used herein covers any treatment of a disease in a mammal and includes: (a) inhibiting the disease, i.e., arresting or slowing its development; or (b) relieving the disease, i.e., causing regression or reduction of the disease or reducing the severity of the disease. The therapeutic agent may be administered before, during or after the onset of disease or injury. The treatment of ongoing disease, where the treatment stabilizes or reduces the undesirable clinical symptoms of the patient, is of particular interest. Such treatment is desirably performed prior to complete loss of function in the affected tissues. The subject therapy will desirably be administered during the symptomatic stage of the disease, and in some cases after the symptomatic stage of the disease. The practice of the present invention will employ, unless otherwise indicated, conventional techniques of cell biology, molecular biology techniques), microbiology, biochemistry and immunology, which are within the scope of those of skill in the art. Such techniques are explained fully in the literature, such as, “Molecular Cloning: A Laboratory Manual”, second edition (Sambrook et al., 1989); “Oligonucleotide Synthesis” (M. J. Gait, ed., 1984); “Animal Cell Culture” (R. I. Freshney, ed., 1987); “Methods in Enzymology” (Academic Press, Inc.); “Handbook of Experimental Immunology” (D. M. Weir & C. C. Blackwell, eds.); “Gene Transfer Vectors for Mammalian Cells” (J. M. Miller & M. P. Calos, eds., 1987); “Current Protocols in Molecular Biology” (F. M. Ausubel et al., eds., 1987); “PCR: The Polymerase Chain Reaction”, (Mullis et al., eds., 1994); and “Current Protocols in Agent’s File Ref. SRZN-029 / 01WO 328202-2197 Immunology” (J. E. Coligan et al., eds., 1991), each of which is expressly incorporated by reference herein. Several aspects of the invention are described below with reference to example applications for illustration. It should be understood that numerous specific details, relationships, and methods are set forth to provide a full understanding of the invention. One having ordinary skill in the relevant art, however, will readily recognize that the invention can be practiced without one or more of the specific details or with other methods. The present invention is not limited by the illustrated ordering of acts or events, as some acts may occur in different orders and / or concurrently with other acts or events. Furthermore, not all illustrated acts or events are required to implement a methodology in accordance with the present invention. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, to the extent that the terms “including”, “includes”, “having”, “has”, “with”, or variants thereof are used in either the detailed description and / or the claims, such terms are intended to be inclusive in a manner similar to the term “comprising”. The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value should be assumed. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. It is understood that the present disclosure supersedes any disclosure of an incorporated publication to the extent there is a contradiction. Agent’s File Ref. SRZN-029 / 01WO 328202-2197 It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely”, “only” and the like in connection with the recitation of claim elements, or the use of a “negative” limitation. Unless otherwise indicated, all terms used herein have the same meaning as they would to one skilled in the art and the practice of the present invention will employ, conventional techniques of microbiology and recombinant DNA technology, which are within the knowledge of those of skill of the art. II. General The present invention provides methods of modulating WNT signals and WNT signaling pathways to treat lacrimal gland disorders due to, including but not limited to, Sjögren’s syndrome disorder, chronic graft versus host disease (cGHVD), rheumatoid arthritis (RA), Stephen’s Johnson syndrome, Ocular Rosacea, chemotherapy, radiation oncology treatments, diabetes, roasacea, or lupus, etc. WNT (“Wingless-related integration site” or “Wingless and Int-1” or “Wingless- Int”) ligands and their signals play key roles in the control of development, homeostasis and regeneration of many essential organs and tissues, including bone, liver, skin, stomach, intestine, kidney, central nervous system, mammary gland, taste bud, ovary, cochlea, lung, and many other tissues (reviewed, e.g., by Clevers, Loh, and Nusse, 2014; 346:1248012). Modulation of WNT signaling pathways has potential for treatment of degenerative diseases and tissue injuries. One of the challenges for modulating WNT signaling as a therapeutic is the existence of multiple WNT ligands and WNT receptors, Frizzled 1-10 (Fzd1-10), with many tissues expressing multiple and overlapping Fzds. Canonical WNT signals also involve Low- density lipoprotein (LDL) receptor-related protein 5 (LRP5) or Low-density lipoprotein (LDL) receptor-related protein 6 (LRP6) as co-receptors, which are broadly expressed in various tissues, in addition to Fzds. R-spondins 1–4 are a family of ligands that amplify WNT signals. Each of the R-spondins work through a receptor complex that contains Zinc and Ring Finger 3 (ZNRF3) or Ring Finger Protein 43 (RNF43) on one end and a Leucine-rich repeat- containing G-protein coupled receptor 4-6 (LGR4-6) on the other (reviewed, e.g., by Knight & Hankenson 2014, Matrix Biol.; 37: 157-161). R-spondins might also work through additional mechanisms of action. ZNRF3 and RNF43 are two membrane-bound E3 ligases specifically targeting WNT receptors (Fzd1-10 and LRP5 or LRP6) for degradation. Binding Agent’s File Ref. SRZN-029 / 01WO 328202-2197 of an R-spondin to ZNRF3 / RNF43 and LGR4-6 causes clearance or sequestration of the ternary complex, which removes E3 ligases from WNT receptors and stabilizes WNT receptors, resulting in enhanced WNT signals. Each R-spondin contains two Furin domains (1 and 2), with Furin domain 1 binding to ZNRF3 / RNF43, and Furin domain 2 binding to LGR4-6. Fragments of R-spondins containing Furin domains 1 and 2 are sufficient for amplifying WNT signaling. While R-spondin effects depend on WNT signals, since both LGR4-6 and ZNRF3 / RNF43 are widely expressed in various tissues, the effects of R- spondins are not tissue-specific.  Activating WNT signaling by a WNT agonist may be used for the treatment of a variety of lacrimal gland diseases and disorders, including dry eye diseases. Similarly, amplifying WNT signaling by RSPO or an RSPO mimetic may be used for the treatment of a variety of lacrimal gland diseases and disorders, including various dry eye and salivary gland diseases. A WNT agonist molecule may also be used for the treatment of dry eye and salivary gland disorders. In particular, active WNT signaling can provide a major stem cell maintenance signal and plays a key role in regulating regeneration of the acinar cells, e.g., in salivary glands. III. Engineered WNT Agonists The present disclosure provides engineered WNT agonists and contemplates the use of engineered WNT agonists to stimulate, agonize, or promote WNT signaling, e.g., through the canonical WNT / β-catenin signaling pathway. Such engineered WNT agonists may also be referred to as WNT / β -catenin signaling agonists or WNT mimetics. The disclosure provides engineered WNT mimetics with drug-like properties, particularly in the form of recombinant, multivalent bi-specific antibodies that bring together Fzd and Lrp to stimulate signaling, mimicking endogenous WNT ligands. The WNT mimetics of the disclosure may freely diffuse, access damaged tissues and guide tissue repair where WNT signals are needed. The disclosure also provides WNT mimetics that are capable of repairing damaged lacrimal or salivary gland tissue without being combined with RSPO. In some embodiments, the WNT / ^-catenin signaling antagonist or agonist can include binding agents or epitope binding domains that bind one or more Fzd receptors and inhibit or enhance WNT signaling. In certain embodiments, the agent or antibody specifically binds to the cysteine-rich domain (CRD) within the human frizzled receptor(s) to which it binds. Agent’s File Ref. SRZN-029 / 01WO 328202-2197 Additionally, antagonistic binding agents containing epitope binding domains against LRP can also be used. In some embodiments, the WNT / ^-catenin antagonist possesses binding agents or epitope binding domains that bind E3 ligases ZNRF3 / RNF43 and one or more FZD receptors or one or more LRP co-receptors to promote the degradation of FZD or LRP receptors, and this molecule can also contain a binding domain that binds a cell type specific epitope for targeting. The E3 ligase agonist antibodies or fragments thereof can be single molecules or combined with other WNT antagonists, e.g., Fzd receptor antagonists, LRP receptor antagonists, etc. As is well known in the art, an antibody is an immunoglobulin molecule capable of specific binding to a target such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least on epitope binding domain, located on the variable region of the immunoglobulin molecule. As used herein, the term encompasses not only intact polyclonal or monoclonal antibodies, but also fragments thereof containing epitope binding domains (e.g., dAb, Fab, Fab’, (F(ab’)2, Fv, single chain (scFv), VHH (i.e., Nanobodies®) or single domain antibodies (sdAb), DVD-Igs (also known as Fv-Igs), synthetic variants thereof, naturally occurring variants, fusion proteins comprising and epitope binding domain, humanized antibodies, chimeric antibodies, and any other modified configuration of the immunoglobulin molecule that comprises an antigen-binding site or fragment (epitope recognition site) of the required specificity. “Diabodies,” multivalent or multispecific fragments constructed by gene fusion (WO94 / 13804; P. Holliger et al., Proc. Natl. Acad. Sci. USA 906444-6448, 1993) are also a particular form of antibody contemplated herein. Minibodies comprising a scFv joined to a CH3 domain are also included herein (S. Hu et al., Cancer Res., 56, 3055-3061, 1996). See e.g., Ward, E. S. et al., Nature 341, 544-546 (1989); Bird et al., Science, 242, 423-426, 1988; Huston et al., Proc. Natl. Acad. Sci. USA, 85, 5879- 5883, 1988); PCT / US92 / 09965; WO94 / 13804; P. Holliger et al., Proc. Natl. Acad. Sci. USA 906444–6448, 1993; Y. Reiter et al., Nature Biotech, 14, 1239-1245, 1996; S. Hu et al., Cancer Res., 56, 3055-3061, 1996; C. Bever et al., Anal Bioanal Chem.2016 Sept; 408(22); 5985–6002. The proteolytic enzyme papain preferentially cleaves IgG molecules to yield several fragments, two of which (the F(ab) fragments) each comprise a covalent heterodimer that includes an intact antigen-binding site. The enzyme pepsin is able to cleave IgG molecules to provide several fragments, including the F(ab')2 fragment which comprises both antigen-binding sites. An Fv fragment for use according to certain embodiments of the Agent’s File Ref. SRZN-029 / 01WO 328202-2197 present disclosure can be produced by preferential proteolytic cleavage of an IgM, and on rare occasions of an IgG or IgA immunoglobulin molecule. Fv fragments are, however, more commonly derived using recombinant techniques known in the art. The Fv fragment includes a non-covalent VH::VL heterodimer including an antigen-binding site which retains much of the antigen recognition and binding capabilities of the native antibody molecule. Inbar et al. (1972) Proc. Nat. Acad. Sci. USA 69:2659-2662; Hochman et al. (1976) Biochem 15:2706- 2710; and Ehrlich et al. (1980) Biochem 19:4091-4096. In certain embodiments, single chain Fv or scFV antibodies are contemplated. For example, Kappa bodies (Ill et al., Prot. Eng. 10: 949-57 (1997)); minibodies (Martin et al., EMBO J 13: 5305-9 (1994)); diabodies (Holliger et al., Proc. Nat. Acad. Sci. 90: 6444-8 (1993)); or Janusins (Traunecker et al., EMBO J 10: 3655-59 (1991) and Traunecker et al., Int. J. Cancer Suppl. 7: 51-52 (1992)), may be prepared using standard molecular biology techniques following the teachings of the present application with regard to selecting antibodies having the desired specificity. In still other embodiments, bispecific or chimeric antibodies may be made that encompass the ligands of the present disclosure. For example, a chimeric antibody may comprise CDRs and framework regions from different antibodies, while bispecific antibodies may be generated that bind specifically to one or more Fzd receptors through one binding domain and to a second molecule through a second binding domain. These antibodies may be produced through recombinant molecular biological techniques or may be physically conjugated together. A single chain Fv (scFv) polypeptide is a covalently linked VH:VL heterodimer which is expressed from a gene fusion including VH- and VL-encoding genes linked by a peptide-encoding linker. Huston et al. (1988) Proc. Nat. Acad. Sci. USA 85(16):5879-5883. A number of methods have been described to discern chemical structures for converting the naturally aggregated—but chemically separated—light and heavy polypeptide chains from an antibody V region into an scFv molecule which will fold into a three-dimensional structure substantially similar to the structure of an antigen-binding site. See, e.g., U.S. Pat. Nos. 5,091,513 and 5,132,405, to Huston et al.; and U.S. Pat. No. 4,946,778, to Ladner et al. In certain embodiments, an antibody as described herein is in the form of a diabody. Diabodies are multimers of polypeptides, each polypeptide comprising a first domain comprising a binding region of an immunoglobulin light chain and a second domain comprising a binding region of an immunoglobulin heavy chain, the two domains being linked (e.g., by a peptide linker) but unable to associate with each other to form an antigen binding site: antigen binding sites are formed by the association of the first domain of one Agent’s File Ref. SRZN-029 / 01WO 328202-2197 polypeptide within the multimer with the second domain of another polypeptide within the multimer (WO94 / 13804). A dAb fragment of an antibody consists of a VH domain (Ward, E. S. et al., (1989) Nature 341:544-546 ). Where bispecific antibodies are to be used, these may be conventional bispecific antibodies, which can be manufactured in a variety of ways (Holliger, P. & Winter G., Curr. Opin. Biotech. 4, 446-449 (1993)), e.g., prepared chemically or from hybrid hybridomas, or may be any of the bispecific antibody fragments mentioned above. Diabodies and scFv can be constructed without an Fc region, using only variable domains, potentially reducing the effects of anti-idiotypic reaction. Bispecific diabodies, as opposed to bispecific whole antibodies, may also be particularly useful because they can be readily constructed and expressed in E. coli. Diabodies (and many other polypeptides such as antibody fragments) of appropriate binding specificities can be readily selected using phage display (WO94 / 13804) from libraries. If one arm of the diabody is to be kept constant, for instance, with a specificity directed against antigen X, then a library can be made where the other arm is varied and an antibody of appropriate specificity selected. Bispecific whole antibodies may be made by knobs-into- holes engineering (J. B. B. Ridgeway et al., Protein Eng., 9, 616-621 (1996)). In certain embodiments, the antibodies described herein may be provided in the form of a UniBody®. A UniBody® is an IgG4 antibody with the hinge region removed (see GenMab Utrecht, The Netherlands; see also, e.g., US2009 / 0226421). This proprietary antibody technology creates a stable, smaller antibody format with an anticipated longer therapeutic window than current small antibody formats. IgG4 antibodies are considered inert and thus do not interact with the immune system. Fully human IgG4 antibodies may be modified by eliminating the hinge region of the antibody to obtain half-molecule fragments having distinct stability properties relative to the corresponding intact IgG4 (GenMab, Utrecht). Halving the IgG4 molecule leaves only one area on the UniBody® that can bind to cognate antigens (e.g., disease targets) and the UniBody® therefore binds univalently to only one site on target cells. In certain embodiments, antibodies and antigen-binding fragments thereof as described herein include a heavy chain and a light chain CDR set, respectively interposed between a heavy chain and a light chain framework region (FR) set which provide support to the CDRs and define the spatial relationship of the CDRs relative to each other. As used herein, the term “CDR set” refers to the three hypervariable regions of a heavy or light chain Agent’s File Ref. SRZN-029 / 01WO 328202-2197 V region. Proceeding from the N-terminus of a heavy or light chain, these regions aredenoted as “CDR1,” “CDR2,” and “CDR3” respectively. An antigen-binding site, therefore, includes six CDRs, comprising the CDR set from each of a heavy and a light chain V region. A polypeptide comprising a single CDR, (e.g., a CDR1, CDR2 or CDR3) is referred to herein as a “molecular recognition unit.” Crystallographic analysis of a number of antigen-antibody complexes has demonstrated that the amino acid residues of CDRs form extensive contact with bound antigen, wherein the most extensive antigen contact is with the heavy chain CDR3. Thus, the molecular recognition units are primarily responsible for the specificity of an antigen-binding site. As used herein, the term “FR set” refers to the four flanking amino acid sequences which frame the CDRs of a CDR set of a heavy or light chain V region. Some FR residues may contact bound antigen; however, FRs are primarily responsible for folding the V region into the antigen-binding site, particularly the FR residues directly adjacent to the CDRs. Within FRs, certain amino residues and certain structural features are very highly conserved. In this regard, all V region sequences contain an internal disulfide loop of around 90 amino acid residues. When the V regions fold into a binding-site, the CDRs are displayed as projecting loop motifs which form an antigen-binding surface. It is generally recognized that there are conserved structural regions of FRs which influence the folded shape of the CDR loops into certain “canonical” structures—regardless of the precise CDR amino acid sequence. Further, certain FR residues are known to participate in non-covalent interdomain contacts which stabilize the interaction of the antibody heavy and light chains. A “monoclonal antibody” refers to a homogeneous antibody population wherein the monoclonal antibody is comprised of amino acids (naturally occurring and non-naturally occurring) that are involved in the selective binding of an epitope. Monoclonal antibodies are highly specific, being directed against a single epitope. The term “monoclonal antibody” encompasses not only intact monoclonal antibodies and full-length monoclonal antibodies, but also fragments thereof (such as Fab, Fab', F(ab')2, Fv), single chain (scFv), Nanobodies®, variants thereof, fusion proteins comprising an antigen-binding fragment of a monoclonal antibody, humanized monoclonal antibodies, chimeric monoclonal antibodies, and any other modified configuration of the immunoglobulin molecule that comprises an antigen- binding fragment (epitope recognition site) of the required specificity and the ability to bind to an epitope, including WNT surrogate molecules disclosed herein. It is not intended to be limited as regards the source of the antibody or the manner in which it is made (e.g., by hybridoma, phage selection, recombinant expression, transgenic animals, etc.). The term includes whole Agent’s File Ref. SRZN-029 / 01WO 328202-2197 immunoglobulins as well as the fragments etc. described above under the definition of “antibody”. In certain embodiments, the antibodies of the present disclosure may take the form of a single domain antibody (sdAb). SdAb technology was originally developed following the discovery and identification that camelidae (e.g., camels, alpacas, and llamas) possess fully functional antibodies that consist of heavy chains only and therefore lack light chains. These heavy-chain only antibodies contain a single variable domain (VHH) and two constant domains (CH2, CH3). The cloned and isolated single variable domains have full antigen binding capacity and are very stable. These single variable domains, with their unique structural and functional properties, form the basis of sdAbs. SdAb are encoded by single genes and are efficiently produced in almost all prokaryotic and eukaryotic hosts, e.g., E. coli (see, e.g., U.S. Pat. No. 6,765,087), molds (for example Aspergillus or Trichoderma) and yeast (for example Saccharomyces, Kluyvermyces, Hansenula, or Pichia (see, e.g., U.S. Pat. No. 6,838,254). The production process is scalable and multi-kilogram quantities of sdAbs have been produced. SdAbs may be formulated as a ready-to-use solution having a long shelf life. The Nanoclone® method (see, e.g., WO 06 / 079372) is a proprietary method for generating sdAbs against a desired target, based on automated high-throughput selection of B-cells. SdAb are single-domain antigen-binding fragments of camelid-specific heavy-chain only antibodies. sdAb, also referred to as VHH antibodies, typically have a small size of around 15 kDa. See C. Bever et al., Anal Bioanal Chem. 2016 Sept; 408(22); 5985–6002. Another antibody fragment contemplated is a dual-variable domain- immunoglobulin (DVD-Ig or Fv-Ig) is an engineered protein that combines the function and specificity of two monoclonal antibodies in one molecular entity. An Fv-Ig is designed as an IgG-like molecule, except that each light chain and heavy chain contains two variable domains in tandem through a short peptide linkage, instead of one variable domain in IgG. The fusion orientation of the two variable domains and the choice of linker sequence are critical to functional activity and efficient expression of the molecule. An Fv-Ig can be produced by conventional mammalian expression systems as a single species for manufacturing and purification. An Fv-Ig has the specificity of the parental antibodies, is stable in vivo, and exhibits IgG-like physicochemical and pharmacokinetic properties. Fv- Igs and methods for making them are described in Wu, C., et al., Nat Biotech, 25:1290–1297 (2007)). In certain embodiments, the antibodies or antigen-binding fragments thereof as disclosed herein are humanized. This refers to a chimeric molecule, generally prepared using Agent’s File Ref. SRZN-029 / 01WO 328202-2197 recombinant techniques, having an antigen- binding site derived from an immunoglobulin from a non-human species and the remaining immunoglobulin structure of the molecule based upon the structure and / or sequence of a human immunoglobulin. The antigen-binding site may comprise either complete variable domains fused onto constant domains or only the CDRs grafted onto appropriate framework regions in the variable domains. Epitope binding sites may be wild type or modified by one or more amino acid substitutions. This eliminates the constant region as an immunogen in human individuals, but the possibility of an immune response to the foreign variable region remains (LoBuglio, A. F. et al., (1989) Proc Natl Acad Sci USA 86:4220–4224; Queen et al., PNAS (1988) 86:10029–10033; Riechmann et al., Nature (1988) 332:323–327). Illustrative methods for humanization of the anti-Fzd or LRP antibodies disclosed herein include the methods described in U.S. Pat. No.7,462,697. Another approach focuses not only on providing human-derived constant regions but modifying the variable regions as well so as to reshape them as closely as possible to human form. It is known that the variable regions of both heavy and light chains contain three complementarity-determining regions (CDRs) which vary in response to the epitopes in question and determine binding capability, flanked by four framework regions (FRs) which are relatively conserved in a given species and which putatively provide a scaffolding for the CDRs. When nonhuman antibodies are prepared with respect to a particular epitope, the variable regions can be “reshaped” or “humanized” by grafting CDRs derived from nonhuman antibody on the FRs present in the human antibody to be modified. Application of this approach to various antibodies has been reported by Sato, K., et al., (1993) Cancer Res 53:851-856; Riechmann, L., et al., (1988) Nature 332:323-327; Verhoeyen, M., et al., (1988) Science 239:1534-1536; Kettleborough, C. A., et al., (1991) Protein Engineering 4:773-3783; Maeda, H., et al., (1991) Human Antibodies Hybridoma 2:124-134; Gorman, S. D., et al., (1991) Proc Natl Acad Sci USA 88:4181-4185; Tempest, P. R., et al., (1991) Bio / Technology 9:266-271; Co, M. S., et al., (1991) Proc Natl Acad Sci USA 88:2869-2873; Carter, P., et al., (1992) Proc Natl Acad Sci USA 89:4285-4289; and Co, M. S. et al., (1992) J Immunol 148:1149-1154. In some embodiments, humanized antibodies preserve all CDR sequences (for example, a humanized mouse antibody which contains all six CDRs from the mouse antibodies). In other embodiments, humanized antibodies have one or more CDRs (one, two, three, four, five, six) which are altered with respect to the original antibody, which are also termed one or more CDRs “derived from” one or more CDRs from the original antibody. In certain embodiments, the antibodies of the present disclosure may be chimeric antibodies. In this regard, a chimeric antibody is comprised of an antigen-binding fragment of Agent’s File Ref. SRZN-029 / 01WO 328202-2197 an antibody operably linked or otherwise fused to a heterologous Fc portion of a different antibody. In certain embodiments, the heterologous Fc domain is of human origin. In other embodiments, the heterologous Fc domain may be from a different Ig class from the parent antibody, including IgA (including subclasses IgA1 and IgA2), IgD, IgE, IgG (including subclasses IgG1, IgG2, IgG3, and IgG4), and IgM. In further embodiments, the heterologous Fc domain may be comprised of CH2 and CH3 domains from one or more of the different Ig classes. As noted above with regard to humanized antibodies, the antigen-binding fragment of a chimeric antibody may comprise only one or more of the CDRs of the antibodies described herein (e.g., 1, 2, 3, 4, 5, or 6 CDRs of the antibodies described herein), or may comprise an entire variable domain (VL, VH or both). The structures and locations of immunoglobulin CDRs and variable domains may be determined by reference to Kabat, E. A. et al., SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST, 4th Edition, US Department of Health and Human Services. 1987, and updates thereof, now available on the Internet (immuno.bme.nwu.edu). In certain embodiments, the antagonist or agonist binding agent binds with a dissociation constant (KD) of about 1 µM or less, about 100 nM or less, about 40 nM or less, about 20 nM or less, or about 10 nM or less. For example, in certain embodiments, a FZD binding agent or antibody described herein that binds to more than one FZD, binds to those FZDs with a KDof about l00nM or less, about 20 nM or less, or about 10 nM or less. In certain embodiments, the binding agent binds to one or more its target antigen with an EC50 of about 1 µM or less, about 100 nM or less, about 40 nM or less, about 20 nM or less, about 10 nM or less, or about 1 nM 20 or less. The antibodies or other agents of the present invention can be assayed for specific binding by any method known in the art. Immunoassays that can be used include, but are not limited to, competitive and non-competitive assay systems using techniques such as biolayer interferometry (BLI) analysis, FACS analysis, immunofluorescence, immunocytochemistry, Western blots, radioimmunoassays, ELISA, “sandwich” immunoassays, immunoprecipitation assays, precipitation reactions, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, and protein A immunoassays. Such assays are routine and well known in the art (see, e.g., Ausubel et al, eds, 1994, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, Vol. 1, John Wiley & Sons, Inc., New York, which is incorporated by reference herein in its entirety). Agent’s File Ref. SRZN-029 / 01WO 328202-2197 For example, the specific binding of an antibody to a target antigen may be determined using ELISA. An ELISA assay comprises preparing antigen, coating wells of a 96 well microtiter plate with antigen, adding the antibody or other binding agent conjugated to a detectable compound such as an enzymatic substrate (e.g., horse-radish peroxidase or alkaline phosphatase) to the well, incubating for a period of time and detecting the presence of the antigen. In some embodiments, the antibody or agent is not conjugated to a detectable compound, but instead a second conjugated antibody that recognizes the first antibody or agent is added to the well. In some embodiments, instead of coating the well with the antigen, the antibody or agent can be coated to the well and a second antibody conjugated to a detectable compound can be added following the addition of the antigen to the coated well. One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the signal detected as well as other variations of ELISAs known in the art (see, e.g., Ausubel et al, eds, 1994, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, Vol. 1, John Wiley & Sons, Inc., New York at 11.2.1). The binding affinity of an antibody or other agent to a target antigen and the off- rate of the antibody-antigen interaction can be determined by competitive binding assays. One example of a competitive binding assay is a radioimmunoassay comprising the incubation of labeled antigen (e.g., Fzd, LRP), or fragment or variant thereof, with the antibody of interest in the presence of increasing amounts of unlabeled antigen followed by the detection of the antibody bound to the labeled antigen. The affinity of the antibody and the binding off-rates can be determined from the data by scattered plot analysis. In some embodiments, BLI analysis is used to determine the binding on and off rates of antibodies or agents. BLI kinetic analysis comprises analyzing the binding and dissociation of antibodies from chips with immobilized antigens on their surface. IV. Compositions and Methods of Use of WNT Agonists The present description provides methods of treating lacrimal gland diseases and disorders, including but not limited to dry eye disorders, e.g., by activation and / or regeneration of lacrimal gland acinar cells, and compositions therefore. It will be readily understood to persons skilled in the art that lacrimal gland is homologous to Meibomian gland and accessory lacrimal glands, and the methods and compositions described herein may be applied for treatment of the Meibomian glands and / or accessory lacrimal glands, e.g., in aqueous-deficient or evaporative dry eye. Meibomian glands are oil glands which line the margin of eyelids. These glands cause the eyelids to Agent’s File Ref. SRZN-029 / 01WO 328202-2197 secrete oils that blend with natural tears, preventing excessive evaporation of the natural tears. Patients suffering from ocular rosacea often have Meibomian gland dysfunction (MGD) where the eyelids secrete fewer oils resulting dry eyes. MGD is thought to be the leading cause of dry eye disease. A WNT agonist molecule may also be used for the treatment of Meibomian gland disorders. In particular, active WNT signaling can potentially provide a maintenance signal to basal progenitor cells and plays a key role in regulating regeneration of the meibocytes (see, e.g., Parfitt et al (2016) Stem Cell 410). In one aspect, the present invention comprises a method of regenerating lacrimal gland acinar cells in a subject, comprising administering a WNT signaling modulator to the subject. In an embodiment, the WNT signaling modulator may be an engineered WNT signaling modulator such as a SWAP™ compound. In another embodiment, the WNT signaling modulator is an engineered WNT agonist or an engineered WNT antagonist. In yet a further embodiment, the WNT signaling modulator is a tissue-specific WNT signal enhancing molecule, such as a SWEETS™ molecule. A WNT signaling modulator may also be a combination of a WNT agonist and a tissue-specific WNT signal enhancer.  In particular embodiments of any of the methods disclosed herein, the WNT agonist is selected from those disclosed in any of the following: PCT Application Publication No. WO 2016 / 040895; US Application Publication No. US 2017-0306029; US Application Publication No. US 2017-0349659; PCT Application Publication No. WO 2019 / 126398; PCT Application Publication No. WO 2020 / 01030, PCT Application Publication No. WO 2021 / 173726, or U.S. Application No. 17 / 806,624, all of which are herein incorporated by reference in their entireties. In particular embodiments of any of the methods disclosed herein, the tissue-specific WNT signal enhancing molecule is selected from those disclosed in any of the following: PCT Application Publication No. WO 2018 / 140821; US Application Publication No. US 2020-0048324; or PCT Application Publication No. WO 2020 / 14271, all of which are herein incorporated by reference in their entireties. In particular embodiments of any of methods disclosed herein, WNT surrogate agents and methods for lacrimal gland generation is selected from those disclosed in the PCT Application No. PCT / US2022 / 081884, which is incorporated by reference in its entirety. In an embodiment of the method of regenerating lacrimal gland acinar cells, the WNT signaling modulator may comprise at least one engineered bi-specific full-length IgG antibody that directly activates a canonical WNT signaling pathway. In any embodiment, the engineered WNT agonist may be selected from: (i) WNT3a; (ii) a WNT mimetic; or (iii) an R-spondin mimetic. The WNT mimetic may be a SWAP™ compound. The R-spondin Agent’s File Ref. SRZN-029 / 01WO 328202-2197 mimetic may be a SWEETS™ compound. The WNT mimetics may comprise one or more polypeptides comprising or having a polypeptide sequence set forth in any of SEQ ID Nos: 1- 13 isoforms and homologs thereof, and suitable expression vectors therefor. The WNT mimetics may comprise one or more polypeptides having 80% to 100% homology (or at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identity) with any of the polypeptide sequences set forth in SEQ ID Nos 1-13. In certain embodiments, the WNT mimetic comprises two polypeptide sequences, each having 80% to 100% homology (or at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identity) with any of the polypeptide sequences set forth in SEQ ID Nos 1-13. In certain embodiments, the WNT mimetic comprises a light chain variable region sequence and / or a heavy chain variable region sequence, each independently comprising at least one, at least two, or all three CDR sequences disclosed in any of SEQ ID NOs: 1-13. In certain embodiments, the light chain variable region and / or heavy chain variable region each independently comprise zero, less than two, less than three, less than four, less than five, less than six, less than seven, or less than eight amino acid substitutions within the CDRs. In certain embodiments, the Wnt agonist comprises zero, less than two, less than three, less than four, less than five, less than six, less than seven, less than eight, less than nine, less than ten, less than eleven, or less than twelve amino acid substitutions within the CDRs. In certain embodiments, the engineered WNT signaling modulator is a tetravalent bispecific molecule comprising two heavy chain and two light chain polypeptide sequences, each having 80% to 100% homology (or at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identity) with any of the polypeptide sequences set forth in SEQ ID NOs 1-6. In particular embodiments, the heavy chain and light chain polypeptides present in the WNT mimetic have at least 80%, at least 90%, at least 95%, at least 98%, or 100% identity to any of following combinations: SEQ ID NOs: 1 and 2; SEQ ID NOs: 3 and 4; SEQ ID NOs: 3 and 5; or SEQ ID NOs: 3 and 6. In particular embodiments fo the engineered WNT signaling modulator, each of the two heavy chain and two light chain polypeptides, each having 80% to 100% homology (or at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identity) with any of the polypeptide sequences set forth in SEQ ID NOs: 1-6, comprise VHH, light chain and heavy chain CDR sequences set forth in any of SEQ ID NOs: 1-6. In particular embodiments, the light chain polypeptides comprise the VHH CDRs set forth in SEQ ID NOs: 14-16 or SEQ ID NOs: 23, 15, and 24. In particular embodiments, the light chain polypeptides comprise the light chain variable region CDRs set forth in SEQ ID NOs: 17-19 or SEQ ID NOs: 25, 18, and 19. In Agent’s File Ref. SRZN-029 / 01WO 328202-2197 particular embodiments, the heavy chain polypeptides comprise the heavy chain CDRs set forth in SEQ ID NOs: 20-22. In particular embodiments, the WNT mimetic has an IgG antibody structure comprising two heavy and two light chains, wherein the two heavy chains are bound to each other, and each of the light chains is bound to a different one of the two heavy chains. In certain embodiments, the WNT signaling modulator comprises a VHH sequence comprising at least one, at least two, or all three VHH CDR sequences disclosed in any of SEQ ID NOs: 1-6. In certain embodiments, the VHH region comprise zero, less than two, less than three, less than four, less than five, less than six, less than seven, or less than eight amino acid substitutions within the VHH CDRs. In certain embodiments, the WNT signaling modulator comprises a light chain variable region sequence and / or a heavy chain variable region sequence, each independently comprising at least one, at least two, or all three CDR sequences disclosed in any of SEQ ID NOs: 1-6. In certain embodiments, the light chain variable region and / or heavy chain variable region each independently comprise zero, less than two, less than three, less than four, less than five, less than six, less than seven, or less than eight amino acid substitutions within the CDRs. In certain embodiments, the Wnt agonist comprises zero, less than two, less than three, less than four, less than five, less than six, less than seven, less than eight, less than nine, less than ten, less than eleven, or less than twelve amino acid substitutions within the CDRs. In particular embodiments, Wnt signaling modulators and variants thereof, and heavy chains and light chains thereof (e.g., those having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identity to any one of SEQ ID NOs: 1-6) comprise one or more the amino acid modifications introduced into hp1SH1-03, hp1SH1-03_AAA, or hp1SH1-03_AAQ as compared to 1SH1- 03, e.g., one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or all) of the amino acid modifications shown in any of FIGs. 2-5. In particular embodiments, the WNT mimetic comprises amino acid modifications corresponding to one or more of N29Q or D102E in the VHH, N33, N36T, or V124I in the 1SH1 light chain, or V5Q or N85S in the 1SH1 heavy chain. In particular embodiments, the Wnt mimetic comprises a light chain polypeptide comprising the CDRs set forth in SEQ ID NO: 1 or SEQ ID NO:3 and one or more of the amino acid substitutions corresponding to N29Q or D102E in the VHH, N33, N36T, or V124I in the 1SH1 light chain, or V5Q or N85S in the 1SH1 heavy chain. In particular embodiments, the engineered WNT signaling modulator is a trivalent bispecific molecule, wherein the anti-LRP 5 and / or LRP 6 binder is a VHH appended either from N- or C- terminal of either hole or knob of the heavy chain polypeptide sequence each having 80% to 100% homology (or at least 80%, at least 85%, at least 90%, at least 95%, at Agent’s File Ref. SRZN-029 / 01WO 328202-2197 least 98%, at least 99%, or 100% identity) with any of the polypeptide sequences set forth in SEQ ID NOs: 7-13. In particular embodiments, the heavy chain and light chain polypeptides present in the WNT mimetic have at least 80%, at least 90%, at least 95%, at least 98%, or 100% identity to any of following combinations: SEQ ID NOs: 7, 8, and 9; SEQ ID NOs: 7, 9 13; SEQ ID NOs: 7, 11, 12; SEQ ID NOs: 7,10 and 12. In certain embodiments, the WNT signaling modulator comprises a light chain variable region sequence and / or a heavy chain variable region sequence, each independently comprising at least one, at least two, or all three CDR sequences disclosed in any of SEQ ID NOs: 7-13. In certain embodiments, the light chain variable region and / or heavy chain variable region each independently comprise zero, less than two, less than three, less than four, less than five, less than six, less than seven, or less than eight amino acid substitutions within the CDRs. In certain embodiments, the Wnt agonist comprises zero, less than two, less than three, less than four, less than five, less than six, less than seven, less than eight, less than nine, less than ten, less than eleven, or less than twelve amino acid substitutions within the CDRs. . In particular embodiments, Wnt signaling modulators and variants thereof, and heavy chains and light chains thereof (e.g., those having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identity to any one of SEQ ID NOs: 7-13) comprise one or more the amino acid modifications introduced into 1SH1-03, e.g., one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or all) of the amino acid modifications shown in any of FIGs. 2-5. In certain embodiments, the disclosure provides WNT signaling agonists, including but not limited to hp1SH1-03, and also fragments and variants thereof. In particular embodiments, the WNT signaling agonist has a structure diagrammed in Fig. 3, which is a humanized structure of the antibody showed in Fig1. Fig. 3 shows hp1SH1-03 comprises one or both of the sequences disclosed in Fig. 3, or any functional fragment or variant thereof, e.g., an antigen-binding fragment thereof, such as a VHH domain, VL domain, or VH domain, or an Fc domain, or a variant of any of these functional domains, e.g., a variant having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any functional fragment of antibody sequence disclosed herein. In some embodiments, a WNT signaling agonist comprises a variant sequence having at least 90% identity (e.g., 95%, 98% or 100% identity) to a sequence disclosed in Fig. 3 or set forth in SEQ ID Nos: 3 and / or 4, or any or any functional fragment thereof, e.g., an antigen-binding fragment thereof. In some embodiments, a WNT signaling agonist comprises a wild type or variant sequence having at least 90% identity (e.g., 95%, 98% or 100% identity) to a light chain sequence disclosed in Fig. 3 or set forth in SEQ ID NO: 3, and a wild type or variant Agent’s File Ref. SRZN-029 / 01WO 328202-2197 sequence having at least 90% identity (e.g., 95%, 98% or 100% identity) to a heavy chain sequence disclosed in Fig. 3 or set forth in SEQ ID NO:4. In particular embodiments, any variant sequence comprises one or more of the amino acid residues introduced into the parental molecule, 1SH1-03, to generate hp1SH1-03, including but not limited to, e.g., those in VHH3-H4 in Fig. 2, VHH3-H4 N29Q, VHH3-H4 DDD substituted with DED in Fig. 2, 1SH1 HC CDR1 N31S, and CDR2 D62E in Fig 3, and / or those in the humanized 1SH1 framework, as shown in Fig. 2. In certain embodiments, CDRH3 D108 and D111 are maintained. In certain embodiments, VHH3 M51 and M57 in VHH CDR3 are maintained. In further embodiments, mutations may be present in 1SH1 IgG framework on the light chain V2I, and / or on the heavy chain, e.g., V5Q and N92S, which mutations were made to de-risk immunogenicity to closest germline sequence of hp-1SH1; the sequences of hp1SH1-03 is shown in Fig. 3. In certain embodiments, the WNT signaling modulator comprises a light chain variable region sequence and / or a heavy chain variable region sequence, each independently comprising at least one, at least two, or all three CDR sequences disclosed in Fig. 3, or variants thereof, wherein the sequence comprises zero, less than two, less than three, less than four, less than five, less than six, less than seven, or less than eight amino acid modifications, e.g., substitutions, within the CDRs. In certain embodiments, the light chain variable region and / or heavy chain variable region each independently comprise zero, less than two, less than three, less than four, less than five, less than six, less than seven, or less than eight amino acid substitutions within the CDRs. In certain embodiments, the Wnt agonist comprises zero, less than two, less than three, less than four, less than five, less than six, less than seven, less than eight, less than nine, less than ten, less than eleven, or less than twelve amino acid substitutions within the CDRs. In some embodiments, the hp1SH1-03 comprises one or more (e.g., one, two, or three) of the following amino acid modifications: L234A, L235A, and P329G amino acid substitutions, and optionally all three. In particular embodiments of any of the IgG disclosed herein, the Fc of the IgG comprises one or more of the following amino acid substitutions: N297G, N297A, N297E, L234A, L235A, P236G. In further embodiments, in an effort to generate variants with shorter in vivo circulation time, the Fc region of hp1SH1-03 was modified to further have the following amino acid substitutions: I253A, H310A, and H435A (also referred to as IAHAHA or AAA herein); or I253A, H310A, and H435Q (also referred to as IAHAHQ or AAQherein). The hp1SH1-03 variant that additionally comprises IAHAHA was named hp1SH1-03 AAA, and the hp1SH1-03 variant that additionally comprises IAHAHQ was named hp1SH1-03 AAQ. No changes were made to the light chain of Agent’s File Ref. SRZN-029 / 01WO 328202-2197 hp1SH1-03. Amino acid sequences of the heavy and light chains of hp1SH1-03AAA (SEQ ID NOs: 3 and 5), and hp1SH1-03 AAQ (SEQ ID NOs: 3 and 6) are shown in FIGS. 4 and 5, respectively. Without wishing to be bound by theory, reduced in vivo circulation time (half- life, T½) may provide reduced toxicity. In an embodiment of the method of regenerating lacrimal gland acinar cells, the WNT signaling modulator may affect expression of any one or more of: Fzd1, Fzd2, Fzd5, Fzd7, Fzd8, and Lrp6, and / or Lrp5. For example, the WNT signaling modulator may target any one or more of the group consisting of: Fzd1, Fzd2, and Fzd7; or any one or more of the group consisting of: Fzd5 and Fzd8, while also targeting Lrp6 and / or Lrp5. For another example, the WNT signaling modulator may affect expression of any one or more of: Fzd1, Fzd2, and Fzd7. The WNT signaling modulator may cause an increase or decrease in any of these Fzds. In one embodiment of the method of regenerating lacrimal gland acinar cells, the method further comprises the step of administering at least one of the group consisting of: RSPO, RSPO fragment, and engineered RSPO mimetic. In some embodiment the WNT signaling modulator may be a superagonist of WNT platform. This superagonist activity was observed with LRP, FZD, and RSPO fused WNT molecule acting as a robust activator of WNT signaling pathway. the WNT superagonist is selected from those disclosed in the following: PCT Application Publication No. WO 2021 / 173726. In some embodiments, the WNT signaling modulator may be present in a pharmaceutical composition in a concentration ≥1µM. For example, the WNT signaling modulator may be in a concentration of 1µM, 1.1µM, 1.5µM, 2.0µM, 2.5µM, 3.0µM, 3.5µM, 4.0µM, 4.5µM, 5.0µM. In certain embodiments, the concentration of WNT signaling modulator may be ≥5µM. In any embodiment, the WNT signaling modulator may be in a concentration ≥1nM. For example, the WNT signaling modulator may be in a concentration of 1nM, 1.1nM, 1.5nM, 2.0nM, 2.5nM, 3.0nM, 3.5nM, 4.0nM, 4.5nM, 5.0nM. In certain embodiments, the concentration of WNT signaling modulator may be ≥5nM. In any embodiment, the WNT signaling modulator may be in a concentration ≥100 pM. For example, the WNT signaling modulator may be in a concentration of 100 pM, 200 pM, 400 pM, 800p M, 1.0 nM, 10,0 nM, 100.0nM, 1 µM, 2 uM, 3µM, 5.0µM. In certain embodiments, the concentration of WNT signaling modulator may be ≥5nM. In any embodiment, the WNT signaling modulator may be administered in a therapeutically effective amount. Agent’s File Ref. SRZN-029 / 01WO 328202-2197 In any embodiment, the subject may be a live mammal. For example, the subject may be mouse, rat, dog, cat, horse, or cow. In any embodiment, the subject may be a mammal, e.g., a human patient. In any embodiment, the WNT signaling modulator may be administered systemically or locally. For example, the WNT signaling modulator may be administered locally via aqueous eyedrop solution or local intra-lacrimal gland injection. In another aspect, the present invention comprises a method of treating a lacrimal gland disorder in a subject, comprising administering a WNT signaling modulator to the subject. In an embodiment, the WNT signaling modulator may be an engineered WNT signaling modulator. In another embodiment, the WNT signaling modulator is an engineered WNT agonist In an embodiment of the method of treating a lacrimal gland disorder, the WNT signaling modulator may affect expression of any one or more of: Fzd1, Fzd2, Fzd5, Fzd7, Fzd8, and Lrp6 and / or Lrp5. For example, the WNT signaling modulator may target any one or more of the group consisting of: Fzd1, Fzd2, and Fzd7; or any one or more of the group consisting of: Fzd5 and Fzd8, while also targeting Lrp6 and / or Lrp5. For another example, the WNT signaling modulator may affect expression of any one or more of: Fzd1, Fzd2, and Fzd7. In one embodiment of the method of treating a lacrimal gland disorder, the method further comprises the step of administering at least one of the group consisting of: RSPO2, RSPO2 fragment, and engineered RSPO2 mimetic. In any embodiment, the subject may be a live mammal. For example, the subject may be mouse, rat, dog, cat, horse, or cow. In any embodiment, the subject may be a human patient. In any embodiment, the WNT signaling modulator may be administered systemically or locally. For example, i) to one or more of the subject’s eyes, optionally intravitreally or via ocular drops; ii)locally administering, optionally to the eye, ear, nose (optionally intranasally), skin (optionally transdermally or epicutaneously), mucosa, skin, or vagina, or by inhalation; or iii) parenterally administering, optionally by injection (optionally intravenous, intramuscular, subcutaneous, intradermal, intrathecal, intra-arterial, intraarticular, intraosseous, or intraperitoneal administration) or by inhalation; or iv) enterally administering, optionally orally, sublingually, buccally, or rectally. In still another aspect, the present invention comprises a composition for the treatment of a dry eye disorder in a subject, the composition comprising a WNT signaling Agent’s File Ref. SRZN-029 / 01WO 328202-2197 modulator. In any embodiment of the composition, the dry eye disorder may be a Sjögren’s syndrome disorder. In an embodiment of the composition, the WNT signaling modulator may comprise at least one engineered bi-specific full-length IgG antibody that directly activates a canonical WNT signaling pathway. The at least one engineered bi-specific full-length IgG antibody may be specific for any one or more of Fzd1, Fzd,2, Fzd5, Fzd7, Fzd8, and Lrp6 or Lrp5. In an embodiment, the composition may further comprise an at least one additional agent, including an anti-inflammatory agent, an artificial tear agent, or an lacrimal gland secretagogue. In particular, the anti-inflammatory agent may be antibiotics or steroids including cyclosporine A (e.g., Restasis®) and lifitegrast ophthalmic solution (e.g., Xiidra®). Artificial tears agent may include non-prescription eye drops that simulate tears, e.g., hydroxypropyl cellulose (Lacrisert®) inserts. Lacrimal gland secretagogue agents may include varenicline nasal spray, which selectively agonizes nicotinic acetylcholine receptors. Also, contemplated are autologous blood serum eye drops. In any embodiment of the composition, the composition may comprise therapeutically effective amounts of each of its components. In any embodiment of the composition, the subject may be a live mammal. For example, the subject may be mouse, rat, dog, cat, horse, or cow. In any embodiment of the composition, the subject may be a human patient. In further embodiments, pharmaceutical compositions comprising an expression vector, e.g., a viral vector, comprising a polynucleotide comprising a nucleic acid sequence encoding a WNT antagonist / agonist molecule described herein and one or more pharmaceutically acceptable diluent, carrier, or excipient are also disclosed. In certain embodiments, the nucleic acid sequence encoding the WNT antagonist molecule and the nucleic acid sequence encoding the WNT agonist are in the same polynucleotide, e.g., expression cassette. The present disclosure further contemplates a pharmaceutical composition comprising a cell comprising an expression vector comprising a polynucleotide comprising a promoter operatively linked to a nucleic acid encoding a WNT antagonist / agonist molecule and one or more pharmaceutically acceptable diluent, carrier, or excipient. In particular embodiments, the pharmaceutical composition further comprises a cell comprising an expression vector comprising a polynucleotide comprising a promoter operatively linked to a nucleic acid sequence encoding a WNT antagonist and a WNT agonist. In certain Agent’s File Ref. SRZN-029 / 01WO 328202-2197 embodiments, the nucleic acid sequence encoding the WNT antagonist molecule and the nucleic acid sequence encoding the WNT agonist molecule are present in the same polynucleotide, e.g., expression cassette and / or in the same cell. In particular embodiments, the cell is a heterologous cell or an autologous cell obtained from the subject to be treated. In particular embodiments, the cell is a stem cell, e.g., an adipose-derived stem cell or a hematopoietic stem cell. The present disclosure contemplates pharmaceutical compositions comprising a first molecule for delivery of a WNT antagonist molecule as a first active agent, and a WNT agonist as a second molecule. The first and second molecule may be the same type of molecule or different types of molecules. For example, in certain embodiments, the first and second molecule may each be independently selected from the following types of molecules: polypeptides, small organic molecules, nucleic acids encoding the first or second active agent (optionally DNA or mRNA, optionally modified RNA), vectors comprising a nucleic acid sequence encoding the first or second active agent (optionally expression vectors or viral vectors), and cells comprising a nucleic acid sequence encoding the first or second active agent (optionally an expression cassette). The subject molecules, alone or in combination, can be combined with pharmaceutically acceptable carriers, diluents, excipients and reagents useful in preparing a formulation that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for mammalian, e.g., human or primate, use. Such excipients can be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous. Examples of such carriers, diluents and excipients include, but are not limited to, water, saline, Ringer's solutions, dextrose solution, and 5% human serum albumin. Supplementary active compounds can also be incorporated into the formulations. Solutions or suspensions used for the formulations can include a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial compounds such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating compounds such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates; detergents such as Tween 20 to prevent aggregation; and compounds for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. In particular embodiments, the pharmaceutical compositions are sterile. Pharmaceutical compositions may further include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological Agent’s File Ref. SRZN-029 / 01WO 328202-2197 saline, bacteriostatic water, or phosphate buffered saline (PBS). In some cases, the composition is sterile and should be fluid such that it can be drawn into a syringe or delivered to a subject from a syringe. In certain embodiments, it is stable under the conditions of manufacture and storage and is preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, e.g., a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the internal compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. Sterile solutions can be prepared by incorporating the WNT antagonist / agonist antibody or antigen-binding fragment thereof (or encoding polynucleotide or cell comprising the same) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof. In one embodiment, the pharmaceutical compositions are prepared with carriers that will protect the antibody or antigen-binding fragment thereof against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. Agent’s File Ref. SRZN-029 / 01WO 328202-2197 It may be advantageous to formulate the pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active antibody or antigen-binding fragment thereof calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms is dictated by and directly dependent on the unique characteristics of the antibody or antigen-binding fragment thereof and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active antibody or antigen-binding fragment thereof for the treatment of individuals. The pharmaceutical compositions can be included in a container, pack, or dispenser, e.g., eye dropper, e.g., a prefilled eye dropper, together with instructions for administration. The pharmaceutical compositions of the present disclosure may be delivered to a subject in the form of a pill, capsule, cream, salve, syrup, dermal patch, suppository, intravenous drip, local injection aqueous solution, non-aqueous solution, eye wash solution, or any combination of thereof. The pharmaceutical compositions of the present disclosure may be delivered to a subject by direct ophthalmic application, muscular injection, intra-lacrimal gland injection, subconjunctival injection, meibomian gland injection, intravenous injection, peritoneal injection, nasally, orally, rectally, or any combination thereof. The pharmaceutical compositions of the present disclosure encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other compound which, upon administration to an animal comprising a human, is capable of providing (directly or indirectly) the biologically active antibody or antigen-binding fragment thereof. The present disclosure includes pharmaceutically acceptable salts of a WNT antagonist / agonist molecule described herein. The term “pharmaceutically acceptable salt” refers to physiologically and pharmaceutically acceptable salts of the compounds of the present disclosure: i.e., salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto. A variety of pharmaceutically acceptable salts are known in the art and described, e.g., in “Remington’s Pharmaceutical Sciences”, 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and more recent editions thereof), in the “Encyclopedia of Pharmaceutical Technology”, 3rd edition, James Swarbrick (Ed.), Informa Healthcare USA (Inc.), NY, USA, Agent’s File Ref. SRZN-029 / 01WO 328202-2197 2007, and in J. Pharm. Sci.66:2 (1977). Also, for a review on suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, 2002). Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Metals used as cations comprise sodium, potassium, magnesium, calcium, and the like. Amines comprise N-N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N- methylglucamine, and procaine (see, for example, Berge et al., “Pharmaceutical Salts,” J. Pharma Sci., 1977, 66, 119). The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present disclosure. In some embodiments, the pharmaceutical composition provided herein comprise a therapeutically effective amount of a WNT antagonist / agonist molecule or pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier, diluent and / or excipient, for example saline, phosphate buffered saline, phosphate and amino acids, polymers, polyols, sugar, buffers, preservatives and other proteins. Exemplary amino acids, polymers and sugars and the like are octylphenoxy polyethoxy ethanol compounds, polyethylene glycol monostearate compounds, polyoxyethylene sorbitan fatty acid esters, sucrose, fructose, dextrose, maltose, glucose, mannitol, dextran, sorbitol, inositol, galactitol, xylitol, lactose, trehalose, bovine or human serum albumin, citrate, acetate, Ringer's and Hank's solutions, cysteine, arginine, carnitine, alanine, glycine, lysine, valine, leucine, polyvinylpyrrolidone, polyethylene and glycol. Preferably, this formulation is stable for at least six months at 4ºC. In some embodiments, the pharmaceutical composition provided herein comprises a buffer, such as phosphate buffered saline (PBS) or sodium phosphate / sodium sulfate, tris buffer, glycine buffer, sterile water and other buffers known to the ordinarily skilled artisan such as those described by Good et al. (1966) Biochemistry 5:467. The pH of the buffer may be in the range of 6.5 to 7.75, preferably 7 to 7.5, and most preferably 7.2 to 7.4. From the foregoing it will be appreciated that, although specific embodiments of the present disclosure have been described herein for purposes of illustration, various Agent’s File Ref. SRZN-029 / 01WO 328202-2197 modifications may be made without deviating from the spirit and scope of the present disclosure. The broad scope of this invention is best understood with reference to the following examples, which are not intended to limit the inventions to the specific embodiments. EXAMPLES Methods Standard methods in molecular biology were used, including methods described, e.g., in Maniatis et al. (1982) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Sambrook and Russell (2001) Molecular Cloning, 3rded., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Wu (1993) Recombinant DNA, Vol. 217, Academic Press, San Diego, Calif. Standard methods also appear in Ausbel et al. (2001) Current Protocols in Molecular Biology, Vols. 1-4, John Wiley and Sons, Inc. New York, N.Y., which describes cloning in bacterial cells and DNA mutagenesis (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), glycoconjugates and protein expression (Vol. 3), and bioinformatics (Vol. 4). Methods for protein purification including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization are described, e.g., in Coligan et al. (2000) Current Protocols in Protein Science, Vol. 1, John Wiley and Sons, Inc., New York. Chemical analysis, chemical modification, post-translational modification, production of fusion proteins, glycosylation of proteins are described in, e.g., Coligan et al. (2000) Current Protocols in Protein Science, Vol. 2, John Wiley and Sons, Inc., New York; Ausubel et al. (2001) Current Protocols in Molecular Biology, Vol. 3, John Wiley and Sons, Inc., NY, N.Y., pp. 16.0.5-16.22.17; Sigma-Aldrich, Co. (2001) Products for Life Science Research, St. Louis, Mo.; pp. 45-89; Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, N.J., pp. 384-391. Production, purification, and fragmentation of polyclonal and monoclonal antibodies are described, e.g., in Coligan et al. (2001) Current Protocols in Immunology, Vol. 1, John Wiley and Sons, Inc., New York; Harlow and Lane (1999) Using Antibodies, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Harlow and Lane, supra. Standard techniques for characterizing ligand / receptor interactions are available in, e.g., Coligan et al. (2001) Current Protocols in Immunology, Vol. 4, John Wiley, Inc., New York. Methods for flow cytometry, including fluorescence activated cell sorting detection systems (FACS®), are available in, e.g., Owens et al. (1994) Flow Cytometry Agent’s File Ref. SRZN-029 / 01WO 328202-2197 Principles for Clinical Laboratory Practice, John Wiley and Sons, Hoboken, N.J.; Givan (2001) Flow Cytometry, 2nded.; Wiley-Liss, Hoboken, N.J.; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, N.J. Fluorescent reagents suitable for modifying nucleic acids, including nucleic acid primers and probes, polypeptides, and antibodies, for use, e.g., as diagnostic reagents, are available In, e.g., Molecular Probes (2003) Catalogue, Molecular Probes, Inc., Eugene, Oreg.; Sigma-Aldrich (2003) Catalogue, St. Louis, Mo. Standard methods of histology of the immune system are described in, e.g., Muller-Harmelink (ed.) (1986) Human Thymus: Histopathology and Pathology, Springer Verlag, New York, N.Y.; Hiatt, et al. (2000) Color Atlas of Histology, Lippincott, Williams, and Wilkins, Phila, Pa.; Louis, et al. (2002) Basic Histology: Text and Atlas, McGraw-Hill, New York, N.Y. Software packages and databases for determining, e.g., antigenic fragments, leader sequences, protein folding, functional domains, glycosylation sites, and sequence alignments, are available, in, e.g., GenBank, Vector NTI® Suite (Informax, Inc, Bethesda, Md.); GCG Wisconsin Package (Accelrys, Inc., San Diego, Calif.); DeCypher® (TimeLogic Corp., Crystal Bay, Nev.); Menne et al. (2000) Bioinformatics 16: 741-742; Menne et al. (2000) Bioinformatics Applications Note 16:741-742; Wren et al. (2002) Comput. Methods Programs Biomed. 68:177-181; von Heijne (1983) Eur. J. Biochem. 133:17-21; von Heijne (1986) Nucleic Acids Res. 14:4683-4690. Female C57BL / 6 mice (8–10-week-old) were purchased from Jackson Laboratory (Bar Harbor, ME). All animal procedures were performed in accordance with IACUC committee’s regulations. Mice were anesthetized and the left extraorbital lacrimal glands were left untreated while the right lacrimal glands were injected with IL-1α or a cocktail of IL-1α and SWAP™, i.e., WNT mimetic, as shown. Example 1 Activity of WNT Signaling Agonists GFP reporter WNT signaling activity was measured using Hek293T cells containing a GFP-reporter gene controlled by a WNT-responsive promoter (GFP reporter assay). In brief, cells were seeded at a density of 20,000 per well in 96-well plates 24 hours prior to treatment in the presence of 3 μM IWP2 to inhibit the production of endogenous WNTs. The recombinant WNT mimetics were then added to the cells overnight. After removing the culture media, GFP fluorescence was measured using a microplate reader with Agent’s File Ref. SRZN-029 / 01WO 328202-2197 a positive control (R2M3-26), parental 1SH1-03 and the humanized polished hp1SH1-03 with and without FcRn mutations AAA and AAQ shown in Fig 7; molecules are active with slight difference in EC50. Fig. 8 describes GFP reporter for engineered trivalent bispecific using WNT signaling modulator reader with a positive control (R2M3-26), parental 1SH1-03 and the humanized polished hp1SH1-03. Mouse Axin2 induction in Surrogate WNT screen was performed in mouse lacrimal gland explant cultures, derived from fresh mouse lacrimal gland tissue, in complete expansion medium. Cells were plated in Matrigel as described above and exposed to different surrogate WNTs ( R2M3-null, as negaticve control,1SH1-03, hp1SH1-03, hp1SH1-03, hp1SH1-03AAA, hp1SH1-03AAQ) at different concentrations. After 24-hour exposure, the RNA was extracted using the QIAGEN miniprep kit according to manufacturer’s protocol. Expression of Axin2 was determined by qPCR using SYBR Green (Thermo Fisher) according to manufacturer’s protocol (primers sequences provided below), and the results are shown in Fig. 9. Fig.10 shows WNT target gene Axin2 expression 24h after local injection in IL-1a model. All treatment groups were given a single dose of 10 ug injection. Data was normalized to anti-GFP control group. Significant elevation was observed in all 1SH1-03 groups but not in negative control R2M3-null. Fig. 11 shows WNT target gene Axin2 expression 24h after local treatment in duct ligation damage mouse model of dry eye. All treatment groups at a single dose of 10 ug injection. Data normalized to R2M3-null negative control group. Significant elevation all 1SH1-03 groups except hp1SH1-03-AAQ. Example 2 Intra-Lacrimal Gland Injection Intra-lacrimal gland injection was performed as previously described with minor alteration in Zoukhri et al. A Single Injection of Interleukin-1 Induces a Reversible Aqueous- tear Deficiency, Lacrimal Gland Inflammation, and Acinar and Ductal Cell Proliferation, 84 EXP. EYE RES. 894-904 (2007). Briefly, a small incision anterior to the ear of isoflurane- anesthetized animal was made to expose the extraorbital lacrimal gland. A volume of 1 μL was injected 3 times (total volume of 3 μL) to the exposed lacrimal gland. Agent’s File Ref. SRZN-029 / 01WO 328202-2197 The following procedure was established for lacrimal gland duct ligation, adapted from Liu et al. 2017. Animals were anesthetized with isoflurane. After the mouse was no longer responsive to pinches on two extremities in two different body quadrants, it was moved to the stage of a dissecting scope and fashioned with a nosecone to continue anesthesia by isoflurane. A small incision anterior to the ear was made to expose the extraorbital lacrimal gland which is lifted to expose the main excretory duct. A size 4-0 silk thread was then used to ligate the duct. After duct ligation, the skin incision was closed, sutured, and antibiotic ointment is then applied to the skin. The contralateral lacrimal gland was not operated on and served as a control. After three days, the skin suture was reopened to expose the lacrimal gland. The duct ligation was then released by cutting the silk suture with micro scissors. In the same surgery, treatment groups were injected with 2 mL of test article into the lacrimal gland ipsilateral to the ligation. After injection, the skin incision was closed, sutured, and antibiotic ointment was then applied. The animals were then sacrificed, and ipsilateral and contralateral lacrimal glands collected 24h, 3 days or 14 days after releasing the ligation. For induction of dry eye, 3 μL of recombinant human IL-1α (Peprotech) at 2 μg / μL was injected to the lacrimal gland. For local SWAP™ treatment, SWAP™ (3.5 μg / μL) was mixed with IL-1α (2 μg / μL) in a total volume of 3 μL then injected to the lacrimal gland. For systemic SWAP™ treatment, SWAP™ was intraperitoneally injected at 10 mg / kg twice a week for 2 weeks. Aqueous tear secretion was measured using phenol-impregnated cotton threads (Zone-Quick, Menicon) on restrained, unanesthetized mice. The threads were held with forceps and applied to the lateral canthus of both eyes for 30 seconds. Wetting of the thread which turned from yellow to red in contact with tears was measured in millimeters. Tear volume measurements using phenol red thread in the IL-1a model. Data represents an average of twelve animals. Treatments included three different doses of hp1SH1-03 (10, 2 and 0.4 ug) and compared to parental 1SH1-03 and negative control R2M3-null. Significant tear volume elevation in several treatment groups on day 2 and 3 compared to R2M3-null negative control except the lowest dose, and the results are shown in Fig.12. FIG. 13 describes tear volume measurements using phenol red thread in the IL-1a model. Data represents an average of twelve animals. Treatments included two different doses of hp1SH1-03 and hp1SH1-03-AAA (10 and 2 ug) and compared to parental 1SH1-03 and negative control R2M3-null. Significant tear volume elevation in several treatment groups on day 3 compared to R2M3-null negative control. Agent’s File Ref. SRZN-029 / 01WO 328202-2197 Fig. 14 describes tear volume measurements using phenol red thread in the mouse duct ligation model of dry eye. Data represents an average of twelve animals per group per timepoint. Treatments included 1SH1-03, hp1SH1-03, hp1SH1-03-AAA at 2 or 10 ug compared to 10 ug negative control R2M3-null. Two groups were dosed again for a second time on day 7 (indicated with x2). Significant tear volume increase starts at day 7 for some groups and all treatments reach statistically significant increase at day 14. The group with 2x dosing of hp1SH1-03-AAA trends the highest. Example 3 WNT Agonist Treatment in Primary Human Corneal Endothelium Cell Culture Human corneal endothelial cells with attached Descemet membrane were received from Eversight (Ann Arbor, MI). Multiple donor samples were pooled and digested in 2 mg / mL collagenase A in MEM-alpha + 15% FBS + 20 μg / mL gentamicin sulfate for 3 hours at 37℃ with occasional trituration. Samples were then washed with MEM-alpha + 15% FBS + 20 μg / mL gentamicin before resuspension and plating in Human Endothelial SFM + 5% FBS + 2 ng / mL EGF + 20 μg / mL gentamicin sulfate. Endothelial cells were treated with test proteins (5 nM hp1SH1-03 and anti GFP antibody as a negative control) or left untreated in Human Endothelial SFM + 5% FBS + 2ng / mL EGF + 20 μg / mL gentamicin sulfate. After 14 days, cells were fixed and immunofluorescence performed for Ki67 (Abcam #ab16667, 1:100) and Na+K+ ATPase (Sigma #05-369, 1:100) prior to nuclear staining with DAPI. Ki67 is a well-known marker for cell proliferation. See discussion in, e.g., Aung TN et al., Mod Pathol (2021), https: / / doi.org / 10.1038 / s41379-021-00745-6. Samples were imaged on a Leica Dmi8 microscope. The percentage of Ki67+ cells (# of Ki67+ cells / total # of cells) in the resulting images were quantified using a custom Python script. Treatment with humanized polished (hp) 1SH1-03 significantly increased the number of proliferating cells compared to negative control anti-GFP antibody. Data normalized to negative control matched per experiment. Pooled material from seven endothelial skirts are used for one experiment result depicted in Fig. 15. Treatment with hp1SH1-03-AAA (5nM) increased WNT target gene expression (AXIN2, LEF1, RNF43) and proliferation marker (CCND1) compared to the negative control anti-GFP antibody (5nM) after 24h. Data are normalized to the negative control treatment. Agent’s File Ref. SRZN-029 / 01WO 328202-2197 Cells were expanded for two weeks from primary cell material prior to the 24h treatment; results are depicted in Fig. 16 A to Fig. 16 D. Proliferation of cornea endothelial cells from human skirt material after 14 days of treatment. Treatment with humanized polished hp1SH1-03 in combination with engineered FGF TTHX1114 significantly increased the number of proliferating cells compared to negative control anti-GFP antibody. All treatments at 5nM final concentrations. Data was normalized to negative control matched per experiment. Pooled material from seven endothelial skirts are used for one experiment. This demonstrates the potential utilization of combining WNT and FGF pathway activation in cornea endothelial cell disease (Fig. 17). Example 4 WNT Agonist Treatments in Naïve Mice by Intracameral and Intravitreal Injection 6 to 12-week-old female Balb / C mice were anesthetized by placing the animal in an induction chamber connected to an oxygen source and isoflurane vaporizer and adjusting oxygen flow to 0.9 liters / min and the isoflurane vaporizer to 3-4%. As soon as the mouse became unresponsive and had shallow breathing, it was transferred to the anesthesia platform with the nose cone. The head was positioned so that the eye to be injected is facing up towards the microscope objective. Only one eye per mouse was injected, the contralateral used as control. 1 drop of Proparacaine was placed on the cornea for 30 seconds. The cornea was punctured closely anterior to the iridocorneal angle. The fluid that emanates from the anterior chamber was wiped off with a weck-cell before 1 microliter of wnt agonist hp1SH1-03 (0.1 µg and 0.001 µg), hp1SH1-03-AAA (0.1 µg and 0.001 µg), and vehicle was injected into the anterior chamber (intracamerally) or posterior chamber (intravitreally) using a 33 gauge needle attached to Hamilton syringe. The mice were allowed to recover from the anesthesia. The mice were taken down the next day, the eyes harvested, and the corneas were dissected, fixed in 10% formalin, and embedded in paraffin. For half of the eye samples, sections of paraffin-embedded tissue were made and Axin2 levels measured using an RNAscope® kit including RNAscope Multiplex Fluorescent Reagent Kit v2 (ACDBio) according to the manufacturer’s instructions. For the remaining eye samples, RT- qPCR for Wnt target gene Axin2 was carried out using TaqMan™ Gene Expression Assay reagents (ThermoFisher) on a CFX96™ thermocycler (BioRad). β-actin was used for normalization. Cornea WNT target gene Axin2 expression 24h after treatment Agent’s File Ref. SRZN-029 / 01WO 328202-2197 of non-injured mouse eyes through intracameral injection. Only cornea cell material was isolated for gene expression analysis. Treatment includes negative control vehicle injection and several different doses of hp1SH1-03-AAA. All treatment groups increase target gene expression with a significant increase in the lowest two doses. Results from such studies are described in Fig. 18. Example 5 Cryoinjury Model Mice were randomly divided into two groups, and 2 cycles of cryoinjury were applied to the right eye of each mouse (Han et al., 2013). Under Isoflurane anesthesia, transcorneal freezing was initiated by gently placing a cryoprobe made of stainless steel (2.5 mm indiameter; flat tip; ERBE Elektromedizin GmbH, Tübingen, Germany), precooled in liquid nitrogen for a minute on the central cornea. A cryoprobe with a diameter of 2.5 mm was be chosen as it is similar to the corneal diameter (2.6 mm) of C57BL / 6 mice. be chosen as it is similar to the corneal diameter (2.6 mm) of C57BL / 6 mice. No pressure was applied to avoid damage to adjacent tissue including the lens and the trabecular meshwork. The cryoprobe was kept on the corneal surface until an ice ball was formed on the cornea and covered the entire corneal surface, which corresponds to the duration of 3 seconds, as the defect on the endothelium was shown to be the same size as the ice ball. This injury was repeated after a 1min interval. Immediately after freezing, the cryoprobe was freed from the corneal surface with irrigation with a balanced salt solution, and the cornea was allowed to thaw spontaneously. Only the right eye was treated with the cryoprobe and the left eye served as an untreated control. We followed the recovery of the cornea over 4-5 days typically by following corneal thickness via OCT and corneal clarity via bright field imaging (both Phoenix micron IV). Fig. 19 describes cornea WNT target gene Axin2 expression 24h after treatment of cryoinjured mouse eyes through intracameral injection. Only cornea cell material was isolated for gene expression analysis. Treatment included negative control vehicle injection and several different doses of hp1SH1-03-AAA. All treatment groups increased target gene expression with a significant increase in the lowest three doses. Central corneal thickness (CCT) following corneal freeze (cryoinjury) and treatment over the course of 8 days was measured. Treatment groups included negative control vehicle and two different doses of hp1SH1-03-AAA. Corneal freeze was performed Agent’s File Ref. SRZN-029 / 01WO 328202-2197 on day 0 which led to an increase in CCT to around 300 µm. Treatment with hp1SH1-03- AAA lowered the corneal thickness compared to vehicle control. The difference was significantly lower on day 7 for the lowest dose (Fig. 20 and Fig. 21). Fig. 22 describes pharmacokinetic measurement of serum drug concentration following IV injection (3mg / kg) of hp1SH1-03 with or without the FcRn mutation AAA. The addition of AAA mutation (hp1SH1-03-AAA) led to lower exposure, faster clearance and shorter residence time. The experiment was performed in humanized FcRn mice (JAX#014565). Example 6 ISH1-03 Humanization (hp-1SH1) VHH 03 Humanization In order to humanize the camelid antibody (VHH3) sequence, the sequence database of human germline IgG heavy chain (HC) was searched. 3-66*01 was found as the closest match. Four different mutants (H1-H4) were generated and purified. The “VHH3- H4,” which showed the best yield of production, was picked as a humanized VHH3. Polishing VHH3 To de-risk potential liabilities of deamidation, isomerization, and oxidation in VHH3 CDR regions, VHH3 mutants were generated. N29Q mutation at CDR1 Three different N29 mutants (N29Q, N29A, N29S) of VHH3 were generated and purified, but N29Q VHH3 only showed good yield for high purity expression. The mutation in SWAP, combined with the 1RC07 (1RC07-3_H4_N29Q) showed no changes in STF response. The asparagine in CDR1 is replaced to glutamine to mitigate the potential liability of deamidation. D102E mutation at CDR3 Five different mutants (DED, SDE, EDE ESD, SSD) in VHH3 CDR3 were generated and purified to de-risk “DD” motif isomerization in VHH3. All mutants in SWAP, combined with the 1RC07 (1RC07-3 formats) showed no changes in STF response. The DED Agent’s File Ref. SRZN-029 / 01WO 328202-2197 mutant, which shows good expression and may have minimal structural change, was picked. The aspartic acid in CDR3 was replaced to glutamic acid to mitigate the potential liability of isomerization. No changes of M51 and M57 in VHH3 CDR2. Three different mutants at each methionine residue in VHH3 CDR2 (M51K, M51L, M51I. M57K, M57L, M57I) were generated and purified to de-risk potential oxidation liability. All mutants showed a big decrease of expression, and it is decided to keep both methionine residues, and to check their oxidation in the further Mass-spec analyses. Polishing and germlining 1SH1 IgG V124I mutation in 1SH1 LC To de-risk immunogenicity, the position was mutated to the closest germline sequence. N155G mutation in 1SH1 LC To de-risk potential deamidation, all possible point mutants were made and assessed for impact on binding to target Fzd, with those showing the least impact to STF activity when paired with other polishing positions being identified. N158T mutation in 1SH1 LC To de-risk potential deamidation, all possible point mutants were made and assessed for impact on binding to target Fzd. Final candidate selected based on least impact to STF activity when paired with other polishing positions V5Q mutation in 1SH1 HC To de-risk immunogenicity, position was mutated to closest germline sequence. N85S mutation in 1SH1 HC To de-risk immunogenicity, position was mutated to closest germline sequence. D108 position in 1SH1 HC Theoretical isomerization position could not be mutated to any residue that maintained binding. Agent’s File Ref. SRZN-029 / 01WO 328202-2197 D111 position in 1SH1 HC Theoretical isomerization position could not be mutated to any residue that maintained binding. Reagents and Materials WNT mimetics were constructed as described in WO 2020 / 010308 A1, which is incorporated herein in its entirety. All recombinant proteins were produced in Expi293F™ cells (Thermo Fisher Scientific) by transient transfection unless otherwise specified. All IgG- based and Fc-containing constructs were first purified with Protein-A resin and eluted with 0.1 M glycine pH 3.5. All proteins were then polished by a size exclusion column in HBS buffer (10 mM HEPES pH 7.2, 150 mM NaCl). Proteins were supplemented with glycerol to 10% for long term storage at -80°C. Reagents used in lacrimal gland regeneration experiments included (but were not limited to): Reagent List Component Catalog number Advanced DMEM / F-12 Thermo Scientific 12634-010 HEPES Thermo Scientific 15630080 GlutaMAX Thermo Scientific 35050061 Penicillin-Streptomycin Thermo Scientific 15140122 B27 Thermo Scientific 17504044 N2 Thermo Scientific 17502048 Human Growth Factors Peprotech Recombinant Human R-Spondin 1 R&D 4645RS Surrogate WNT In-house production Matrigel™ GFR Membrane Matrix Corning CB40230C Y-27632 MilliporeSigma 5092280001 Primers used in the experiments included: Primer name Primer sequence SEQ ID No. Mouse forward Axin2 CAGCCCAAGAACCGGGAAAT 40 Mouse reverse Axin2 GAGCCTCCTCTCTTTTACAGCA 41 Mouse forward Actb ACCTTCTACAATGAGCTGCGT 42 Agent’s File Ref. SRZN-029 / 01WO 328202-2197 Mouse reverse Actb AGGTCTCAAACATGATCTGGGT 43 Mouse forward Rnf43 CGGAGCCGTACTGGGTTAAG 44 Mouse reverse Rnf43 GGCACGGGGATGAAACAAAT 45 Mouse forward Mist1 CCAAGATCGAGACCCTCACG 46 Mouse reverse Mist1 GCGGCTGCTGGACATAGTAA 47 Mouse forward Krt7 GCGGAGATGAACCGCTCTAT 48 Mouse reverse Krt7 TCTAACTTGGCACGCTGGTT 49 Human forward AXIN2 TCATTTCCCGAGAACCCACC 50 Human reverse AXIN2 AGCTTCAGCTTTTCCAGCCT 51 Human forward ACTB CTGGAACGGTGAAGGTGACA 52 Human reverse ACTB AAGGGACTTCCTGTAACAATGCA 53 Mouse forward Fzd1 CATCGAGGCCAACTCACAGT 54 Mouse reverse Fzd1 TGAGCCCCACAAAACACACT 55 Mouse forward Fzd2 AGCGATTTCGCTACCCAGAG 56 Mouse reverse Fzd2 AGAACGAAGCCCGCAATGTA 57 Mouse forward Fzd3 GCCCTTTGTGAGACCAGGTT 58 Mouse reverse Fzd3 ATATGCCTGCAGGTCTCAGC 59 Mouse forward Fzd4 CCTGAGCGCCCCATCATATT 60 Mouse reverse Fzd4 CTTTCCCGGCCTACAGTCAG 61 Mouse forward Fzd5 CCGCCACAGGTACCTAGCTT 62 Mouse reverse Fzd5 AAGGACAGAACTCTCGGAGGA 63 Mouse forward Fzd6 CCCGAGGTGAGGCGTCC 64 Mouse reverse Fzd6 TGAATTCTGGGGCAACTGCT 65 Mouse forward Fzd7 ATGCTCTATGTACGCACCCG 66 Mouse reverse Fzd7 CGAACTTGTTCATGAGCGCC 67 Mouse forward Fzd8 TGTTGGAAGTGACCTCGCTC 68 Mouse reverse Fzd8 AACCGATGCCTTTGCACAAC 69 Mouse forward Fzd9 TAAGGACTTCGCGCTGGTTT 70 Mouse reverse Fzd9 AAGATAATCGGGCGCTCTGG 71 Mouse forward Fzd10 CCTTCCTCATCGACCCATCG 72 Mouse reverse Fzd10 TAGCCCACCGAATAAACGCA 73 Mouse forward Lrp5 CCATTGTGTTGCACCCTGTG 74 Agent’s File Ref. SRZN-029 / 01WO 328202-2197 Mouse reverse Lrp5 CAGGACATGCCGATCTCTCC 75 Mouse forward Lrp6 TGCAAACAGACGGGACTTGA 76 Mouse reverse Lrp6 CCAAACACAAAGTCCACCGC 77 WNT mimetic constructs used in the experiments comprised the following amino acid sequences (Bold = LRP binding variable domain; underline = linker; italics = FZD binding variable domain; Plain (non bold, non italic, no underline=constant domain).

[0002] Agent’s File Ref. SRZN-029 / 01WO 328202-2197 1SH1-03 Light Chain SEQ ID NO: 1 DVQLVESGGGLVQPGGSLRLSCTSSANINSIETLGWYRQAPGKQRELI ANMRGGGYMKYAGSLKGRFTMSTESAKNTMYLQMNSLKPEDTAVY YCYVKLRDDDYVYRGQGTQVTVSSGGSGSDVVMTQSPLSLPVTPGEPASI SCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSKRASGVPDRFSGSGSGTD FTLKISRVEAEDVGVYYCMQALQIPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 1SH1-03 Heavy Chain SEQ ID NO: 2 EVQLVESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYY SGSTYYNPSLKSRVTISVDTSKNQFSLKLNSVTAADTAVYYCARHAGFYGLADYF DYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSR EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK hp1SH1-03 Light Chain SEQ ID NO: 3 hp1SH1-03 EVQLVESGGGLVQPGGSLRLSCASSANIQSIETLGWYRQAPGKQRELI AAA ANMRGGGYMKYADSLKGRFTMSTDNSKNTMYLQMNSLRAEDTAVY YCYVKLRDEDYVYRGQGTQVTVSSGGGGSDIVMTQSPLSLPVTPGEPASI hp1SH1-03 SCRSSQSLLHSGGYTYLDWYLQKPGQSPQLLIYLGSKRASGVPDRFSGSGSGTD AAQ FTLKISRVEAEDVGVYYCMQALQIPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQ Agent’s File Ref. SRZN-029 / 01WO 328202-2197 LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC hp1SH1-03 heavy Chain SEQ ID NO: 4 EVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIY YSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTA ADTAVYYCARHAGFYGLADYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTS GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW LNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTL PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK hp1SH1-03 heavy Chain SEQ ID NO: 5 AAA EVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIY YSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSV ADTAVYYCARHAGFYGLADYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTS GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPEAAGGPSVFLFPPKPKDTLMASRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLAQDW LNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTL PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSL SPGK hp1SH1-03 heavy Chain SEQ ID NO: 6 AAQ Agent’s File Ref. SRZN-029 / 01WO 328202-2197 EVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIY YSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTA ADTAVYYCARHAGFYGLADYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTS GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPEAAGGPSVFLFPPKPKDTLMASRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLAQDW LNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTL PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNQYTQKSLSL SPGK Light chain SEQ ID NO:7 hp1SH1 DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSGGYTYLDWYLQKPGQSPQLLIYL GSKRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQIPPTFGQGTK VEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC Heavy Chain SEQ ID NO:8 hpVhh03_h p1SH1_HC EVQLVESGGGLVQPGGSLRLSCASSANIQSIETLGWYRQAPGKQRELI _hole_T36 ANMRGGGYMKYADSLKGRFTMSTDNSKNTMYLQMNSLRAEDTAVY 6S_L368A YCYVKLRDEDYVYRGQGTQVTVSSGGGGSEVQLQESGPGLVKPSQTLSL _Y407V TCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTS KNQFSLKLSSVTAADTAVYYCARHAGFYGLADYFDYWGQGTLVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLSCAVKGFYPS Agent’s File Ref. SRZN-029 / 01WO 328202-2197 DIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGK Heavy Chain SEQ ID NO:9 hp1SH1_k nob EVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIY YSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHAGFYGLADY FDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSR EEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Heavy chain SEQ ID NO: 10 hp1SH1_H C_knob_T EVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIY 366W_hpV YSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHAGFYGLADY HH03 FDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSR EEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSEVQ LVESGGGLVQPGGSLRLSCASSANIQSIETLGWYRQAPGKQRELIANM RGGGYMKYADSLKGRFTMSTDNSKNTMYLQMNSLRAEDTAVYYCY VKLRDEDYVYRGQGTQVTVSS Heavy Chain SEQ ID NO: 11 hpVHH03_ 1SH1_HC_ Agent’s File Ref. SRZN-029 / 01WO 328202-2197 knob_T366 EVQLVESGGGLVQPGGSLRLSCASSANIQSIETLGWYRQAPGKQRELI W ANMRGGGYMKYADSLKGRFTMSTDNSKNTMYLQMNSLRAEDTAVY YCYVKLRDEDYVYRGQGTQVTVSSGGGGSEVQLQESGPGLVKPSQTLSL TCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTS KNQFSLKLSSVTAADTAVYYCARHAGFYGLADYFDYWGQGTLVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALGAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLWCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGK Heavy Chain SEQ ID NO: 12 hp1SH1_H C_hole_T3 EVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIY 66S_L368 YSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHAGFYGLADY A_Y407V FDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK PSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPS REEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0003] Agent’s File Ref. SRZN-029 / 01WO 328202-2197 Heavy chains SEQ ID NO: 13 hp1SH1_H C_hole_T3 EVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIY 66S_L368 YSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHAGFYGLADY A_Y407V_ FDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT hpVHH03 VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSR EEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSEVQ LVESGGGLVQPGGSLRLSCASSANIQSIETLGWYRQAPGKQRELIANM RGGGYMKYADSLKGRFTMSTDNSKNTMYLQMNSLRAEDTAVYYCY VKLRDEDYVYRGQGTQVTVSS VHH03 SEQ ID NO: 14 CDR1 ANINSIET VHH03 SEQ ID NO: 15 CDR2 MRGGGYM VHH03 SEQ ID NO: 16 CDR3 YVKLRDDDYVY 1SH1- SEQ ID NO: 17 CDRL1 QSLLHSNGYNY Agent’s File Ref. SRZN-029 / 01WO 328202-2197 1SH1 - CDRL2 LGS (SEQ ID NO: 18) 1SH1- SEQ ID NO: 19 CDRL3 MQALQIPPT 1SH1- SEQ ID NO: 20 CDRH1 GGSISSGGYY 1SH1- SEQ ID NO: 21 CDRH2 IYYSGST 1SH1- SEQ ID NO: 22 CDRH3 ARHAGFYGLADYFDY hp-VHH03 SEQ ID NO: 23 CDR1 ANIQSIET hp-VHH03 SEQ ID NO: 15 CDR 2 MRGGGYM hp-VHH03 SEQ ID NO: 24 CDR 3 YVKLRDEDYVY Agent’s File Ref. SRZN-029 / 01WO 328202-2197 hp-1SH1- SEQ ID NO: 25 CDRL1 QSLLHSGGYTY hp-1SH1- CDRL2 LGS (SEQ ID NO: 18) hp-1SH1- SEQ ID NO: 19 CDRL3 MQALQIPPT hp-1SH1- SEQ ID NO: 20 CDRH1 GGSISSGGYY hp-1SH1- SEQ ID NO: 21 CDRH2 IYYSGST hp-1SH1- SEQ ID NO: 22 CDRH2 ARHAGFYGLADYFDY Linker SEQ IDNO: 26 GGSGS It will be readily understood to those skilled in the art that the above constructs may be altered and expressed as various homologs and isoforms, may be edited at non- binding-domain sequences, and may be expressed using various synonymous nucleotide sequences using various suitable expression vector systems. Agent’s File Ref. SRZN-029 / 01WO 328202-2197 REFERENCES The following references are incorporated herein in their entireties: Marie Bannier-Hélaouët et al., Exploring the human lacrimal gland using organoids and single-cell sequencing, CELL STEM CELL (2021); Liana Basova et al., Origin and Lineage Plasticity of Endogenous Lacrimal Gland Epithelial Stem / Progenitor Cells, ISCIENCE 23.6 (2020): 101230; Darlene A. Dartt, Signal transduction and control of lacrimal gland protein secretion: A review, 8 CURRENT EYE RES.619 (1989); Charlotte H. Dean et al., Canonical WNT signaling negatively regulates branching morphogenesis of the lung and lacrimal gland, 286 DEVELOPMENTAL BIO.270 (2005); T Farmer D'Juan et al., Defining epithelial cell dynamics and lineage relationships in the developing lacrimal gland, DEVELOPMENT 144.13 (2017): 2517-28; Galina Dvoriantchikova et al., Molecular Profiling of the Developing Lacrimal Gland Reveals Putative Role of Notch Signaling in Branching Morphogenesis, 58 INVEST. OPHTHALMOL. VIS. SCI.1098 (2017); Ankur Garg & Xin Zhang, Lacrimal Gland Development: From Signaling Interactions to Regenerative Medicine, 246 DEVELOPMENTAL DYNAMICS 970 (2017); Hodges, Robin R., and Darlene A. Dartt. "Regulatory pathways in lacrimal gland epithelium." International review of cytology 231 (2003): 129-196; John A. MacMillan, Diseases of the Lacrimal Gland and Ocular Complications, 138 JAMA 801 (1948); Shubha Tiwari, Human lacrimal gland regeneration: Perspective and review of literature, 28 SAUDI J. OPHTHALMOL.12 (2014); Yupeng Yao & Yan Zhang, The lacrimal gland: development, wound repair and regeneration, 39 BIOTECH. LETTERS 939 (2017); Driss Zoukhri et al. A Single Injection of Interleukin-1 Induces a Reversible Aqueous-tear Deficiency, Lacrimal Gland Inflammation, and Acinar and Ductal Cell Proliferation, 84 EXP. EYE RES.894-904 (2007); Darlene A. Dartt, OCULAR DISEASE: MECHANISMS AND MANAGEMENT 105–13 (Leonard A. Levin & Daniel M. Albert eds., 2010); Liu, Y., Hirayama, M., Kawakita, T. and Tsubota, K., 2017. A ligation of the lacrimal excretory duct in mouse induces lacrimal gland inflammation with proliferative cells. Stem Cells International, 2017.; Agent’s File Ref. SRZN-029 / 01WO 328202-2197 Zhang, Z., Broderick, C., Nishimoto, M., Yamaguchi, T., Lee, S.J., Zhang, H., Chen, H., Patel, M., Ye, J., Ponce, A., et al. (2020). Tissue-targeted R-spondin mimetics for liver regeneration. Sci Rep 10, 13951; Xie, Y., Zamponi, R., Charlat, O., Ramones, M., Swalley, S., Jiang, X., Rivera, D., Tschantz, W., Lu, B., Quinn, L., et al. (2013). Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R-spondin. EMBO Rep 14, 1120-1126.10.1038 / embor.2013.167. Tetsuya Kawakita, (2018) Regeneration of Lacrimal Gland Function to Maintain the Health of the Ocular Surface, Invest Ophthalmol Vis Sci.2018;59:DES169–DES173. 10.1167 / iovs.17-23576.

Claims

Agent’s File Ref. SRZN-029 / 01WO 328202-2197 CLAIMS WHAT IS CLAIMED IS:

1. An engineered multivalent bispecific WNT signaling modulator, wherein the WNT signaling modulator comprises: a. at least one first antigen binding domain that binds to at least one of Lrp6 and / or Lrp5; and b. at least one-second antigen binding domains bind to at least one FZD receptors.

2. The engineered WNT signaling modulator of claim 1, wherein the modulator is a tetravalent bispecific molecule.

3. The engineered WNT signaling modulator of claim 2, wherein the WNT signaling modulator comprises: a. two light chains, each comprising a polypeptide sequence having at least 95% identity to SEQ ID NO:3; and b. two heavy chains, each comprising a polypeptide sequence having at least 95% identity to SEQ ID NO: 4, 5, or 6.

4. The engineered WNT signaling modulator of claim 3, wherein each of the two light chains comprises a VHH domain comprising one or more or more of the following amino acid residues: N29Q and / or VHH3-H4 DDD substituted with DED.

5. The engineered WNT signaling modulator of claim 3, wherein each heavy chain comprises amino acid residues: a CDRH1 SEQ ID NO: 20, a CDRH2 SEQ ID NO: 21, and CDRH3 SEQ ID NO:

22.

6. The engineered WNT signaling modulator of any one of claims 2-5, wherein the WNT signaling modulator molecule further has amino acid modifications comprising: L234A, L235A, and P329G amino acid substitutions, as numbered according to the EU index.Agent’s File Ref. SRZN-029 / 01WO 328202-2197 7. The engineered WNT signaling modulator of claims 2-6 wherein the heavy chain of SEQ ID NO: 5 comprises Fc region mutation with at least three amino acid modifications selected from the group consisting of: I253A, H310A, and H435A, as numbered according to the EU index.

8. The engineered WNT signaling modulator of claims 2-6, wherein the heavy chain of SEQ ID NO: 6 comprises Fc region mutation with at least three amino acid modifications selected from the group consisting of: I253A, H310A and H435Q, as numbered according to the EU index.

9. The engineered WNT signaling modulator of claim 1, wherein the modulator is a trivalent bispecific molecule.

10. The engineered WNT signaling modulator of claim 9, wherein the WNT signaling modulator comprises: a. a first antigen binding domain that bind to one of Lrp6 and / or Lrp5; and b. two second antigen binding domains that bind to at least two FZD receptors.

11. The engineered WNT signaling modulator of claim 10, wherein the anti-LRP 5 / 6 is an N-terminal ‘Hole’ appended comprising a polypeptides sequence having 95% identity to the combination of SEQ ID NOs: 8, 7, and 9.

12. The engineered WNT signaling modulator of claim 10, wherein the anti-LRP 5 / 6 is a C-terminal ‘Hole’ appended comprising a polypeptides sequence having 95% identity to the combination of SEQ ID NOs: 13, 7, and 9.

13. The engineered WNT signaling modulator of claim10, wherein the anti-LRP 5 / 6 is an N-terminal ‘Knob’ appended comprising a polypeptides sequence having 95% identity to the combination of SEQ ID NOs: 11, 7, and 12.

14. The engineered WNT signaling modulator of claim 10, wherein the anti-LRP 5 / 6 is a C-terminal ‘Knob’ appended comprising a polypeptides sequence having 95% identity to the combination of SEQ ID NOs: 10, 7, and 12.Agent’s File Ref. SRZN-029 / 01WO 328202-2197 15. A nucleic acid comprising a sequence encoding the engineered multivalent bispecific WNT signaling modulator of any one of claims 1-14 optionally wherein the nucleic acid(s) is / are DNA, cDNA, RNA, mRNA, modified mRNA, or a DNA / RNA hybrid.

16. A vector comprising the nucleic acid of claim 15.

17. The vector of claim 16, wherein the vector is an expression vector comprising a promoter operatively linked to the nucleic acid of claim 15.

18. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or carrier, and: a. the engineered WNT signaling modulator of any one of claims 1-14; b. the nucleic acid of any one of claim 15; and / or c. the vector of any one of claims 16-17.

19. A method of regenerating lacrimal gland cells in a subject, comprising administering a WNT signaling modulator to the subject.

20. The method of claim 19, wherein the subject is a mammal animal or human patient.

21. The method of claim 19, wherein the lacrimal gland cells are acinar cells, progenitor cells, ductal cells, myoepithelial cells, or immune cells.

22. The method of claim 19, wherein the engineered WNT signaling modulator is a WNT agonist.

23. The method of claim 19-22, wherein the engineered WNT signaling agonist is administered: i. to one or more of the subject’s eyes, optionally intra-lacrimal gland or via ocular drops; ii. locally administering, optionally to the eye, ear, nose (optionally intranasally), skin (optionally transdermally or epicutaneously), mucosa, skin, or vagina, or by inhalation; orAgent’s File Ref. SRZN-029 / 01WO 328202-2197 iii. parenterally administering, optionally by injection (optionally intravenous, intramuscular, subcutaneous, intradermal, intrathecal, intra-arterial, intraarticular, intraosseous, or intraperitoneal administration) or by inhalation; or iv. enterally administering, optionally orally, sublingually, buccally, or rectally.

Images