CD-38 protein binding compositions and methods related thereto

Abstract

Disclosed are single-chain variable fragments, chimeric antigen receptors, and methods to treat and prevent CD38-associated pathologies, such as hematologic cancers and neurological disorders.

Description

[0001] Docket No.10935-022WO2 CD-38 PROTEIN BINDING COMPOSITIONS AND METHODS RELATED THERETO RELATED APPLICATION This PCT application claims priority to, and the benefit of, U.S. Provisional Patent Application No. 63 / 651,616, filed May 24, 2024, entitled “CD-38 PROTEIN BINDING COMPOSITIONS AND METHODS RELATED THERETO,” which is incorporated by reference herein in its entirety. REFERENCE TO SEQUENCE LISTING The sequence listing submitted on May 27th, 2025, as an .XML file entitled “10935- 022WO2_ST26” created on May 24th, 2025, and having a file size of 21,968 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52(e)(5). FIELD The present disclosure relates compositions comprising single chain variable fragments (scFv) and nucleic acid encoding scFvs that bind to CD38, and related methods thereof. BACKGROUND The present disclosure relates to compositions and methods useful to bind CD38 and affect cells that express CD38, including cancer cells. CD38 is a 45kD type II transmembrane glycoprotein with a long C-terminal extracellular domain and a short N-terminal cytoplasmic domain. The CD38 protein is a bifunctional extracellular enzyme that catalyzes the conversion of NAD+ to cyclic ADP-ribose (cADPR) and also hydrolyzes cADPR to ADP-ribose. CD38 is up-regulated in many hematopoietic malignancies and cell lines derived from various hematologic malignancies, including non-Hodgkin's lymphoma (NHL), Burkitt's lymphoma (Burkitt's lymphoma (BL), multiple myeloma (MM), chronic B lymphocytic leukemia (B-CLL), acute B and T lymphocytic leukemia (ALL), T cell lymphoma (TCL), acute myeloid leukemia ( AML), hair cell leukemia (HCL), Hodgkin's Lymphoma (HL), and chronic myelogenous leukemia (CML). Treatments of CD38-associated disease states are limited and additional treatments are needed. Docket No.10935-022WO2 SUMMARY The present disclosure provides single chain variable fragment (scFv) compositions, nucleic acids encoding scFv capable of targeting and / or binding CD38, and methods related thereof. In one aspect disclosed herein is an antigen binding molecule (such as, for example a chimeric antigen receptor (CAR) or an antibody or epitope binding fragment thereof including, but not limited to scFv, Fab, Fab^, F(ab^)2 or Fv fragment) comprising light chain complementarity determining regions (CDR) 1(CDR-L1), CDR-L2, and CDR-L3 as set forth in SEQ ID NO: 16, SEQ ID NO: 18, and SEQ ID NO: 20, respectively (including, but not limited to SEQ ID NO: 9) and / or heavy CDR- H1, CDR-H2, and CDR-H3 as set forth in SEQ ID NO: 22, SEQ ID NO: 24, and SEQ ID NO: 26, respectively (including, but not limited to SEQ ID NO: 10), wherein said antigen binding molecule specifically binds CD38. Also disclosed herein are antigen binding molecules of any preceding aspect, wherein the antigen binding molecule comprises an antibody or epitope binding fragment thereof, and wherein the or epitope binding fragment thereof comprises at least one human constant region (such as, for example, a human IgG1 / IgKappa constant region). In some aspects the antibody comprises a humanized or resurfaced antibody. In one aspect, disclosed herein are immunotoxins comprises the antigen binding molecules of any preceding aspect and a cytotoxic agent (such as, for example, a maytansinoid, a small drug, a tomaymycin derivative, a leptomycin derivative, a prodrug, a toxoid (including, but not limited to tetanus toxoid), diphtheria toxin, Pseudomonas exotoxin, A chain of ricin, ribosome inactivating proteins gelonin, saporin, bouganin, pokeweed antiviral protein, dodecandron, CC-1065 and a CC- 1065 analog) In some aspects, the antigen binding molecules of any preceding aspect is cytotoxic to a CD38+cell (such as, for example, a lymphoma cell, a leukemia cell, or a multiple myeloma cell. In some embodiments, the CD38+cell includes, but is not limited to a non-Hodgkin's lymphoma (NHL) cell, a Burkitt's lymphoma (BL) cell, a multiple myeloma (MM) cell, a B chronic lymphocytic leukemia (B-CLL) cell, a B and T acute lymphocytic leukemia (ALL) cell, a T cell lymphoma (TCL) cell, an acute myeloid leukemia (AML) cell, a hairy cell leukemia (HCL) cell, a Hodgkin's Lymphoma (HL) cell, or a chronic myeloid leukemia (CML) cell) by inducing apoptosis, antibody- dependent cell-mediated cytotoxicity (ADCC), and / or complement-dependent cytoxicity (CDC). In some embodiments, killing said CD38+cell by apoptosis can occur in the absence of stroma cells or stroma- derived cytokines. Docket No.10935-022WO2 In some aspects, disclosed herein is a pharmaceutical composition comprising the antigen binding molecules of any preceding aspect (including, but not limited to CAR, immunotoxin, antibody or epitope-binding fragment thereof) and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a therapeutic agent, including but not limited to antagonist of epidermal-growth factor (EGF), fibroblast-growth factor (FGF), hepatocyte growth factor (HGF), tissue factor (TF), protein C, protein S, platelet-derived growth factor (PDGF), heregulin, macrophage-stimulating protein (MSP), vascular endothelial growth factor (VEGF), a receptor for epidermal-growth factor (EGF), a receptor for fibroblast-growth factor (FGF), a receptor for hepatocyte growth factor (HGF), a receptor for tissue factor (TF), a receptor for protein C, a receptor for protein S, a receptor for platelet-derived growth factor (PDGF), a receptor for heregulin, a receptor for macrophage-stimulating protein (MSP), a receptor for vascular endothelial growth factor (VEGF); HER2 receptor, HER3 receptor, c-MET, other receptor tyrosine kinases. In some embodiments, the therapeutic agent includes, but is not limited to an antibody targeting a cluster of differentiation (CD) antigen selected from a group comprising CD3, CD14, CD19, CD20, CD22, CD25, CD28, CD30, CD38, CD36, CD40, CD44, CD52, CD55, CD59, CD56, CD70, CD79, CD80, CD103, CD134, CD137, CD138, and CD152. In some aspects, disclosed herein is a recombinant nucleic acid encoding the antigen binding molecule of any preceding aspect. In some aspects, disclosed herein is an expression vector encoding the recombinant nucleic acid of any preceding aspect. In some aspects, disclosed herein is a cell (such as, a T-cell, natural killer (NK) cell, NK T cell, macrophage, genetically-modified T-cell, or genetically-modified NK cell) for example, expressing the expression vector of any preceding aspect. In some aspects, disclosed herein is a method of treating, decreasing, reducing, inhibiting, ameliorating, and / or preventing a CD38-associated pathology, including but not limited to a cancer (such as, for example a leukemia, myeloma, or solid tumor, including, but not limited to Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic B lymphocytic leukemia, acute B and T lymphocytic leukemia, T cell lymphoma, acute myeloid leukemia, hairy cell leukemia, Hodgkin's Lymphoma, or chronic myelogenous leukemia), metabolic disorder, inflammatory disorder, endothelial disorder, virus susceptibility, neurological disorder, or aging in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of any preceding aspect. In some aspects, disclosed herein is a method of improving cancer cell / tumor / load Docket No.10935-022WO2 reduction, the method comprising administering to a subject in need thereof, the pharmaceutical composition of any preceding aspect in combination with all-trans retinoic acid (ATRA). BRIEF DESCRIPTION OF FIGURES The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects described below. Figures 1A, 1B, and 1C show the schematic for generation of CD38-cAR NK cells and confirmation of the CD38-CAR expression in NK cells using CRISPR-Cas9 and AAV transduction. Figures 2A, 2B, 2C, 2D, and 2E show that CD38-CAR expression is detectable at high levels on NK cells and CD38-CAR NK cells proliferate similarly to non-transduced (wildtype) NK cells, and that the CAR elicits higher cytotoxicity toward CD38 expressing hematological malignancies. Figures 3A and 3B show that ATRA increases CD38 expression and improves CAR killing in certain cancer cell lines. Figure 4 shows that inflammatory cytokines are released by CD38-CAR NK cells in the presence of CD38 expressing malignancies. Figure 4 also shows that interferon gamma (IFN-^), tumor necrosis factor-alpha (TNF-^), granulocyte macrophage colony-stimulating factor (GM-CSF), and chemokines (CCL2 (MCP-1), CCL3 (MIP-1^, and CCL5 (RANTES)) are more released by CD38-CAR NK cells compared to wildtype in the presence of CD38 expressing malignancies. These cytokines are secreted after NK cell activation and help regulate the function of other immune cells. Figures 5A, 5B, and 5C show that CD38KO / CD38-CAR is reproducible and functional in T cells. Figures 6A, 6B, and 6C show the CD38KO does not appear to be necessary to avoid fratricide. Figures 6A and 6B surprisingly show that CD38-CAR NK cells with intact CD38 genes were able to grow and express the CAR similar to CD38KO cells. Figure 6C shows that when the CD38-CAR is put into the AAVS1 locus and CD38 is not deleted, that the expression of CD38 is not changed at the mRNA level (left) but surprisingly is reduced at the protein level (right). Thus, CD38KO does not appear to be necessary to develop CD38-CAR NK cells with an isutaximab based scFv. Figures 7A, 7B, and 7C show that CD38-CAR NK cells are similarly active against CD38- positive targets and similarly increased in their metabolic fitness whether or not CD38 is deleted. The CD38-CAR surprisingly results in increased cytotoxicity and metabolism without deletion of CD38. Figure 8 shows that CD38-CAR NK cells are broadly active against more of the subclusters of a primary AML sample (C vs E, 80.3% to 12%) than wild-type NK cells (C vs D, 80.3% to 32%), Docket No.10935-022WO2 and that the addition of ATRA does not impact AML growth (C vs F) or the activity of wild-type NK cells (D vs G), but significantly improves the killing of AML by CD38CAR-NK cells (E vs H). DETAILED DESCRIPTION The following description of the disclosure is provided as an enabling teaching of the disclosure in its best, currently known embodiment(s). To this end, those skilled in the relevant art will recognize and appreciate that many changes can be made to the various embodiments of the invention described herein, while still obtaining the beneficial results of the present disclosure. It will also be apparent that some of the desired benefits of the present disclosure can be obtained by selecting some of the features of the present disclosure without utilizing other features. Accordingly, those who work in the art will recognize that many modifications and adaptations to the present disclosure are possible and can even be desirable in certain circumstances and are a part of the present disclosure. Thus, the following description is provided as illustrative of the principles of the present disclosure and not in limitation thereof. Reference will now be made in detail to the embodiments of the invention, examples of which are illustrated in the drawings and the examples. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Terminology Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. The term “comprising” and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consisting essentially of” and “consisting of” can be used in place of “comprising” and “including” to provide for more specific embodiments and are also disclosed. As used in this disclosure and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly dictates otherwise. The following definitions are provided for the full understanding of terms used in this specification. The terms "about" and "approximately" are defined as being “close to” as understood by one of ordinary skill in the art. In one non-limiting embodiment the terms are defined to be within 10%. Docket No.10935-022WO2 In another non-limiting embodiment, the terms are defined to be within 5%. In still another non- limiting embodiment, the terms are defined to be within 1%. As used herein, the terms "may," "optionally," and "may optionally" are used interchangeably and are meant to include cases in which the condition occurs as well as cases in which the condition does not occur. Thus, for example, the statement that a formulation "may include an excipient" is meant to include cases in which the formulation includes an excipient as well as cases in which the formulation does not include an excipient. “Composition” refers to any agent that has a beneficial biological effect. Beneficial biological effects include both therapeutic effects, e.g., treatment of a disorder or other undesirable physiological condition, and prophylactic effects, e.g., prevention of a disorder or other undesirable physiological condition. The terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of beneficial agents specifically mentioned herein, including, but not limited to, a vector, polynucleotide, cells, salts, esters, amides, proagents, active metabolites, isomers, fragments, analogs, and the like. When the term “composition” is used, then, or when a particular composition is specifically identified, it is to be understood that the term includes the composition per se as well as pharmaceutically acceptable, pharmacologically active vector, polynucleotide, salts, esters, amides, proagents, conjugates, active metabolites, isomers, fragments, analogs, etc. The term “comprising”, and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consisting essentially of” and “consisting of” can be used in place of “comprising” and “including” to provide for more specific embodiments and are also disclosed. An "increase" can refer to any change that results in a greater amount of a symptom, disease, composition, condition, or activity. An increase can be any individual, median, or average increase in a condition, symptom, activity, composition in a statistically significant amount. Thus, the increase can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100% or more increase so long as the increase is statistically significant. A "decrease" can refer to any change that results in a smaller amount of a symptom, disease, composition, condition, or activity. A substance is also understood to decrease the genetic output of a gene when the genetic output of the gene product with the substance is less relative to the output of the gene product without the substance. Also, for example, a decrease can be a change in the symptoms of a disorder such that the symptoms are less than previously observed. A decrease can be any individual, median, or average decrease in a condition, symptom, activity, composition in a Docket No.10935-022WO2 statistically significant amount. Thus, the decrease can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100%, or more decrease so long as the decrease is statistically significant. "Inhibit," "inhibiting," and "inhibition" mean to decrease an activity, response, condition, disease, or other biological parameter. This can include but is not limited to the complete ablation of the activity, response, condition, or disease. This may also include, for example, a 10% reduction in the activity, response, condition, or disease as compared to the native or control level. Thus, the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction below, above, or in between the given ranges as compared to native or control levels. By “reduce” or other forms of the word, such as “reducing” or “reduction,” means lowering of an event or characteristic (e.g., tumor growth). It is understood that this is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to. For example, “reduces tumor growth” means reducing the rate of growth of a tumor relative to a standard or a control. By “prevent” or other forms of the word, such as “preventing” or “prevention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce. As used herein, something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed. The terms “treat,” “treating,” and grammatical variations thereof as used herein, include partially or completely delaying, alleviating, mitigating or reducing the intensity of one or more attendant symptoms of a disorder or condition and / or alleviating, mitigating or impeding one or more causes of a disorder or condition. Treatments according to the disclosure may be applied preventively, prophylactically, palliatively or remedially. Treatments are administered to a subject prior to onset (e.g., before obvious signs of any disease or disorder disclosed herein), during early onset (e.g., upon initial signs and symptoms of any disease or disorder disclosed herein), or after an established development of any disease or disorder disclosed herein. The term “subject” refers to any individual who is the target of administration or treatment. The subject can be a vertebrate, for example, a mammal. In one aspect, the subject can be human, non-human primate, bovine, equine, porcine, canine, or feline. The subject can also be a guinea pig, Docket No.10935-022WO2 rat, hamster, rabbit, mouse, or mole. Thus, the subject can be a human or veterinary patient. The term “patient” refers to a subject under the treatment of a clinician, e.g., physician. The term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. The term “amino acid,” includes but is not limited to amino acids contained in the group consisting of alanine (Ala or A), cysteine (Cys or C), aspartic acid (Asp or D), glutamic acid (Glu or E), phenylalanine (Phe or F), glycine (Gly or G), histidine (His or H), isoleucine (Ile or I), lysine (Lys or K), leucine (Leu or L), methionine (Met or M), asparagine (Asn or N), proline (Pro or P), glutamine (Gln or Q), arginine (Arg or R), serine (Ser or S), threonine (Thr or T), valine (Val or V), tryptophan (Trp or W), and tyrosine (Tyr or Y) residues. The term “amino acid residue” also may include amino acid residues contained in the group consisting of homocysteine, 2-Aminoadipic acid, N- Ethylasparagine, 3-Aminoadipic acid, Hydroxylysine, ^-alanine, ^-Amino-propionic acid, allo- Hydroxylysine acid, 2-Aminobutyric acid, 3-Hydroxyproline, 4-Aminobutyric acid, 4- Hydroxyproline, piperidinic acid, 6-Aminocaproic acid, Isodesmosine, 2-Aminoheptanoic acid, allo- Isoleucine, 2-Aminoisobutyric acid, N-Methylglycine, sarcosine, 3-Aminoisobutyric acid, N- Methylisoleucine, 2-Aminopimelic acid, 6-N-Methyllysine, 2,4-Diaminobutyric acid, N- Methylvaline, Desmosine, Norvaline, 2,2^-Diaminopimelic acid, Norleucine, 2,3-Diaminopropionic acid, Ornithine, and N-Ethylglycine. Typically, the amide linkages of the peptides are formed from an amino group of the backbone of one amino acid and a carboxyl group of the backbone of another amino acid. Reference also is made herein to peptides, polypeptides, proteins, and compositions comprising peptides, polypeptides, and proteins. As used herein, a polypeptide and / or protein is defined as a polymer of amino acids, typically of length^100 amino acids (Garrett & Grisham, Biochemistry, 2nd edition, 1999, Brooks / Cole, 110). A peptide is defined as a short polymer of amino Docket No.10935-022WO2 acids, of a length typically of 20 or less amino acids, and more typically of a length of 12 or less amino acids (Garrett & Grisham, Biochemistry, 2nd edition, 1999, Brooks / Cole, 110). The peptides, polypeptides, and proteins disclosed herein may be modified to include non- amino acid moieties. Modifications may include but are not limited to carboxylation (e.g., N-terminal carboxylation via addition of a di-carboxylic acid having 4-7 straight-chain or branched carbon atoms, such as glutaric acid, succinic acid, adipic acid, and 4,4-dimethylglutaric acid), amidation (e.g., C- terminal amidation via addition of an amide or substituted amide such as alkylamide or dialkylamide), PEGylation (e.g., N-terminal or C-terminal PEGylation via additional of polyethylene glycol), acylation (e.g., O-acylation (esters), N-acylation (amides), S-acylation (thioesters)), acetylation (e.g., the addition of an acetyl group, either at the N-terminus of the protein or at lysine residues), formylation lipoylation (e.g., attachment of a lipoate, a C8 functional group), myristoylation (e.g., attachment of myristate, a C14 saturated acid), palmitoylation (e.g., attachment of palmitate, a C16 saturated acid), alkylation (e.g., the addition of an alkyl group, such as an methyl at a lysine or arginine residue), isoprenylation or prenylation (e.g., the addition of an isoprenoid group such as farnesol or geranylgeraniol), amidation at C-terminus, glycosylation (e.g., the addition of a glycosyl group to either asparagine, hydroxylysine, serine, or threonine, resulting in a glycoprotein). Distinct from glycation, which is regarded as a nonenzymatic attachment of sugars, polysialylation (e.g., the addition of polysialic acid), glypiation (e.g., glycosylphosphatidylinositol (GPI) anchor formation, hydroxylation, iodination (e.g., of thyroid hormones), and phosphorylation (e.g., the addition of a phosphate group, usually to serine, tyrosine, threonine, or histidine). The phrases “percent identity” and “% identity,” as applied to polypeptide sequences, refer to the percentage of residue matches between at least two polypeptide sequences aligned using a standardized algorithm. Methods of polypeptide sequence alignment are well-known. Some alignment methods consider conservative amino acid substitutions. Such conservative substitutions, explained in more detail above, generally preserve the charge and hydrophobicity at the site of substitution, thus preserving the structure (and therefore function) of the polypeptide. Percent identity for amino acid sequences may be determined as understood in the art. (See, e.g., U.S. Pat. No. 7,396,664, which is incorporated herein by reference in its entirety). A suite of commonly used and freely available sequence comparison algorithms is provided by the National Center for Biotechnology Information (NCBI) Basic Local Alignment Search Tool (BLAST) (Altschul, S. F. et al. (1990) J. Mol. Biol. 215:403410), which is available from several sources, including the NCBI, Bethesda, Md., at its website. The BLAST software suite includes various sequence analysis programs including “blastp,” that is used to align a known amino acid sequence with other amino Docket No.10935-022WO2 acids sequences from a variety of databases. Percent identity may be measured over the length of an entire defined polypeptide sequence or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined polypeptide sequence, for instance, a fragment of at least 15, at least 20, at least 30, at least 40, at least 50, at least 70 or at least 150 contiguous residues. Such lengths are exemplary only, and it is understood that any fragment length may be used to describe a length over which percentage identity may be measured. The term “variant” means a polypeptide derived from a parent polypeptide by one or more (several) alteration(s), i.e., a substitution, insertion, and / or deletion, at one or more (several) positions. A substitution means a replacement of an amino acid occupying a position with a different amino acid; a deletion means removal of an amino acid occupying a position; and an insertion means adding 1 or more, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1-3 amino acids immediately adjacent an amino acid occupying a position. In relation to substitutions, ‘immediately adjacent’ may be to the N-side (‘upstream’) or C-side (‘downstream’) of the amino acid occupying a position (‘the named amino acid’). Therefore, for an amino acid named / numbered ‘X,’ the insertion may be at position ‘X+1’ (‘downstream’) or at position ‘X−1’ (‘upstream’). A “variant” of a particular polypeptide sequence may be defined as a polypeptide sequence having at least 50% sequence identity to the particular polypeptide sequence over a certain length of one of the polypeptide sequences using blastp with the “BLAST 2 Sequences” tool available at the National Center for Biotechnology Information's website. (See Tatiana A. Tatusova, Thomas L. Madden (1999), “Blast 2 sequences—a new tool for comparing protein and nucleotide sequences”, FEMS Microbiol Lett. 174:247-250). In some embodiments a variant polypeptide may show, for example, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% or greater sequence identity over a certain defined length relative to a reference polypeptide. A “nucleic acid” is a chemical compound that serves as the primary information-carrying molecules in cells and make up the cellular genetic material. Nucleic acids comprise nucleotides, which are the monomers made of a 5-carbon sugar (usually ribose or deoxyribose), a phosphate group, and a nitrogenous base. A nucleic acid can also be a deoxyribonucleic acid (DNA) or a ribonucleic acid (RNA). A chimeric nucleic acid comprises two or more of the same kind of nucleic acid fused together to form one compound comprising genetic material. The terms “percent identity” and “% identity,” as applied to polynucleotide sequences, refer to the percentage of residue matches between at least two polynucleotide sequences aligned using a Docket No.10935-022WO2 standardized algorithm. Such an algorithm may insert, in a standardized and reproducible way, gaps in the sequences being compared in order to optimize alignment between two sequences, and therefore achieve a more meaningful comparison of the two sequences. Percent identity for a nucleic acid sequence may be determined as understood in the art. (See, e.g., U.S. Pat. No. 7,396,664, which is incorporated herein by reference in its entirety). A suite of commonly used and freely available sequence comparison algorithms is provided by the National Center for Biotechnology Information (NCBI) Basic Local Alignment Search Tool (BLAST) (Altschul, S. F. et al. (1990) J. Mol. Biol. 215:403 410), which is available from several sources, including the NCBI, Bethesda, Md., at its website. The BLAST software suite includes various sequence analysis programs including “blastn,” that is used to align a known polynucleotide sequence with other polynucleotide sequences from a variety of databases. Also available is a tool called “BLAST 2 Sequences” that is used for direct pairwise comparison of two nucleotide sequences. “BLAST 2 Sequences” can be accessed and used interactively at the NCBI website. The “BLAST 2 Sequences” tool can be used for both blastn and blastp (discussed above). Percent identity may be measured over the length of an entire defined polynucleotide sequence or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined sequence, for instance, a fragment of at least 20, at least 30, at least 40, at least 50, at least 70, at least 100, or at least 200 contiguous nucleotides. Such lengths are exemplary only, and it is understood that any fragment length may be used to describe a length over which percentage identity may be measured. A “full length” polynucleotide sequence is one containing at least a translation initiation codon (e.g., methionine) followed by an open reading frame and a translation termination codon. A “full length” polynucleotide sequence encodes a “full length” polypeptide sequence. A “variant,” “mutant,” or “derivative” of a particular nucleic acid sequence may be defined as a nucleic acid sequence having at least 50% sequence identity to the particular nucleic acid sequence over a certain length of one of the nucleic acid sequences using blastn with the “BLAST 2 Sequences” tool available at the National Center for Biotechnology Information's website. (See Tatiana A. Tatusova, Thomas L. Madden (1999), “Blast 2 sequences—a new tool for comparing protein and nucleotide sequences”, FEMS Microbiol Lett. 174:247-250). In some embodiments a variant polynucleotide may show, for example, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% or greater sequence identity over a certain defined length relative to a reference Docket No.10935-022WO2 polynucleotide. As used herein, the term “genetically modified” refers to a living cell, tissue, or organism whose genetic material has been altered using genetic engineering techniques. The genetic modification results in an alteration that does not occur naturally by mating and / or natural recombination. Modified genes can be transferred within the same species, across species (creating transgenic organisms), and across kingdoms. New, exogenous genes can be introduced, or endogenous genes can be enhanced, altered, or knocked out. CD38 Compositions The present disclosure provides single chain variable fragment (scFv) compositions, nucleic acids encoding scFv capable of targeting and / or binding CD38, and methods related thereof. The present disclosure also provides single chain variable fragment (scFv) compositions that bind to CD38, useful for generating CD38 binding protein including: chimeric antigen receptors (CARs), single-chain antibodies, soluble CD38 binders, polyfunctional proteins, and multi-specific engagers. Compositions comprising the present invention are useful as anti-cancer therapeutics. Further embodiments of the invention provide related nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions relating to the CAR constructs of the invention. Additional embodiments of the present disclosure provide methods of detecting the presence of cancer in a mammal. Additional embodiments of the present disclosure also provides methods of treating, decreasing, reducing, inhibiting, ameliorating, and / or preventing cancer in a mammal. The details of one or more embodiments of the present disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. In one aspect disclosed herein is an antigen binding molecule (such as, for example a chimeric antigen receptor (CAR), immunotoxin, or an antibody or epitope binding fragment thereof including, but not limited to scFv, Fab, Fab^, F(ab^)2 or Fv fragment) comprising light chain complementarity determining regions (CDR) 1(CDR-L1), CDR-L2, and CDR-L3 as set forth in SEQ ID NO: 16, SEQ ID NO: 18, and SEQ ID NO: 20, respectively (including, but not limited to SEQ ID NO: 9) and / or heavy CDR-H1, CDR-H2, and CDR-H3 as set forth in SEQ ID NO: 22, SEQ ID NO: 24, and SEQ ID NO: 26, respectively (including, but not limited to SEQ ID NO: 10), wherein said antigen binding molecule specifically binds CD38. Docket No.10935-022WO2 The term “antibody” is used herein in the broadest sense and specifically covers monoclonal antibodies (including full length monoclonal antibodies) of any isotype such as IgG, IgM, IgA, IgD and IgE, polyclonal antibodies, multispecific antibodies, chimeric antibodies, and antibody fragments. An antibody reactive with a specific antigen can be generated by recombinant methods such as selection of libraries of recombinant antibodies in phage or similar vectors, or by immunizing an animal with the antigen or an antigen-encoding nucleic acid. The term "antibody," refers to an immunoglobulin molecule which specifically binds with an antigen. Antibodies can be intact immunoglobulins derived from natural sources or from recombinant sources and can be immunoreactive portions of intact immunoglobulins. Antibodies are typically tetramers of immunoglobulin molecules. The antibodies in the present invention may exist in a variety of forms including, for example, polyclonal antibodies, monoclonal antibodies, Fv, Fab and F(ab)2, as well as single chain antibodies, VHH single domain antibody and humanized antibodies (Harlow et al,, 1999, In: Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, NY; Harlow et al., 1989, in: Antibodies: A Laboratory Manual, Cold Spring Harbor, New York; Houston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; Bird et al., 1988, Science 242:423-426). By the term "synthetic antibody" as used herein, is meant an antibody which is generated using recombinant DNA technology, such as, for example, an antibody expressed by a bacteriophage. The term should also be construed to mean an antibody which has been generated by the synthesis of a DNA molecule encoding the antibody and which DNA molecule expresses an antibody protein, or an amino acid sequence specifying the antibody, wherein the DNA or amino acid sequence has been obtained using synthetic DNA or amino acid sequence technology which is available and well known in the art. As used herein, the term “antibody” encompasses, but is not limited to, whole immunoglobulin (i.e., an intact antibody) of any class. Native antibodies are usually heterotetrameric glycoproteins, composed of two identical light (L) chains and two identical heavy (H) chains. Typically, each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies between the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains. Each light chain has a variable domain at one end (VL) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. Particular amino acid Docket No.10935-022WO2 residues are believed to form an interface between the light and heavy chain variable domains. The light chains of antibodies from any vertebrate species can be assigned to one of two clearly distinct types, called kappa (k) and lambda (l), based on the amino acid sequences of their constant domains. Depending on the amino acid sequence of the constant domain of their heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of human immunoglobulins: IgA, IgD, IgE, IgG and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG-1, IgG-2, IgG-3, and IgG-4; IgA-1 and IgA- 2. One skilled in the art would recognize the comparable classes for mouse. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. As used herein, the term “antibody or fragments thereof” encompasses chimeric antibodies and hybrid antibodies, with dual or multiple antigen or epitope specificities, and fragments, such as F(ab’)2, Fab’, Fab, Fv, scFv, VHH, single domain antibody, and the like, including hybrid fragments. Thus, fragments of the antibodies that retain the ability to bind their specific antigens are provided. For example, fragments of antibodies which maintain prostate-specific membrane antigen (PSMA) binding activity are included within the meaning of the term “antibody or fragment thereof.” Such antibodies and fragments can be made by techniques known in the art and can be screened for specificity and activity according to the methods set forth in the Examples and in general methods for producing antibodies and screening antibodies for specificity and activity (See Harlow and Lane. Antibodies, A Laboratory Manual. Cold Spring Harbor Publications, New York, (1988)). The term "antigen" or "Ag" as used herein is defined as a molecule that provokes an immune response. This immune response may involve either antibody production, or the activation of specific immunologically competent cells (e.g., T cells or NK cells), or both. The skilled artisan will understand that any macromolecule, including virtually all proteins or peptides, can serve as an antigen. Furthermore, antigens can be derived from recombinant or genomic DNA. A skilled artisan will understand that any DNA, which comprises a nucleotide sequence or a partial nucleotide sequence encoding a protein that elicits an immune response therefore encodes an "antigen" as that term is used herein. Furthermore, one skilled in the art will understand that an antigen need not be encoded solely by a full-length nucleotide sequence of a gene. In one example, the antigen described herein is a PSMA or a functional fragment thereof. A typical IgG antibody is comprised of two identical heavy chains and two identical light chains that are joined by disulfide bonds. Each heavy and light chain contains a constant region and Docket No.10935-022WO2 a variable region. Each variable region contains three segments called “complementarity- determining regions” (“CDRs”) or “hypervariable regions”, which are primarily responsible for binding an epitope of an antigen. They are usually referred to as CDR1, CDR2, and CDR3, numbered sequentially from the N-terminus. The more highly conserved portions of the variable regions are called the “framework regions”. As used herein, “VH” or “VH” refers to the variable region of an immunoglobulin heavychainof an antibody, including the heavy chain of an Fv, scFv, dsFv, Fab, Fab^ or F(ab^)2 fragment. Reference to “VL” or “VL” refers to the variable region of the immunoglobulin light chain of an antibody, including the light chain of an Fv, scFv, dsFv, Fab, Fab^ or F(ab^)2 fragment. In one aspect, disclosed herein is an anti-CD38 scFv comprising light chain complementarity determining regions (CDR) 1(CDR-L1), CDR-L2, and CDR-L3 as set forth in SEQ ID NO: 16, SEQ ID NO: 18, and SEQ ID NO: 20, respectively (including, but not limited to SEQ ID NO: 9) and / or heavy CDR-H1, CDR- H2, and CDR-H3 as set forth in SEQ ID NO: 22, SEQ ID NO: 24, and SEQ ID NO: 26, respectively (including, but not limited to SEQ ID NO: 10). An antibody “heavy chain”, as used herein, refers to the larger of the two types of polypeptide chains present in all antibody molecules in their naturally occurring conformations. An antibody “light chain”, as used herein, refers to the smaller of the two types of polypeptide chains present in all antibody molecules in their naturally occurring conformations, ^ and ^ light chains refer to the two major antibody light chain isotypes. A “polyclonal antibody” is an antibody which was produced among or in the presence of one or more other, non-identical antibodies. In general, polyclonal antibodies are produced from a B- lymphocyte in the presence of several other B-lymphocytes producing non-identical antibodies. Usually, polyclonal antibodies are obtained directly from an immunized animal. A “monoclonal antibody”, as used herein, is an antibody obtained from a population of substantially homogeneous antibodies, i.e. the antibodies forming this population are essentially identical except for possible naturally occurring mutations which might be present in minor amounts. These antibodies are directed against a single epitope and are therefore highly specific. An “epitope” is the site on the antigen to which an antibody binds. If the antigen is a polymer, such as a protein or polysaccharide, the epitope can be formed by contiguous residues or by non-contiguous residues brought into close proximity by the folding of an antigenic polymer. In proteins, epitopes formed by contiguous amino acids are typically retained on exposure to denaturing solvents, whereas epitopes formed by non-contiguous amino acids are typically lost under said exposure. Docket No.10935-022WO2 As used herein, the term “KD” refers to the dissociation constant of a particular antibody / antigen interaction. The terms “antigen binding site”, “binding site” or “binding domain” of an amino acid sequence (such as an antibody, a scFv a polypeptide of the invention, or generally an antigen binding protein or polypeptide or a fragment thereof) refers to the specific elements, parts or amino acid residues of the amino acid sequence with which said amino acid sequence interacts with a specific antigenic determinant, epitope, antigen or protein (or for at least one part, fragment or epitope thereof). Accordingly, the term “CD38 binding domain” used herein refers to the specific elements, parts or amino acid residues of an amino acid sequence with which said amino acid sequence specifically bind to a CD38 or an epitope thereof. The term “variable” is used herein to describe certain portions of the variable domains that differ in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. However, the variability is not usually evenly distributed through the variable domains of antibodies. It is typically concentrated in three segments called complementarity determining regions (CDRs) or hypervariable regions both in the light chain and the heavy chain variable domains. The more highly conserved portions of the variable domains are called the framework (FR). The variable domains of native heavy and light chains each comprise four FR regions, largely adopting a beta-sheet configuration, connected by three CDRs, which form loops connecting, and in some cases forming part of, the beta-sheet structure. The CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, contribute to the formation of the antigen binding site of antibodies (see Kabat E. A. et al., “Sequences of Proteins of Immunological Interest,” National Institutes of Health, Bethesda, Md. (1987)). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity. Also disclosed herein are antigen binding molecules, wherein the antigen binding molecule comprises an antibody or epitope binding fragment thereof, and wherein the or epitope binding fragment thereof comprises at least one human constant region (such as, for example, a human IgG1 / IgKappa constant region). In some aspects the antibody comprises a humanized or resurfaced antibody. It is understood and herein contemplated that the disclosed CD38 binding molecules can be an immunotoxin. By "immunotoxin", it is meant a chimeric protein made of an antibody or modified antibody or antibody fragment (also called in the present application "antibody"), covalently linked Docket No.10935-022WO2 to a fragment of a toxin. For use with the disclosed immunotoxins, the toxin can be a maytansinoid, a small drug, a tomaymycin derivative, a leptomycin derivative, a prodrug, a toxoid (including, but not limited to tetanus toxoid), diphtheria toxin, Pseudomonas exotoxin, A chain of ricin, ribosome inactivating proteins gelonin, saporin, bouganin, pokeweed antiviral protein, dodecandron, CC-1065 and a CC-1065 analog. In one aspect, disclosed herein are immunotoxins comprises any of the antigen binding molecules disclosed herien and a cytotoxic agent (such as, for example, a maytansinoid, a small drug, a tomaymycin derivative, a leptomycin derivative, a prodrug, a toxoid (including, but not limited to tetanus toxoid), diphtheria toxin, Pseudomonas exotoxin, A chain of ricin, ribosome inactivating proteins gelonin, saporin, bouganin, pokeweed antiviral protein, dodecandron, CC-1065 and a CC-1065 analog). Thus, for example, disclosed herein is an anti-CD38 immunotoxin comprising a light chain variable region and wherein the light chain variable region comprises three complementarity determining regions (CDRs) referred to as CDR1, CDR2, and CDR3 as set forth in SEQ ID NO: 16, SEQ ID NO: 18, and SEQ ID NO: 20, respectively (such as, for example SEQ ID NO: 9) and / or a heavy chain variable region; wherein the heavy chain variable region comprises three complementarity determining regions (CDRs) referred to as CDR1, CDR2, and CDR3 as set forth in SEQ ID NO: 22, SEQ ID NO: 24, and SEQ ID NO: 26, respectively (such as, for example SEQ ID NO: 10) and a a cytotoxic agent (such as, for example, a maytansinoid, a small drug, a tomaymycin derivative, a leptomycin derivative, a prodrug, a toxoid (including, but not limited to tetanus toxoid), diphtheria toxin, Pseudomonas exotoxin, A chain of ricin, ribosome inactivating proteins gelonin, saporin, bouganin, pokeweed antiviral protein, dodecandron, CC-1065 and a CC-1065 analog). Chimeric antigen receptor (CAR) cells (such as, for example, a CAR T cell, CAR macrophage (CARMA), CAR natural killer (NK) cell, or CAR NK T) are immune cells (such as, for example T cells, macrophage, NK cells, or NK T cells) that have been modified to express a chimeric antigen receptor that targets a peptide, protein, or ligand on the surface of a target cell thereby directing the modified immune cell to the target. The extracellular domain of a typical CAR consists of the VHand VLdomains--single-chain fragment variable (scFv)--from the antigen binding sites of a monoclonal antibody. The scFv is linked to a flexible transmembrane domain followed by a tyrosine- based activation motif such as that from CD3ζ. Second and third generation CARs include additional activation domains from co-stimulatory molecules such as CD27, CD28, inducible T cell co- stimulator (ICOS), OX40, and / or CD137 (41BB) which serve to enhance T cell survival and proliferation. In one aspect, disclosed herein CAR T cells, CAR macrophage, CAR NK cells, and CAR NK T cells; wherein the CAR comprises an CD38 binding molecule comprising a light chain variable region and wherein the light chain variable region comprises three complementarity Docket No.10935-022WO2 determining regions (CDRs) referred to as CDR1, CDR2, and CDR3 as set forth in SEQ ID NO: 16, SEQ ID NO: 18, and SEQ ID NO: 20, respectively (such as, for example SEQ ID NO: 9) and / or a heavy chain variable region; wherein the heavy chain variable region comprises three complementarity determining regions (CDRs) referred to as CDR1, CDR2, and CDR3 as set forth in SEQ ID NO: 22, SEQ ID NO: 24, and SEQ ID NO: 26, respectively (such as, for example SEQ ID NO: 10). Accordingly, in some embodiments, disclosed herein is a CAR comprising a CD38 binding domain comprising SEQ ID NO: 9 and / or SEQ ID NO:10. In some embodiments, the CD38 binding domain is an antibody or an antigen-binding fragment thereof. In some embodiments, the antigen- binding fragment is a single chain variable fragment (scFv). In some aspects, disclosed herein is a recombinant nucleic acid encoding any of the antigen binding molecules disclosed herein. For example, disclosed herein are recombinant nucleic acids encoding a variable light chain (VL) or a variable heavy chain (VH), wherein the nucleic acid encodes SEQ ID NO: 12 or SEQ ID NO: 13. As used herein, “expression vector” refers to a plasmid or a virus or viral vector. A plasmid or a viral vector can be capable of extrachromosomal replication or, optionally, can integrate into the host genome. As used herein, the term "integrated" used in reference to an expression vector (e.g., a plasmid or viral vector) means the expression vector, or a portion thereof, is incorporated (physically inserted or ligated) into the chromosomal DNA of a host cell. As used herein, a “viral vector” refers to a virus-like particle containing genetic material which can be introduced into a eukaryotic cell without causing substantial pathogenic effects to the eukaryotic cell. A wide range of viruses or viral vectors can be used for transduction but should be compatible with the cell type the virus or viral vector are transduced into (e.g., low toxicity, capability to enter cells). Suitable viruses and viral vectors include adenovirus, lentivirus, retrovirus, among others. In some embodiments, the expression vector encoding a chimeric polypeptide is a naked DNA or is comprised in a nanoparticle (e.g., liposomal vesicle, porous silicon nanoparticle, gold-DNA conjugate particle, polyethyleneimine polymer particle, cationic peptides, etc.). In some aspects, disclosed herein is an expression vector, wherein the expression vector comprises a first nucleic acid encoding any of the antigen binding molecules disclosed herein, such as, for example,e a variable light chain (VL) and a second nucleic acid encoding a variable heavy chain (VH), wherein the first nucleic acid encodes SEQ ID NO: 12 and the second nucleic acid encodes SEQ ID NO: 13. A) Retroviral Vectors Docket No.10935-022WO2 A retrovirus is an animal virus belonging to the virus family of Retroviridae, including any types, subfamilies, genus, or tropisms. Retroviral vectors, in general, are described by Verma, I.M., Retroviral vectors for gene transfer. A retrovirus is essentially a package which has packed into it nucleic acid cargo. The nucleic acid cargo carries with it a packaging signal, which ensures that the replicated daughter molecules will be efficiently packaged within the package coat. In addition to the package signal, there are a number of molecules which are needed in cis, for the replication, and packaging of the replicated virus. Typically a retroviral genome, contains the gag, pol, and env genes which are involved in the making of the protein coat. It is the gag, pol, and env genes which are typically replaced by the foreign DNA that it is to be transferred to the target cell. Retrovirus vectors typically contain a packaging signal for incorporation into the package coat, a sequence which signals the start of the gag transcription unit, elements necessary for reverse transcription, including a primer binding site to bind the tRNA primer of reverse transcription, terminal repeat sequences that guide the switch of RNA strands during DNA synthesis, a purine rich sequence 5' to the 3' LTR that serve as the priming site for the synthesis of the second strand of DNA synthesis, and specific sequences near the ends of the LTRs that enable the insertion of the DNA state of the retrovirus to insert into the host genome. The removal of the gag, pol, and env genes allows for about 8 kb of foreign sequence to be inserted into the viral genome, become reverse transcribed, and upon replication be packaged into a new retroviral particle. This amount of nucleic acid is sufficient for the delivery of a one to many genes depending on the size of each transcript. It is preferable to include either positive or negative selectable markers along with other genes in the insert. Since the replication machinery and packaging proteins in most retroviral vectors have been removed (gag, pol, and env), the vectors are typically generated by placing them into a packaging cell line. A packaging cell line is a cell line which has been transfected or transformed with a retrovirus that contains the replication and packaging machinery, but lacks any packaging signal. When the vector carrying the DNA of choice is transfected into these cell lines, the vector containing the gene of interest is replicated and packaged into new retroviral particles, by the machinery provided in cis by the helper cell. The genomes for the machinery are not packaged because they lack the necessary signals. B) Adenoviral Vectors The construction of replication-defective adenoviruses has been described (Berkner et al., J. Virology 61:1213-1220 (1987); Massie et al., Mol. Cell. Biol. 6:2872-2883 (1986); Haj-Ahmad et al., J. Virology 57:267-274 (1986); Davidson et al., J. Virology 61:1226-1239 (1987); Zhang Docket No.10935-022WO2 "Generation and identification of recombinant adenovirus by liposome-mediated transfection and PCR analysis" BioTechniques 15:868-872 (1993)). The benefit of the use of these viruses as vectors is that they are limited in the extent to which they can spread to other cell types, since they can replicate within an initial infected cell, but are unable to form new infectious viral particles. Recombinant adenoviruses have been shown to achieve high efficiency gene transfer after direct, in vivo delivery to airway epithelium, hepatocytes, vascular endothelium, CNS parenchyma and a number of other tissue sites (Morsy, J. Clin. Invest. 92:1580-1586 (1993); Kirshenbaum, J. Clin. Invest. 92:381-387 (1993); Roessler, J. Clin. Invest. 92:1085-1092 (1993); Moullier, Nature Genetics 4:154-159 (1993); La Salle, Science 259:988-990 (1993); Gomez-Foix, J. Biol. Chem. 267:25129-25134 (1992); Rich, Human Gene Therapy 4:461-476 (1993); Zabner, Nature Genetics 6:75-83 (1994); Guzman, Circulation Research 73:1201-1207 (1993); Bout, Human Gene Therapy 5:3-10 (1994); Zabner, Cell 75:207-216 (1993); Caillaud, Eur. J. Neuroscience 5:1287-1291 (1993); and Ragot, J. Gen. Virology 74:501-507 (1993)). Recombinant adenoviruses achieve gene transduction by binding to specific cell surface receptors, after which the virus is internalized by receptor-mediated endocytosis, in the same manner as wild type or replication-defective adenovirus (Chardonnet and Dales, Virology 40:462-477 (1970); Brown and Burlingham, J. Virology 12:386- 396 (1973); Svensson and Persson, J. Virology 55:442-449 (1985); Seth, et al., J. Virol. 51:650-655 (1984); Seth, et al., Mol. Cell. Biol. 4:1528-1533 (1984); Varga et al., J. Virology 65:6061-6070 (1991); Wickham et al., Cell 73:309-319 (1993)). A viral vector can be one based on an adenovirus which has had the E1 gene removed and these virons are generated in a cell line such as the human 293 cell line. In another preferred embodiment both the E1 and E3 genes are removed from the adenovirus genome. C) Adeno-asscociated viral vectors Another type of viral vector is based on an adeno-associated virus (AAV). This defective parvovirus is a preferred vector because it can infect many cell types and is nonpathogenic to humans. AAV type vectors can transport about 4 to 5 kb and wild type AAV is known to stably insert into chromosome 19. Vectors which contain this site specific integration property are preferred. An especially preferred embodiment of this type of vector is the P4.1 C vector produced by Avigen, San Francisco, CA, which can contain the herpes simplex virus thymidine kinase gene, HSV-tk, and / or a marker gene, such as the gene encoding the green fluorescent protein, GFP. In another type of AAV virus, the AAV contains a pair of inverted terminal repeats (ITRs) which flank at least one cassette containing a promoter which directs cell-specific expression operably Docket No.10935-022WO2 linked to a heterologous gene. Heterologous in this context refers to any nucleotide sequence or gene which is not native to the AAV or B19 parvovirus. Typically the AAV and B19 coding regions have been deleted, resulting in a safe, noncytotoxic vector. The AAV ITRs, or modifications thereof, confer infectivity and site-specific integration, but not cytotoxicity, and the promoter directs cell-specific expression. United states Patent No.6,261,834 is herein incorporated by reference for material related to the AAV vector. D) Large payload viral vectors Molecular genetic experiments with large human herpesviruses have provided a means whereby large heterologous DNA fragments can be cloned, propagated and established in cells permissive for infection with herpesviruses (Sun et al., Nature genetics 8: 33-41, 1994; Cotter and Robertson,.Curr Opin Mol Ther 5: 633-644, 1999). These large DNA viruses (herpes simplex virus (HSV) and Epstein-Barr virus (EBV), have the potential to deliver fragments of human heterologous DNA > 150 kb to specific cells. EBV recombinants can maintain large pieces of DNA in the infected B-cells as episomal DNA. Individual clones carried human genomic inserts up to 330 kb appeared genetically stable The maintenance of these episomes requires a specific EBV nuclear protein, EBNA1, constitutively expressed during infection with EBV. Additionally, these vectors can be used for transfection, where large amounts of protein can be generated transiently in vitro. Herpesvirus amplicon systems are also being used to package pieces of DNA > 220 kb and to infect cells that can stably maintain DNA as episomes. Other useful systems include, for example, replicating and host-restricted non-replicating vaccinia virus vectors. In some aspects, disclosed herein is a cell (such as, a T-cell, natural killer (NK) cell, NK T cell, macrophage, genetically-modified T-cell, or genetically-modified NK cell) for example, expressing any of the expression vectors disclosed herein. In some embodiments, the the antigen binding molecules of any preceding aspect is cytotoxic to a CD38+cell (such as, for example, a lymphoma cell, a leukemia cell, or a multiple myeloma cell including, but not limited to a non-Hodgkin's lymphoma (NHL) cell, a Burkitt's lymphoma (BL) cell, a multiple myeloma (MM) cell, a B chronic lymphocytic leukemia (B-CLL) cell, a B and T acute lymphocytic leukemia (ALL) cell, a T cell lymphoma (TCL) cell, an acute myeloid leukemia (AML) cell, a hairy cell leukemia (HCL) cell, a Hodgkin's Lymphoma (HL) cell, or a chronic myeloid leukemia (CML) cell) by inducing apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and / or complement-dependent cytotoxicity (CDC). In some embodiments, killing said CD38+cell by apoptosis can occur in the absence of stroma cells or stroma- derived cytokines. Docket No.10935-022WO2 In some embodiments, the CD38+cell includes, but is not limited to a lymphoma cell, a leukemia cell, or a multiple myeloma cell. In some embodiments, the CD38+cell includes, but is not limited to a non-Hodgkin's lymphoma (NHL) cell, a Burkitt's lymphoma (BL) cell, a multiple myeloma (MM) cell, a B chronic lymphocytic leukemia (B-CLL) cell, a B and T acute lymphocytic leukemia (ALL) cell, a T cell lymphoma (TCL) cell, an acute myeloid leukemia (AML) cell, a hairy cell leukemia (HCL) cell, a Hodgkin's Lymphoma (HL) cell, or a chronic myeloid leukemia (CML) cell. In some embodiments, the antibody or epitope-binding fragment thereof comprises at least one human constant region, such as for example a human IgG1 / IgKappa constant region. In some embodiments, the constant region comprises a human IgG1 / IgKappa constant region. In some embodiments, the antibody comprises a humanized or resurfaced antibody. In some embodiments, the antibody or epitope-binding fragment comprises a Fab, Fab^, F(ab^)2 or Fv fragment. In some aspects, disclosed herein is a pharmaceutical composition comprising any of the cells, vectors, and / or antigen binding molecules disclosed herein and a pharmaceutically acceptable carrier. In some aspects, disclosed herein is a recombinant nucleic acid encoding the pharmaceutical composition disclosed herein. In some embodiments, the pharmaceutical composition comprises a therapeutic agent, including but not limited to antagonist of epidermal-growth factor (EGF), fibroblast-growth factor (FGF), hepatocyte growth factor (HGF), tissue factor (TF), protein C, protein S, platelet-derived growth factor (PDGF), heregulin, macrophage-stimulating protein (MSP), vascular endothelial growth factor (VEGF), a receptor for epidermal-growth factor (EGF), a receptor for fibroblast- growth factor (FGF), a receptor for hepatocyte growth factor (HGF), a receptor for tissue factor (TF), a receptor for protein C, a receptor for protein S, a receptor for platelet-derived growth factor (PDGF), a receptor for heregulin, a receptor for macrophage-stimulating protein (MSP), a receptor for vascular endothelial growth factor (VEGF); HER2 receptor, HER3 receptor, c-MET, other receptor tyrosine kinases. In some embodiments, the therapeutic agent includes, but is not limited to an antibody targeting a cluster of differentiation (CD) antigen selected from a group comprising CD3, CD14, CD19, CD20, CD22, CD25, CD28, CD30, CD38, CD36, CD40, CD44, CD52, CD55, CD59, CD56, CD70, CD79, CD80, CD103, CD134, CD137, CD138, and CD152. In some embodiments, the pharmaceutical composition comprises an acceptable carrier including, but not limited to any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations. Docket No.10935-022WO2 Methods In some aspects, disclosed herein is a method of treating, decreasing, reducing, inhibiting, ameliorating, and / or preventing a CD38-associated pathology, including but not limited to a cancer (such as, for example a leukemia, myeloma, or solid tumor), metabolic disorder (including, but not limited to diabetes mellitus Type I, diabetes mellitus Type II, familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe syndrome, metachromatic leukodystrophy, Niemann-Pick syndrome, phenylketonuria (PKU), Tay-Sachs disease, Wilson’s disease, hemachromatosis, mitochondrial disorders or diseases (including, but not limited to Alpers Disease; Barth syndrome; beta.-oxidation defects:carnitine-acyl-carnitine deficiency; carnitine deficiency; coenzyme Q10 deficiency; Complex I deficiency; Complex II deficiency; Complex III deficiency; Complex IV deficiency: Complex V deficiency; cytochrome c oxidase (COX) deficiency, LHON Leber Hereditary Optic Neuropathy; MM Mitochondrial Myopathy: LIMM Lethal Infantile Mitochondrial Myopathy; MMC Maternal Myopathy and Cardiomyopathy; NARP Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa; Leigh Disease: FICP—Fatal Infantile Cardiomyopathy Plus, a MELAS-associated cardiomyopathy: MELAS Mitochondrial Encephalomyopathy with Lactic Acidosis and Strokelike episodes; LDYT Leber's hereditary optic neuropathy and Dystonia; MERRF Myoclonic Epilepsy and Ragged Red Muscle Fibers; MHCM Maternally inherited Hypertrophic CardioMyopathy; CPEO Chronic Progressive External Opthalmoplegia; KSS Kearns Sayre Syndrome; DM Diabetes Mellitus; DMDF Diabetes Mellitus+DeaFness; CIPO Chronic Intestinal Pseudoobstruction with myopathy and Opthalmoplegia; DEAF Maternally inherited DEAFness or aminoglycoside-induced DEAFness; PEM Progressive encephalopathy; SNHL SensoriNeural Hearing Loss; Encephalomyopathy; Mitochondrial cytopathy: Dilated Cardiomyopathy: GER Gastrointestinal Reflux: DEMCHO Dementia and Chorea; AMDF Ataxia, Myoclonus; Exercise Intolerance: ESOC Epilepsy, Strokes, Optic atrophy, & Cognitive decline; FBSN Familial Bilateral Striatal Necrosis: FSGS Focal Segmental Glomerulosclerosis: LIMM Lethal Infantile Mitochondrial Myopathy; MDM Myopathy and Diabetes Mellitus: MEPR Myoclonic Epilepsy and Psychomotor Regression; MERME MERRF / MELAS overlap disease; MHCM Maternally Inherited Hypertrophic CardioMyopathy; MICM Maternally Inherited Cardiomyopathy; MILS Maternally Inherited Leigh Syndrome; Mitochondrial Encephalocardiomyopathy; Multisystem Mitochondrial Disorder (myopathy, encephalopathy, blindness, hearing loss, peripheral neuropathy); NAION Nonarteritic Anterior Ischemic Optic Neuropathy; NIDDM Non-Insulin Dependent Diabetes Mellitus; PEM Progressive Encephalopathy; PME Progressive Myoclonus Epilepsy; RTT Rett Syndrome: SIDS Sudden Infant Death Syndrome: MIDD Maternally Inherited Diabetes and Deafness; and MODY Docket No.10935-022WO2 Maturity-Onset Diabetes of the Young, and MNGIE), and other metabolic diseases), inflammatory disorder, endothelial disorder, virus susceptibility, neurological disorder (including, but not limited to Alzheimer’s disease, ataxia, Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Friedreich ataxia, Lewy body disease, spinal muscular atrophy, Alpers’ disease, Batten disease, Cerebro-oculo-facio-skeletal syndrome, Leigh syndrome, Prion diseases, monomelic amyotrophy, multiple system atrophy, striatonigral degeneration, motor neuron disease, multiple sclerosis (MS), Creutzfeldt-Jakob disease, Parkinsonism, spinocerebellar ataxia, dementia, and other related diseases), or aging in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of any of the pharmaceutical compositions, antigen binding molecules, nucleic acids, vectors, or cells disclosed herein. For example, disclosed herein is a method of treating, decreasing, reducing, inhibiting, ameliorating, and / or preventing a CD38-associated pathology, including but not limited to a cancer (such as, for example a leukemia, myeloma, or solid tumor), metabolic disorder (including, but not limited to diabetes mellitus Type I, diabetes mellitus Type II, familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe syndrome, metachromatic leukodystrophy, Niemann-Pick syndrome, phenylketonuria (PKU), Tay-Sachs disease, Wilson’s disease, hemachromatosis, mitochondrial disorders or diseases (including, but not limited to Alpers Disease; Barth syndrome; beta.-oxidation defects:carnitine-acyl-carnitine deficiency; carnitine deficiency; coenzyme Q10 deficiency; Complex I deficiency; Complex II deficiency; Complex III deficiency; Complex IV deficiency: Complex V deficiency; cytochrome c oxidase (COX) deficiency, LHON Leber Hereditary Optic Neuropathy; MM Mitochondrial Myopathy: LIMM Lethal Infantile Mitochondrial Myopathy; MMC Maternal Myopathy and Cardiomyopathy; NARP Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa; Leigh Disease: FICP—Fatal Infantile Cardiomyopathy Plus, a MELAS-associated cardiomyopathy: MELAS Mitochondrial Encephalomyopathy with Lactic Acidosis and Strokelike episodes; LDYT Leber's hereditary optic neuropathy and Dystonia; MERRF Myoclonic Epilepsy and Ragged Red Muscle Fibers; MHCM Maternally inherited Hypertrophic CardioMyopathy; CPEO Chronic Progressive External Opthalmoplegia; KSS Kearns Sayre Syndrome; DM Diabetes Mellitus; DMDF Diabetes Mellitus+DeaFness; CIPO Chronic Intestinal Pseudoobstruction with myopathy and Opthalmoplegia; DEAF Maternally inherited DEAFness or aminoglycoside-induced DEAFness; PEM Progressive encephalopathy; SNHL SensoriNeural Hearing Loss; Encephalomyopathy; Mitochondrial cytopathy: Dilated Cardiomyopathy: GER Gastrointestinal Reflux: DEMCHO Dementia and Chorea; AMDF Ataxia, Myoclonus; Exercise Intolerance: ESOC Epilepsy, Strokes, Optic atrophy, & Cognitive decline; FBSN Familial Bilateral Striatal Necrosis: FSGS Focal Docket No.10935-022WO2 Segmental Glomerulosclerosis: LIMM Lethal Infantile Mitochondrial Myopathy; MDM Myopathy and Diabetes Mellitus: MEPR Myoclonic Epilepsy and Psychomotor Regression; MERME MERRF / MELAS overlap disease; MHCM Maternally Inherited Hypertrophic CardioMyopathy; MICM Maternally Inherited Cardiomyopathy; MILS Maternally Inherited Leigh Syndrome; Mitochondrial Encephalocardiomyopathy; Multisystem Mitochondrial Disorder (myopathy, encephalopathy, blindness, hearing loss, peripheral neuropathy); NAION Nonarteritic Anterior Ischemic Optic Neuropathy; NIDDM Non-Insulin Dependent Diabetes Mellitus; PEM Progressive Encephalopathy; PME Progressive Myoclonus Epilepsy; RTT Rett Syndrome: SIDS Sudden Infant Death Syndrome: MIDD Maternally Inherited Diabetes and Deafness; and MODY Maturity-Onset Diabetes of the Young, and MNGIE), and other metabolic diseases), inflammatory disorder, endothelial disorder, virus susceptibility, neurological disorder (including, but not limited to Alzheimer’s disease, ataxia, Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Friedreich ataxia, Lewy body disease, spinal muscular atrophy, Alpers’ disease, Batten disease, Cerebro-oculo-facio-skeletal syndrome, Leigh syndrome, Prion diseases, monomelic amyotrophy, multiple system atrophy, striatonigral degeneration, motor neuron disease, multiple sclerosis (MS), Creutzfeldt-Jakob disease, Parkinsonism, spinocerebellar ataxia, dementia, and other related diseases), or aging in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a CD38 specific antigen binding molecule (such as, for example a chimeric antigen receptor (CAR), immunotoxin, or an antibody or epitope binding fragment thereof including, but not limited to scFv, Fab, Fab^, F(ab^)2 or Fv fragment) comprising light chain complementarity determining regions (CDR) 1(CDR-L1), CDR-L2, and CDR-L3 as set forth in SEQ ID NO: 16, SEQ ID NO: 18, and SEQ ID NO: 20, respectively (including, but not limited to SEQ ID NO: 9) and / or heavy CDR-H1, CDR-H2, and CDR-H3 as set forth in SEQ ID NO: 22, SEQ ID NO: 24, and SEQ ID NO: 26, respectively (including, but not limited to SEQ ID NO: 10), pharmaceutical composition comprising said antigen binding molecule, nucleic acid encoding said antigen binding molecule, vector encoding said nucleic acid or cell comprising said nucleic acid, vector, or antigen binding molecule. In some embodiments, the CD-38-associated pathology includes, but is not limited to non- Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic B lymphocytic leukemia, acute B and T lymphocytic leukemia, T cell lymphoma, acute myeloid leukemia, hairy cell leukemia, Hodgkin's Lymphoma, or chronic myelogenous leukemia. In many cancers, including, but not limited to leukemias and lymphomas, the cells remain or are “stuck” in an immature state, wherein said cells are highly proliferative. Recent work has Docket No.10935-022WO2 identified retinoids, such as for example all-trans retinoic acid (ATRA), as a therapeutic agent used to treat leukemias and lymphomas. Retinoids are vitamin A derivatives the work by causing abnormal cancer cells, which are “stuck” in an immature state, to mature and differentiate, which stops the growth and / or hyperproliferation of the cancer. Thus, the present disclosure provides methods of treating, decreasing, reducing, inhibiting, ameliorating, and / or preventing a CD38-associated pathology, including but not limited to a cancer (such as, for example a leukemia, myeloma, or solid tumor), metabolic disorder (including, but not limited to diabetes mellitus Type I, diabetes mellitus Type II, familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe syndrome, metachromatic leukodystrophy, Niemann-Pick syndrome, phenylketonuria (PKU), Tay-Sachs disease, Wilson’s disease, hemachromatosis, mitochondrial disorders or diseases (including, but not limited to Alpers Disease; Barth syndrome; beta.-oxidation defects:carnitine-acyl-carnitine deficiency; carnitine deficiency; coenzyme Q10 deficiency; Complex I deficiency; Complex II deficiency; Complex III deficiency; Complex IV deficiency: Complex V deficiency; cytochrome c oxidase (COX) deficiency, LHON Leber Hereditary Optic Neuropathy; MM Mitochondrial Myopathy: LIMM Lethal Infantile Mitochondrial Myopathy; MMC Maternal Myopathy and Cardiomyopathy; NARP Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa; Leigh Disease: FICP—Fatal Infantile Cardiomyopathy Plus, a MELAS-associated cardiomyopathy: MELAS Mitochondrial Encephalomyopathy with Lactic Acidosis and Strokelike episodes; LDYT Leber's hereditary optic neuropathy and Dystonia; MERRF Myoclonic Epilepsy and Ragged Red Muscle Fibers; MHCM Maternally inherited Hypertrophic CardioMyopathy; CPEO Chronic Progressive External Opthalmoplegia; KSS Kearns Sayre Syndrome; DM Diabetes Mellitus; DMDF Diabetes Mellitus+DeaFness; CIPO Chronic Intestinal Pseudoobstruction with myopathy and Opthalmoplegia; DEAF Maternally inherited DEAFness or aminoglycoside-induced DEAFness; PEM Progressive encephalopathy; SNHL SensoriNeural Hearing Loss; Encephalomyopathy; Mitochondrial cytopathy: Dilated Cardiomyopathy: GER Gastrointestinal Reflux: DEMCHO Dementia and Chorea; AMDF Ataxia, Myoclonus; Exercise Intolerance: ESOC Epilepsy, Strokes, Optic atrophy, & Cognitive decline; FBSN Familial Bilateral Striatal Necrosis: FSGS Focal Segmental Glomerulosclerosis: LIMM Lethal Infantile Mitochondrial Myopathy; MDM Myopathy and Diabetes Mellitus: MEPR Myoclonic Epilepsy and Psychomotor Regression; MERME MERRF / MELAS overlap disease; MHCM Maternally Inherited Hypertrophic CardioMyopathy; MICM Maternally Inherited Cardiomyopathy; MILS Maternally Inherited Leigh Syndrome; Mitochondrial Encephalocardiomyopathy; Multisystem Mitochondrial Disorder (myopathy, encephalopathy, blindness, hearing loss, peripheral neuropathy); NAION Nonarteritic Anterior Docket No.10935-022WO2 Ischemic Optic Neuropathy; NIDDM Non-Insulin Dependent Diabetes Mellitus; PEM Progressive Encephalopathy; PME Progressive Myoclonus Epilepsy; RTT Rett Syndrome: SIDS Sudden Infant Death Syndrome: MIDD Maternally Inherited Diabetes and Deafness; and MODY Maturity-Onset Diabetes of the Young, and MNGIE), and other metabolic diseases), inflammatory disorder, endothelial disorder, virus susceptibility, neurological disorder (including, but not limited to Alzheimer’s disease, ataxia, Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Friedreich ataxia, Lewy body disease, spinal muscular atrophy, Alpers’ disease, Batten disease, Cerebro-oculo-facio-skeletal syndrome, Leigh syndrome, Prion diseases, monomelic amyotrophy, multiple system atrophy, striatonigral degeneration, motor neuron disease, multiple sclerosis (MS), Creutzfeldt-Jakob disease, Parkinsonism, spinocerebellar ataxia, dementia, and other related diseases), or aging in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of any of the pharmaceutical compositions, antigen binding molecules, nucleic acids, vectors, or cells disclosed herein in combination with an all-trans retinoic acid (ATRA). In some aspects, disclosed herein is a method of improving cancer cell / tumor / load reduction, the method comprising administering to a subject in need thereof, of any of the pharmaceutical compositions, antigen binding molecules, nucleic acids, vectors, or cells disclosed herein in combination with all-trans retinoic acid (ATRA). In some aspect, disclosed herein is a method of treating, decreasing, reducing, inhibiting, ameliorating, and / or preventing a CD38-associated pathology, including but not limited to a cancer (such as, for example a leukemia, myeloma, or solid tumor), metabolic disorder (including, but not limited to diabetes mellitus Type I, diabetes mellitus Type II, familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe syndrome, metachromatic leukodystrophy, Niemann-Pick syndrome, phenylketonuria (PKU), Tay-Sachs disease, Wilson’s disease, hemachromatosis, mitochondrial disorders or diseases (including, but not limited to Alpers Disease; Barth syndrome; beta.-oxidation defects:carnitine-acyl-carnitine deficiency; carnitine deficiency; coenzyme Q10 deficiency; Complex I deficiency; Complex II deficiency; Complex III deficiency; Complex IV deficiency: Complex V deficiency; cytochrome c oxidase (COX) deficiency, LHON Leber Hereditary Optic Neuropathy; MM Mitochondrial Myopathy: LIMM Lethal Infantile Mitochondrial Myopathy; MMC Maternal Myopathy and Cardiomyopathy; NARP Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa; Leigh Disease: FICP—Fatal Infantile Cardiomyopathy Plus, a MELAS-associated cardiomyopathy: MELAS Mitochondrial Encephalomyopathy with Lactic Acidosis and Strokelike episodes; LDYT Leber's hereditary optic neuropathy and Dystonia; MERRF Docket No.10935-022WO2 Myoclonic Epilepsy and Ragged Red Muscle Fibers; MHCM Maternally inherited Hypertrophic CardioMyopathy; CPEO Chronic Progressive External Opthalmoplegia; KSS Kearns Sayre Syndrome; DM Diabetes Mellitus; DMDF Diabetes Mellitus+DeaFness; CIPO Chronic Intestinal Pseudoobstruction with myopathy and Opthalmoplegia; DEAF Maternally inherited DEAFness or aminoglycoside-induced DEAFness; PEM Progressive encephalopathy; SNHL SensoriNeural Hearing Loss; Encephalomyopathy; Mitochondrial cytopathy: Dilated Cardiomyopathy: GER Gastrointestinal Reflux: DEMCHO Dementia and Chorea; AMDF Ataxia, Myoclonus; Exercise Intolerance: ESOC Epilepsy, Strokes, Optic atrophy, & Cognitive decline; FBSN Familial Bilateral Striatal Necrosis: FSGS Focal Segmental Glomerulosclerosis: LIMM Lethal Infantile Mitochondrial Myopathy; MDM Myopathy and Diabetes Mellitus: MEPR Myoclonic Epilepsy and Psychomotor Regression; MERME MERRF / MELAS overlap disease; MHCM Maternally Inherited Hypertrophic CardioMyopathy; MICM Maternally Inherited Cardiomyopathy; MILS Maternally Inherited Leigh Syndrome; Mitochondrial Encephalocardiomyopathy; Multisystem Mitochondrial Disorder (myopathy, encephalopathy, blindness, hearing loss, peripheral neuropathy); NAION Nonarteritic Anterior Ischemic Optic Neuropathy; NIDDM Non-Insulin Dependent Diabetes Mellitus; PEM Progressive Encephalopathy; PME Progressive Myoclonus Epilepsy; RTT Rett Syndrome: SIDS Sudden Infant Death Syndrome: MIDD Maternally Inherited Diabetes and Deafness; and MODY Maturity-Onset Diabetes of the Young, and MNGIE), and other metabolic diseases), inflammatory disorder, endothelial disorder, virus susceptibility, neurological disorder (including, but not limited to Alzheimer’s disease, ataxia, Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Friedreich ataxia, Lewy body disease, spinal muscular atrophy, Alpers’ disease, Batten disease, Cerebro-oculo-facio-skeletal syndrome, Leigh syndrome, Prion diseases, monomelic amyotrophy, multiple system atrophy, striatonigral degeneration, motor neuron disease, multiple sclerosis (MS), Creutzfeldt-Jakob disease, Parkinsonism, spinocerebellar ataxia, dementia, and other related diseases), or aging in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount a therapeutically effective amount of any of the pharmaceutical compositions, antigen binding molecules, nucleic acids, vectors, or cells disclosed herein in combination with an anti-cancer agent, including, but not limited to a chemotherapeutic agent. In some aspects, disclosed herein is a method of improving cancer cell / tumor load reduction, the method comprising administering to a subject in need thereof, a therapeutically effective amount of any of the pharmaceutical compositions, antigen binding molecules, nucleic acids, vectors, or cells disclosed herein in combination with an anti-cancer agent, including, but not limited to a Docket No.10935-022WO2 chemotherapeutic agent. Exemplary biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon ^, interferon ^), vaccines, hematopoietic growth factors, monoclonal serotherapy, immunostimulants and / or immunodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) and antibodies (e.g. HERCEPTIN (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab)). In some embodiments, the PD-L1 inhibitor includes, but is not limited to Atezolizumab, Avelumab, Durvalumab, LY3300054 (Eli Lilly and Company), and monoclonal antibodies or monoclonal antibody conjugates that act as a PD-L1 inhibitor. In some embodiments, the PD-1 inhibitor includes, but is not limited to pembrolizumab, Nivolumab, Cemiplimab and monoclonal antibodies or monoclonal antibody conjugates that act as a PD-1 inhibitors. In some embodiments, the CTLA-4 inhibitor includes, but is not limited to Ipilimumab, AGEN1884 and monoclonal antibodies or monoclonal antibody conjugates that act as a CTLA-4 inhibitor. Exemplary chemotherapeutic agents include, but are not limited to, anti-estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g. goscrclin and leuprolide), anti-androgens (e.g. flutamide and bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g. carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g. busulfan and treosulfan), triazenes (e.g. dacarbazine, temozolomide), platinum containing compounds (e.g. cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g. paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel (ABRAXANE), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose- conjugated paclitaxel, e.g., 2^-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors (e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonucleotide reductase inhibitors (e.g. hydroxyurea and deferoxamine), uracil analogs (e.g.5-fluorouracil (5-FU), floxuridine, doxifluridine, Docket No.10935-022WO2 ratitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g. cytarabine (ara C), cytosine arabinoside, and fludarabine), purine analogs (e.g. mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g. 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g. staurosporine), actinomycin (e.g. actinomycin D, dactinomycin), bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline (e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g. verapamil), Ca2+ATPase inhibitors (e.g. thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP- 701), neratinib (HKI-272), nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK / ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD- 2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and / or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), oblimersen, gemcitabine, caminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, caminomycin, aminopterin, and hexamethyl melamine. The treatment methods can include or further include checkpoint inhibitors including, but are not limited to antibodies that block PD-1 (such as, for example, Nivolumab (BMS-936558 or MDX1106), pembrolizumab, cemiplimab , CT-011, MK- 3475), PD-L1 (such as, for example, atezolizumab, avelumab, durvalumab, MDX-1105 (BMS- 936559), MPDL3280A, or MSB0010718C), PD-L2 (such as, for example, rHIgM12B7), CTLA-4 Docket No.10935-022WO2 (such as, for example, Ipilimumab (MDX-010), Tremelimumab (CP-675,206)), IDO, B7-H3 (such as, for example, MGA271, MGD009, omburtamab), B7-H4, B7-H3, T cell immunoreceptor with Ig and ITIM domains (TIGIT)(such as, for example BMS-986207, OMP-313M32, MK-7684, AB-154, ASP-8374, MTIG7192A, or PVSRIPO), CD96, B- and T-lymphocyte attenuator (BTLA), V-domain Ig suppressor of T cell activation (VISTA)(such as, for example, JNJ-61610588, CA-170), TIM3 (such as, for example, TSR-022, MBG453, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, RO7121661), LAG-3 (such as, for example, BMS-986016, LAG525, MK-4280, REGN3767, TSR-033, BI754111, Sym022, FS118, MGD013, and Immutep). It should be understood that any of the pharmaceutical compositions, antigen binding molecules, nucleic acids, vectors, and / or cells disclosed herein may be administered in such amounts, time, and route deemed necessary in order to achieve the desired result. The exact amount of the pharmaceutical compositions, antigen binding molecules, nucleic acids, vectors, and / or cells will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease or disorder, the particular pharmaceutical compositions, antigen binding molecules, nucleic acids, vectors, and / or cells, its mode of administration, its mode of activity, and the like. The pharmaceutical composition is preferably formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the pharmaceutical composition will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disease or disorder being treated and the severity of the disease or disorder; the activity of the pharmaceutical composition employed; the specific pharmaceutical composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific pharmaceutical composition employed; the duration of the treatment; drugs used in combination or coincidental with the specific pharmaceutical composition employed; and like factors well known in the medical arts. The pharmaceutical compositions, antigen binding molecules, nucleic acids, vectors, and / or cells disclosed herein of may be administered by any route. In some embodiments, the pharmaceutical compositions, antigen binding molecules, nucleic acids, vectors, and / or cell are administered via a variety of routes, including oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, enteral, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, Docket No.10935-022WO2 and / or aerosol. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the pharmaceutical composition (e.g., its stability in the environment of the gastrointestinal tract), the condition of the subject (e.g., whether the subject is able to tolerate oral administration), etc. The exact amount of pharmaceutical composition required to achieve a therapeutically effective amount will vary from subject to subject, depending on species, age, and general condition of a subject, severity of the side effects, identity of the particular compound(s), mode of administration, and the like. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. In one aspect, disclosed herein is a pharmaceutical composition and a pharmaceutically acceptable carrier selected from an excipient, a diluent, a salt, a buffer, a stabilizer, a lipid, an emulsion, a nanoparticle, and a cream. One or more active agents can be administered in the “native” form or, if desired in the form of salts, esters, amides, prodrugs, or a derivative that is pharmacologically suitable. Salts, esters, amides, prodrugs, and other derivatives of the active agents can be prepared using standards procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by March (1992) Advanced Organic Chemistry; Reactions, Mechanisms, and Structure, 4thEd. N.Y. Wiley-Interscience. In some embodiments, the pharmaceutical compositions, antigen binding molecules, nucleic acids, vectors, and / or cells are administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or more times. In some embodiments, the pharmaceutical compositions, antigen binding molecules, nucleic acids, vectors, and / or cells are administered daily. In some embodiments, the pharmaceutical compositions, antigen binding molecules, nucleic acids, vectors, and / or cells are administered every day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, or more. In some embodiments, the pharmaceutical compositions, antigen binding molecules, nucleic acids, vectors, and / or cells are administered every week, every 2 weeks, every 3 weeks, every 4 weeks, or more. In some embodiments, the pharmaceutical compositions, antigen binding molecules, nucleic acids, vectors, and / or cells are administered every month, every 2 months, every 3 months, every 4 months, every 5 months, every 6 months, every 7 months, every 8 months, every 9 months, every 10 months, every 11 months, every 12 months, or more. In some embodiments, the Docket No.10935-022WO2 pharmaceutical compositions, antigen binding molecules, nucleic acids, vectors, and / or cells are administered every year, every 2 years, every 3 years, every 4 years, every 5 years, or more. A number of embodiments of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. By way of non-limiting illustration, examples of certain embodiments of the present disclosure are given below. EXAMPLES The following examples are set forth below to illustrate the compositions, devices, methods, and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods and results. These examples are not intended to exclude equivalents and variations of the present invention which are apparent to one skilled in the art. Example 1. Adeno-Associated Virus AAV Integration Site 1 (AAVS1) The following description, based on: www.cell.com / cell-reports- methods / pdfExtended / S2667-2375(22)00105-9, is a production step for the current compositions. Targeting a genomic safe harbor for gene insertion For gene insertion in NK cells, we chose the adeno-associated virusAAV integration site 1 (AAVS1), which is an exemplary genomic safe- harbor locus within the phosphatase 1 regulatory subunit 12C (PPP1R12C) gene (Oceguera-Yanez et al., 2016; Mali et al., 2013). Chromatin accessibility of AAVS1 was similar in naive and day 7 expanded NK cells (n = 2) as determined by assay for transposase-accessible chromatin (ATAC)-seq. Next, AAVS1 was targeted by electroporation of Cas9 / RNP into day 7 expanded NK cells using previously optimized electroporation parameters that yield high NK cell editing efficiency (>80%) and viability (>90%) (Naeimi Kararoudi et al., 2018, 2020a). We did not observe any impact of AAVS1 deletion on NK cell cytotoxicity against AML . After 48 h, the frequency of insertions and deletions (indels) in CRISPR-edited NK cells was determined using Inference of CRISPR Edits (ICE) using primers flanking the AAVS1 locus (Hsiau et al., 2018). The ICE results showed that up to 85% of CRISPR-modified NK cells had at least one indel at the AAVS1 Cas9-targeting site. Example 2. Production method for CAR-NK expressing CD38 scFv The following description, based on: www.cell.com / cell-reports- Docket No.10935-022WO2 methods / pdfExtended / S2667-2375(22)00105-9, which is a production method for the current compositions. Gene insertion in primary human NK cells using single-stranded AAV6 and Cas9 / RNP To compare the efficiency of gene insertion across DNA-repair mechanisms, we generated a parallel series of AAV6 vectors suitable for HDR-mediated gene insertion using both single-stranded and self-complementary designs with varying homology arm lengths and for NHEJ-mediated gene insertion with CRISPaint containing PAMgPAMg sequences. To maximize HDR-mediated gene insertion, we identified homology arms (HAs) for the right and left sides of the flanking regions of the Cas9 targeting site in the AAVS1 locus, cloned these together with the mCherry gene into the backbone of a single-stranded AAV plasmid, and packaged this construct into the AAV6 viral capsid (Foust et al., 2013; Wang et al., 2016; Eyquem et al., 2017). It has been shown that the efficiency of recombination increases as the length of HAs increases (Ran et al., 2013; MacLeod et al., 2017; He et al., 2016; Song and Stieger, 2017; Li et al., 2014). Therefore, for the single-stranded AAV (ssAAV) backbone, we used the longest possible length of the left and right HAs for mCherry (800–1,000 bp of HAs; sequences provided. The constructs also contained a splice acceptor downstream of the transgene to improve the transcription of the mCherry gene. Electroporation of the NK cells with Cas9 / RNP targeting AAVS1 followed 30 min later by AAV transduction (Pomeroy et al., 2020) resulted in 17% (300,000 multiplicities of infection [MOIs]) and 19% (500,000 MOIs) mCherry-positive NK cells. We further expanded these cells for 1 week using FC21, enriched the mCherry-positive cells by fluorescence-activated cell sorting (FACS), and did not see any reduction in the expression level of mCherry during an additional 30 days of expansion, demonstrating stable integration. Improved gene insertion by using self-complementary AAV6 and Cas9 / RNP After transduction, scAAV vectors can acquire the necessary double-stranded state in a shorter time frame than ssAAV, which may impact the efficiency of gene insertion. Due to the size limitation of packaging transgenes in scAAV, we designed HAs of varying lengths to minimize the size needed for scAAV backbones. Hence, HAs of 30, 300, 500, and 1,000 bp length for the right and 30, 300, 500, and 800 bp for the left were cloned with mCherry into the scAAV backbone and packaged into AAV6 capsid. We then followed the same steps as for the ssAAV above to electroporate and transduce the day 7 expanded NK cells. scAAV with HAs R300 bp showed markedly increased efficiency of gene transfer at >80%. Stable mCherry gene expression was observed for at least 3 weeks of additional NK cell expansion. When we used the same approach in freshly isolated NK cells, mCherry expression was significantly lower (1.13% for 800 bp ssAAV6; 2.9% for self-complementary [sc] 300 bp scAAV6. CRISPaint for gene insertion in NK Docket No.10935-022WO2 cells. To overcome the complexity of HA optimization seen in HDR-directed gene insertion, we tested a homology-independent gene-insertion approach called CRISPaint. For the CRISPaint DNA templates, we incorporated double Cas9-targeting sequences of AAVS1 (PAMgPAMg) around the mCherry transgene but within the inverted terminal repeats (ITRs) of scAAV and packaged it into AAV6. Two days after electroporation and transduction, we performed flow cytometry to assess mCherry expression in NK cells. The cells that were electroporated and transduced with 300,000 MOIs of scAAV6 delivering CRISPaint PAMgPAMg were found to be up to 6% mCherry positive. We further sorted and enriched these NK cells and expanded them for 30 days and saw no decline in the percentage that were mCherry positive. Although we saw lower efficiency of gene integration using CRISPaint compared with HDR-directed gene insertion, this method may still be useful because it allows integration into a user-defined locus without designing HAs. Generation of human primary CD38-CAR NK cells We tested two CAR constructs comprising the same CD38- targeting single-chain variable fragment (scFv) but with a CD4 transmembrane domain and CD28 / CD3z signaling domain (Gen2) or an NKG2D transmembrane domain and 2B4 / CD3z signaling domain (Gen4v2) (Li et al., 2018). The CAR constructs were too large for suitable packaging into the scAAV backbone, so they were cloned into the ssAAV backbone with the largest possible HAs of 600 bp. To improve the expression of the CARs, we also incorporated a murine leukemia virus-derived promoter (MND) before the start codon of the CARs instead of the splice acceptor. As with the mCherry vectors, these were packaged into the AAV6 capsid. Seven days after electroporation and transduction, we detected up to 78% CD38 CAR-expressing NK cells (mean 59.3% for Gen2 and 60% for Gen4v2). Of note, the CD38CAR-Gen2 resulted in a higher level of expression on NK cells compared with Gen4v2. We expanded the cells for another week (day 14) and observed no significant reduction in CAR expression or proliferative potential, suggesting that neither the AAV6 transduction event nor the CAR expression impacted NK cell proliferation or survival. Efficient CAR integration (>60%) was also observed with MOIs as low as 10,000, and toxicity of the AAV6 transduction was not observed across the MOIs tested. Detection of the transgene at the targeted AAVS1 locus and unintended insertion sites Using PCR with primers to flanking and inter-transgenic regions, we confirmed the DNA integration of the transgenes. Additionally, targeted locus amplification (TLA) was used for whole-genome mapping of CD38CAR-Gen2 integration in CAR-expressing NK cells with a sensitivity of detecting random integrations of more than 5%. As seen, the vector has integrated as intended in human chromosome chr19: 55,115,754– 55,115,767, which is in intron 1 of PPP1R12C. Other integration sites were observed between chr19: 55,115,155– 55,116,371, which is also in intron 1 of PPP1R12C. Sequence Docket No.10935-022WO2 variants and structural variants were identified in the covered regions. There was no indication of a dominant secondary off-target integration site. One sequence variant and four structural variants were detected. The frequency of detection suggests this variant was present within the AAV6 vector itself. Overall, the TLA demonstrated high prevalence of vector integration at the targeted location in chromosome 19, with low-level random integrations identified throughout the genome. Human primary CAR-NK cells have enhanced antitumor activity. To determine whether the CD38CAR enhanced NK cell killing of AML cells, we performed a calcein-AM-based cytotoxicity assay with two CD38-expressing AML cell lines (Kasumi-1 and HL60) and one patient-derived sample (AML10) using CD38CAR-NK cells generated from three different healthy individuals. CD38CAR-gen2 and -gen4v2 NK cells showed a significantly higher degranulation and target cell lysis when co-cultured with Kasumi-1 or HL60 cell lines compared with wild-type or AAVS1KO NK cells. Importantly, we showed significantly higher antitumor activity of CD38CAR NK cells against AML-10, a primary human AML sample derived from a patient with relapsed and refractory AML (Dutour et al., 2012; Somanchi et al., 2011). Overall, CD38CAR-Gen2 NK showed better cytotoxicity compared with CD38CAR-Gen4v2 NK cells. Due to the higher antitumor activity of CD38CAR-Gen2, we only used these CAR-NK cells for the rest of the functional assessments. Using real-time assessment of cytotoxicity (xCELLigence), we showed that CD38CAR-Gen2- NK cells kill the CD38-expressing AML cells more completely and with faster kinetics than the same donor wild-type (WT) NK cells. CD38CAR-Gen2 NK cells also showed significantly higher secretion of interferon gamma (IFNg) and tumor necrosis factor alpha (TNF-a) when co-cultured with Kasumi-1 compared with non-modified NK cells. Mass cytometry showed enhanced killing and specificity of CD38CAR-NK cells against AML We previously used the combination of pRb and cleaved PARP (Behbehani et al., 2012; Devine et al., 2021) to enable very accurate detection of dead or dying cells in mass cytometry with a wide variety of other extracellular and intracellular markers. Here, we used the same approach to measure the ability of CAR-NK cells to kill AML cells. WT or CD38Gen2-CAR NK cells generated from one donor were co-cultured with primary AML and then assessed for viability across multiple cell populations. Four main populations were identified by both manual gating and SPADE clustering: live proliferating NK cells, quiescent NK cells, live proliferating AML cells, and dying AML cells. At 3 h, control primary AML cells were 66% viable, whereas viability decreased to 56% when co-cultured with WT-NK cells and only 21% when co-cultured with CD38CAR NK cells. At 24 h, control primary AML cells recovered to 89% viability compared with 76% when co-cultured with WT-NK cells and only 42% when co- cultured with CD38CAR NK cells. At 3 h, the surviving AML cells had a 20-fold reduction in CD38 Docket No.10935-022WO2 expression when cultured with the CD38CAR NK cells (median of 104 counts down to 5 counts), while there was minimal change in CD38 expression in the WT NK cell co-culture (median of 104 counts down to 87 counts). This difference persisted at 24 h, at which time the median CD38 counts were 25 for CD38CAR NK cells, 118 for WT NK cells, and 120 in control AML without NK cells. Co- culture with AML also increased NK activation markers (CD69, CD99, CD71, NKG2D, CD16, and CD45) at 24 h compared with the NK cells cultured alone. The CD38CAR NK cells had lower levels of activation markers at baseline that increased more with co-culture. Together, these data show that CD38CAR-NK cells specifically target CD38-expressing AML and are more activated by the AML targets compared with WT-NK cells. It will be apparent to those skilled in the art that various modifications and variations can be made in the present disclosure without departing from the scope or spirit of the invention. Other embodiments of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the methods disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

[0002] Docket No.10935-022WO2 SEQUENCES 1. SEQ ID NO: 1 - CD38 CAR Heavy Chain 25A10-V1 QLQQSGAELVRPGASVKLSCTASGFNWVKQRPEQGLEWIGWIDPEDDKTKYAPKFQDKAT LTADTSSNTAYLQLSTLTSEDTAIYYCVSRYINYYFAYWGQGTTLTVSS 2. SEQ ID NO: 2 - CD38 CAR Heavy Chain 25A10-V2 and 25A10-V3 QLQQSGAELVRPGASVKLSCTASGFNIKDSLIHWVKQRPEQGLEWIGWIDPEDDKTKYAPK FQD KATLTADTSSNTAYLQLSTLTSEDTAIYYCVSRYINYYFAYWGQGTTLTVSS 3. SEQ ID NO: 3 - CD38 CAR Light Chain 25A10-V1, 2, and 3 DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLHSGNQRNYLTWYQQKPGQPPKLLIYWASTRE SGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYDYPYTFGGGTKLEIK 4. SEQ ID NO: 4 - CD38 Variable Heavy Chain (SEQ ID NO: 2) and Variable Light Chain (SEQ ID NO: 3) incorporated into full CAR construct MLLLVTSLLLCELPHPAFLLIPDIVMTQSPSSLTVTAGEKVTMSCKSSQSLLHSGNQRNYLTW YQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYDYPYT FGGGTKLEIKGSTSGSGKPGSGEGSTKGQLQQSGAELVRPGASVKLSCTASGFNIKDSLIHW VKQRPEQGLEWIGWIDPEDDKTKYAPKFQDKATLTADTSSNTAYLQLSTLTSEDTAIYYCVS RYINYYFAYWGQGTTLTVSSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLS LSLGKMFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRGGHSDYMNMTPRRPGPTRKHY QPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMG GKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALH MQALPPR 5. SEQ ID NO: 5 - IgG4 stalk and hinge domain ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVD GVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKG QPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG Docket No.10935-022WO2 6. SEQ ID NO: 6 – CD28 transmembrane and costimulatory domain KMFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRGGHSDYMNMTPRRPGPTRKHYQPYA PPRDFAAYRS 7. SEQ ID NO: 7 – CD3-zeta (^) signaling domain RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLY NELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 8. SEQ ID NO: 8 – GM-CSFR^ (CSF2RA) signal peptide domain MLLLVTSLLLCELPHPAFLLIP 9. SEQ ID NO: 9 - Human CD38 Variable Light Chain CDR DIVMTQSHLSMSTSLGDPVSITCKASQDVSTVVAWYQQKPGQSPRRLIYSASYRYIGVPDRF TGSGAGTDFTFTISSVQAEDLAVYYCQQHYSPPYTFGGGTKLEIKR 10. SEQ ID NO: 10 – Human CD38 Variable Heavy Chain CDR QVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWVKQRPGQGLEWIGTIYPGDGDTG YAQKFQGKATLTADKSSKTVYMHLSSLASEDSAVYYCARGDYYGSNSLDYWGQGTSVTV SS 11. SEQ ID NO: 11 - Variable Heavy Chain (SEQ ID NO: 10) and Variable Light Chain (SEQ ID NO: 9) incorporated into full CAR construct MLLLVTSLLLCELPHPAFLLIPDIVMTQSHLSMSTSLGDPVSITCKASQDVSTVVAWYQQKP GQSPRRLIYSASYRYIGVPDRFTGSGAGTDFTFTISSVQAEDLAVYYCQQHYSPPYTFGGGTK LEIKRGSTSGSGKPGSGEGSTKGQVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWV KQRPGQGLEWIGTIYPGDGDTGYAQKFQGKATLTADKSSKTVYMHLSSLASEDSAVYYCA RGDYYGSNSLDYWGQGTSVTVSSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPE VTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGK EYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKS LSLSLGKMFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRGGHSDYMNMTPRRPGPTRK HYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPE Docket No.10935-022WO2 MGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTY DALHMQALPPR 12. SEQ ID NO: 12 – Modified Light Chain DIVMAQSHKFMSTSVGDRVSITCKASQDVSTVVAWYQQKPGQSPKRLIYSASYRYIGVPDR FTGSGSGTDFTFTISSVQAEDLAVYYCQQHYSPPYTFGGGTKLEIKR 13. SEQ ID NO: 13 – Modified Heavy Chain QVQLQQSGAELARPGTSVKLSCKASGYTFTDYWMQWVKQRPGQGLEWIGTIYPGDGDTG YAQKFKGKATLTADKSSKTVYMHLSSLASEDSAVYYCARGDYYGSNSLDYWGQGTSVTV SS 14. SEQ ID NO: 14 – Modified Heavy Chain (SEQ ID NO: 13) and Modified Light Chain (SEQ ID NO: 12) incorporated into full CAR construct MLLLVTSLLLCELPHPAFLLIPDIVMAQSHKFMSTSVGDRVSITCKASQDVSTVVAWYQQK PGQSPKRLIYSASYRYIGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYCQQHYSPPYTFGGGT KLEIKRGSTSGSGKPGSGEGSTKGQVQLQQSGAELARPGTSVKLSCKASGYTFTDYWMQW VKQRPGQGLEWIGTIYPGDGDTGYAQKFKGKATLTADKSSKTVYMHLSSLASEDSAVYYC ARGDYYGSNSLDYWGQGTSVTVSSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQ KSLSLSLGKMFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRGGHSDYMNMTPRRPGPTR KHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDP EMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTY DALHMQALPPR 15. SEQ ID NO:15 - CDR-L1 Mouse KSSQSLLHSGNQRNYLT 16. SEQ ID NO: 16 - CDR-L1 Human KASQDVSTVVA 17. SEQ ID NO: 17 - CDR-L2 Mouse WASTRES Docket No.10935-022WO2 18. SEQ ID NO: 18 - CDR-L2 Human SASYRYI 19. SEQ ID NO: 19 - CDR-L3 Mouse QNDYDYPYT 20. SEQ ID NO: 20 - CDR-L3 Human QQHYSPPYT 21. SEQ ID NO: 21 - CDR-H1 Mouse NIKDSLI 22. SEQ ID NO: 22 - CDR-H1 Human GYTFTDYWM 23. SEQ ID NO: 23 - CDR-H2 Mouse WIDPEDDKTKYAPKFQD 24. SEQ ID NO: 24 - CDR-H2 Human TIYPGDGDTGYAKFQG 25. SEQ ID NO: 25 - CDR-H3 Mouse RYINYYFAY 26. SEQ ID NO: 26 - CDR-H3 Human GDYYGSNSLDY

Claims

Docket No.10935-022WO2 CLAIMS What is claimed is:

1. An antigen binding molecule comprising light chain complementarity determining regions (CDR) 1(CDR-L1), CDR-L2, and CDR-L3 as set forth in SEQ ID NO: 16, SEQ ID NO: 18, and SEQ ID NO: 20, respectively and / or heavy CDR-H1, CDR-H2, and CDR-H3 as set forth in SEQ ID NO: 22, SEQ ID NO: 24, and SEQ ID NO: 26, respectively, wherein said antigen binding molecule specifically binds CD38.

2. The antigen binding molecule of Claim 1, wherein the light chain comprises SEQ ID NO: 9 and / or the heavy chain comprises SEQ ID NO:

10.

3. The antigen binding molecule of claim 1 or 2, wherein the antigen binding molecule comprises an antibody of epitope binding fragment thereof.

4. The antigen binding molecule of claim 3, wherein the antibody or epitope-binding fragment thereof comprises a single chain variable fragment scFv, Fab, Fab^, F(ab^)2 or Fv fragment.

5. The antigen binding molecule of any one of claims 1-4, wherein the antibody or epitope- binding fragment thereof comprises at least one human constant region.

6. The antigen binding molecule of claim 5, wherein the constant region comprises a human IgG1 / IgKappa constant region.

7. A humanized or resurfaced antibody, wherein the humanized or resurfaced antibody comprises the antigen binding molecule of any one of claims 1-6.

8. An immunotoxin comprising the antigen binding molecule of any one of claims 1-7 and a cytotoxic agent.

9. The immunotoxin of claim 8, wherein the cytotoxic agent is selected from the group consisting of a maytansinoid, a small drug, a tomaymycin derivative, a leptomycin derivative, a prodrug, a taxoid, CC-1065 and a CC-1065 analog.Docket No.10935-022WO2 10. The antigen binding molecule of claim 1 or 2, wherein the antigen binding molecule comprises a chimeric antigen receptor (CAR).

11. The antigen binding molecule of any one of claims 1-10, wherein the antigen binding molecule is cytotoxic to a CD38+cell by inducing apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and / or complement-dependent cytoxicity (CDC).12.The antigen binding molecule of claim 11, wherein killing said CD38+cell by apoptosis can occur in the absence of stroma cells or stroma- derived cytokines.

13. The antigen binding molecule of claim 11 or 12, wherein the CD38+cell is a lymphoma cell, a leukemia cell, or a multiple myeloma cell.

14. The antigen binding molecule of any one of claims 11-13, wherein the CD38+cell is a non- Hodgkin's lymphoma (NHL) cell, a Burkitt's lymphoma (BL) cell, a multiple myeloma (MM) cell, a B chronic lymphocytic leukemia (B-CLL) cell, a B and T acute lymphocytic leukemia (ALL) cell, a T cell lymphoma (TCL) cell, an acute myeloid leukemia (AML) cell, a hairy cell leukemia (HCL) cell, a Hodgkin's Lymphoma (HL) cell, or a chronic myeloid leukemia (CML) cell.

15. A pharmaceutical composition comprising an antigen binding molecule thereof of any one of claims 1-14 and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition comprises a therapeutic agent.

17. The pharmaceutical composition of claim 16, wherein the therapeutic agent is selected from the group consisting of an antagonist of epidermal-growth factor (EGF), fibroblast-growth factor (FGF), hepatocyte growth factor (HGF), tissue factor (TF), protein C, protein S, platelet-derived growth factor (PDGF), heregulin, macrophage-stimulating protein (MSP), vascular endothelial growth factor (VEGF), a receptor for epidermal-growth factor (EGF), a receptor for fibroblast- growth factor (FGF), a receptor for hepatocyte growth factor (HGF), a receptor for tissue factor (TF), a receptor for protein C, a receptor for protein S, a receptor for platelet-derived growth factor (PDGF), a receptor for heregulin, a receptor for macrophage-stimulating protein (MSP), a receptor for vascular endothelial growth factor (VEGF); HER2 receptor, HER3 receptor, c-MET, and other receptorDocket No.10935-022WO2 tyrosine kinases.

18. The pharmaceutical composition of claim 16, wherein the therapeutic agent is an antibody targeting a cluster of differentiation (CD) antigen selected from a group comprising CD3, CD14, CD19, CD20, CD22, CD25, CD28, CD30, CD38, CD36, CD40, CD44, CD52, CD55, CD59, CD56, CD70, CD79, CD80, CD103, CD134, CD137, CD138, and CD152.

19. A recombinant nucleic acid encoding the antigen binding molecule of any one of claims 1- 14.

20. An expression vector encoding the recombinant nucleic acid of claim 19.

21. A cell expressing the expression vector of claim 20.

22. The cell of claim 21, wherein the cell is T-cell, natural killer (NK) cell, genetically-modified T-cell, or genetically-modified NK cell.

23. A method of treating a CD38-associated pathology in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the antigen binding molecules of any one of claims 1-14 pharmaceutical composition of any one of claims 15-18.

24. The method of claim 23, wherein the CD-38-associated pathology comprises a cancer, metabolic disorder, inflammatory disorder, endothelial disorder, virus susceptibility, neurological disorder, or aging.

25. The method of claim 24, wherein the CD-38-associated pathology comprises a leukemia, myeloma, or solid tumor.

26. The method of claim 24 or 25, wherein the CD-38-associated pathology comprises non- Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, chronic B lymphocytic leukemia, acute B and T lymphocytic leukemia, T cell lymphoma, acute myeloid leukemia, hairy cell leukemia, Hodgkin's Lymphoma, or chronic myelogenous leukemia.Docket No.10935-022WO2 27. A method of improving cancer cell / tumor / load reduction, the method comprising administering to a subject in need thereof, the pharmaceutical composition of the antigen binding molecules of any one of claims 1-14 pharmaceutical composition of any one of claims 15-18 in combination with all-trans retinoic acid (ATRA).

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