Anti-CD84 antibody and its use

Abstract

In particular, the present specification provides antibodies (e.g., humanized antibodies, chimeric antibodies, monoclonal antibodies, antibody fragments (e.g., scFv)) that bind to Cluster of Differentiation 84 (CD84) with high efficiency and specificity. The antibodies provided herein include CDRs and framework regions of novel light and heavy chain domains and are particularly useful for treating cancer and other CD84-related diseases.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This international application claims the benefit of priority of U.S. Patent Application No. 63 / 342,521, filed on May 16, 2022, under 35 U.S.C. § 119(e), and the entire disclosure of the above - mentioned application is incorporated herein by reference for all purposes.

[0002] (Reference to Sequence Listing) The sequence listing created on May 14, 2023, and described in the 102,132 - byte file 048440 - 750001US_SL_ST26.xml in machine - format IBM - PC, MS - Windows operating system is incorporated herein by reference in its entirety.

Background Art

[0003] In the art, there is a need for anti - CD84 antibodies that, by acting on the tumor microenvironment, bring about a good immune response and subsequent tumor eradication. In particular, the present specification provides compositions and methods that address the needs in the art, including the above - mentioned ones.

Summary of the Invention

[0004] In one aspect, there is provided an anti - CD84 antibody comprising a light - chain variable domain and a heavy - chain variable domain, wherein the heavy - chain variable domain comprises CDR H1 set forth in SEQ ID NO: 75, CDR H2 set forth in SEQ ID NO: 76, and CDR H3 set forth in SEQ ID NO: 77, and the light - chain variable domain comprises CDR L1 set forth in SEQ ID NO: 78, CDR L2 set forth in SEQ ID NO: 79, and CDR L3 set forth in SEQ ID NO: 80.

[0005] In another aspect, provided is an anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 19, CDR H2 set forth in SEQ ID NO: 20, and CDR H3 set forth in SEQ ID NO: 21, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 22, CDR L2 set forth in SEQ ID NO: 23, and CDR L3 set forth in SEQ ID NO: 24.

[0006] In another aspect, provided is an anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 39, CDR H2 set forth in SEQ ID NO: 40, and CDR H3 set forth in SEQ ID NO: 41, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 42, CDR L2 set forth in SEQ ID NO: 43, and CDR L3 set forth in SEQ ID NO: 44.

[0007] In another aspect, provided is an anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 57, CDR H2 set forth in SEQ ID NO: 58, and CDR H3 set forth in SEQ ID NO: 59, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 60, CDR L2 set forth in SEQ ID NO: 61, and CDR L3 set forth in SEQ ID NO: 62.

[0008] In another aspect, provided is an anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 93, CDR H2 set forth in SEQ ID NO: 94, and CDR H3 set forth in SEQ ID NO: 95, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 96, CDR L2 set forth in SEQ ID NO: 97, and CDR L3 set forth in SEQ ID NO: 98.

[0009] In another aspect, an anti-CD84 antibody is provided, which comprises a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 19, CDR H2 set forth in SEQ ID NO: 20, and CDR H3 set forth in SEQ ID NO: 21, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 22, CDR L2 set forth in SEQ ID NO: 23, and CDR L3 set forth in SEQ ID NO: 24, and an anti-CD84 antibody that binds to the same epitope.

[0010] In another aspect, an anti-CD84 antibody is provided, which comprises a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 39, CDR H2 set forth in SEQ ID NO: 40, and CDR H3 set forth in SEQ ID NO: 41, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 42, CDR L2 set forth in SEQ ID NO: 43, and CDR L3 set forth in SEQ ID NO: 44, and an anti-CD84 antibody that binds to the same epitope.

[0011] In another aspect, an anti-CD84 antibody is provided, which comprises a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 57, CDR H2 set forth in SEQ ID NO: 58, and CDR H3 set forth in SEQ ID NO: 59, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 60, CDR L2 set forth in SEQ ID NO: 61, and CDR L3 set forth in SEQ ID NO: 62, and an anti-CD84 antibody that binds to the same epitope.

[0012] In another aspect, an anti-CD84 antibody is provided, which comprises a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 75, CDR H2 set forth in SEQ ID NO: 76, and CDR H3 set forth in SEQ ID NO: 77, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 78, CDR L2 set forth in SEQ ID NO: 79, and CDR L3 set forth in SEQ ID NO: 80, and an anti-CD84 antibody that binds to the same epitope.

[0013] In another aspect, an anti-CD84 antibody is provided that includes a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 93, CDR H2 set forth in SEQ ID NO: 94, and CDR H3 set forth in SEQ ID NO: 95, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 96, CDR L2 set forth in SEQ ID NO: 97, and CDR L3 set forth in SEQ ID NO: 98, and an anti-CD84 antibody that binds to the same epitope.

[0014] In another aspect, an isolated nucleic acid encoding an anti-CD84 antibody, including the embodiments provided herein, is provided.

[0015] In another aspect, a cell is provided that includes an anti-CD84 antibody, including the embodiments provided herein, or a nucleic acid, including the embodiments provided herein.

[0016] In another aspect, a pharmaceutical composition is provided that includes a therapeutically effective amount of an antibody, including the embodiments provided herein, and a pharmaceutically acceptable excipient.

[0017] In another aspect, a method for generating an antibody capable of binding to CD84 is provided, which includes immunizing a mammal with a peptide comprising the sequence of SEQ ID NO: 111.

[0018] In another aspect, a method for treating cancer in a subject in need thereof is provided, which includes administering to the subject a therapeutically effective amount of an anti-CD84 antibody, including the embodiments provided herein, or a pharmaceutical composition, including the embodiments provided herein, thereby treating the cancer in the subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0019]

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Mode for Carrying Out the Invention

[0020] Definition While various embodiments and aspects of the present disclosure are shown and described herein, it will be apparent to those skilled in the art that such embodiments and aspects are provided by way of example only. Those skilled in the art will envision many variations, modifications, and substitutions without departing from the present invention. It should be understood that various alternatives to the embodiments described herein may be employed in the practice of the present invention.

[0021] The headings of the items used in this document are for organizational purposes and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application (including, but not limited to, patents, patent applications, treatises, books, manuals, papers) are hereby expressly incorporated by reference in their entirety.

[0022] The abbreviations used in this specification have their conventional meanings within the chemical and biological arts. The chemical structures and formulas described herein are constructed in accordance with the standard rules of chemical valence well known in the chemical art.

[0023] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. See, for example, Singleton et al., Dictionary Of Microbiology And Molecular Biology 2nd ed., J. Wiley & Sons (New York, NY 1994), Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, devices, and materials similar or equivalent to those described herein may be used in the practice of the present invention. The following definitions are provided to facilitate understanding of certain terms that are frequently used herein and are not meant to limit the scope of the present disclosure.

[0024] Although various embodiments and aspects of the present disclosure are shown and described herein, it will be apparent to those skilled in the art that such embodiments and aspects are provided by way of example only. Those skilled in the art will envision many variations, modifications, and substitutions without departing from the present invention. It should be understood that various alternatives to the embodiments described herein may be employed in the practice of the present invention.

[0025] The headings of the sections used in this document are for organizational purposes only and should not be construed as limiting the subject matter described. All documents or portions of documents (including, but not limited to, patents, patent applications, treatises, books, manuals, papers) cited in this application are hereby expressly incorporated by reference in their entirety.

[0026] The abbreviations used in this document have their conventional meanings within the chemical and biological arts. The chemical structures and formulas described herein are constructed in accordance with standard rules of chemical valency well known in the chemical art.

[0027] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. See, for example, Singleton et al., Dictionary Of Microbiology And Molecular Biology 2nd ed., J. Wiley & Sons (New York, NY 1994), Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, devices, and materials similar or equivalent to those described herein may be used in the practice of the present invention. The following definitions are provided to facilitate understanding of certain terms that are frequently used herein and are not meant to limit the scope of the present disclosure.

[0028] "Nucleic acid" refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and their polymers in any form of single-stranded, double-stranded, or multi-stranded, or their complements, or nucleosides (e.g., deoxyribonucleosides or ribonucleosides). In some embodiments, "nucleic acid" does not include nucleosides. Terms such as "polynucleotide", "oligonucleotide", "oligo" refer to a linear sequence of nucleotides in the ordinary and customary sense. The term "nucleoside" refers to a glycosylamine containing a nucleobase and a pentose sugar (ribose or deoxyribose) in the ordinary and customary sense. Non-limiting examples of nucleosides include cytidine, uridine, adenosine, guanosine, thymidine, and inosine. The term "nucleotide" refers to a single polynucleotide unit, i.e., a monomer, in the ordinary and customary sense. Nucleotides can be ribonucleotides, deoxyribonucleotides, or modified forms thereof. Examples of polynucleotides contemplated herein include single-stranded and double-stranded DNA, single-stranded and double-stranded RNA, and hybrid molecules having mixtures of single-stranded and double-stranded DNA and RNA. Examples of nucleic acids contemplated herein, e.g., polynucleotides, include all types of RNA, e.g., mRNA, siRNA, miRNA, and guide RNA, and all types of DNA, genomic DNA, episomal DNA, and minicircle DNA, and any fragments thereof. The term "double-stranded" in the context of polynucleotides refers to double-strandedness in the ordinary and customary sense. Nucleic acids can be linear or branched. For example, a nucleic acid can be a linear chain of nucleotides, or a nucleic acid can be branched, e.g., such that the nucleic acid contains one or more arms or branches of nucleotides. Optionally, branched nucleic acids can be repeatedly branched to form higher-order structures such as dendrimers.

[0029] For example, a nucleic acid containing a nucleic acid having a phosphorothioate backbone may contain one or more reactive moieties. As used herein, the term reactive moiety includes any group that can react with another molecule, such as a nucleic acid or polypeptide, via a covalent bond, non-covalent bond, or other interaction. By way of example, the nucleic acid may contain an amino acid reactive moiety that reacts with an amino acid on a protein or polypeptide via a covalent bond, non-covalent bond, or other interaction.

[0030] This term also encompasses nucleic acids that are synthetic, naturally occurring, or non-naturally occurring, have binding properties similar to a reference nucleic acid, and contain known nucleotide analogs or modified backbone residues or linkages that are metabolized in a manner similar to a reference nucleotide. Examples of such analogs include, for example, phosphoramidates, phosphorodiamidates, phosphorothioates (also known as phosphorothioates where the oxygen in the phosphate is replaced with a double-bonded sulfur), phosphorodiamidates, phosphocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid, phosphonoglycolic acid, methylphosphonates, boranophosphonates, or phosphodiester derivatives containing an O-methylphosphoramidite linkage (see Eckstein, OLIGONUCLEOTIDES AND ANALOGUES: A PRACTICAL APPROACH, Oxford University Press), as well as modifications to the nucleotide base such as in the case of 5-methylcytidine or pseudouridine, and peptide nucleic acid backbones and linkages, but are not limited thereto. Other nucleic acid analogs include those having a positively charged backbone, a non-ionic backbone, modified sugars, and non-ribose backbones (e.g., phosphorodiamidate morpholino oligos or locked nucleic acids (LNA), well known in the art) as described in U.S. Patent Nos. 5,235,033 and 5,034,506, and in Chapters 6 and 7 of Carbohydrate Modifications in Antisense Research, edited by Sanghui and Cook, ASC Symposium Series 580. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids. Modifications to the ribose-phosphate backbone may be made for various reasons, for example, to increase the stability and half-life of such molecules in a physiological environment or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs can be made, or mixtures of different nucleic acid analogs and mixtures of naturally occurring nucleic acids and analogs may be made. In some embodiments, the internucleotide linkages in DNA are phosphodiesters, phosphodiester derivatives, or a combination of both.

[0031] A nucleic acid may contain non-specific sequences. As used herein, the term "non-specific sequence" refers to a nucleic acid sequence containing a series of residues that are not designed to be complementary, or only partially complementary, to any other nucleic acid sequence. By way of example, a non-specific nucleic acid sequence is a sequence of nucleic acid residues that does not function as an inhibitory nucleic acid when contacted with a cell or organism.

[0032] Polynucleotides generally consist of a specific sequence of four nucleotide bases: adenine (A), cytosine (C), guanine (G), and thymine (T) (uracil (U) in place of thymine (T) if the polynucleotide is RNA). Thus, the term "polynucleotide sequence" is the alphabetical representation of a polynucleotide molecule, or alternatively, this term is used for the polynucleotide molecule itself. This alphabetical representation can be input into the data system of a computer equipped with a central processing unit and can be used in bioinformatics applications such as functional genomics and homology searching. Polynucleotides may optionally contain non-standard nucleotide(s), nucleotide analog(s), and / or modified nucleotide(s).

[0033] As used herein, the term "complement" refers to a nucleotide (e.g., RNA or DNA) or a sequence of nucleotides that can base pair with a complementary nucleotide or sequence of nucleotides. As described herein and as generally known in the art, the complementary (matching) nucleotide of adenosine is thymidine, and the complementary (matching) nucleotide of guanidine is cytosine. Thus, a complement may include a sequence of nucleotides that base pairs with the corresponding complementary nucleotides of a second nucleic acid sequence. The nucleotides of the complement may partially or fully match the nucleotides of the second nucleic acid sequence. When the nucleotides of the complement fully match each nucleotide of the second nucleic acid sequence, the complement forms a base pair with each nucleotide of the second nucleic acid sequence. When the nucleotides of the complement partially match the nucleotides of the second nucleic acid sequence, only a portion of the nucleotides of the complement form a base pair with the nucleotides of the second nucleic acid sequence. Examples of complementary sequences include coding and non-coding sequences, where the non-coding sequence contains the complementary nucleotides to the coding sequence and thus forms the complement of the coding sequence. Further examples of complementary sequences are sense and antisense sequences, where the sense sequence contains the complementary nucleotides to the antisense sequence and thus forms the complement of the antisense sequence.

[0034] As described herein, when the complementarity of a sequence is partial, only some of the nucleic acids match according to base pairing, or when complete, all of the nucleic acids match according to base pairing. Thus, two sequences that are complementary to each other may have a certain percentage of identical nucleotides (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more identity over a particular region).

[0035] The term "amino acid" refers to naturally occurring amino acids and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to naturally occurring amino acids. Naturally occurring amino acids include those encoded by the genetic code and amino acids that are later modified (e.g., hydroxyproline, γ-carboxyglutamate, and O-phosphoserine). Amino acid analogs refer to compounds having the same basic chemical structure as naturally occurring amino acids, i.e., compounds having an α-carbon bonded to a hydrogen, a carboxyl group, an amino group, and an R group, such as homoserine, norleucine, methionine sulfoxide, and methionine methyl sulfonium. Such analogs have a modified R group (e.g., norleucine) or a modified peptide backbone but retain the same basic chemical structure as naturally occurring amino acids. Amino acid mimetics refer to compounds having a structure different from the general chemical structure of amino acids but functioning in a manner similar to naturally occurring amino acids. The terms "non-naturally occurring amino acid" and "unnatural amino acid" refer to amino acid analogs, synthetic amino acids, and amino acid mimetics that are not found in nature.

[0036] Amino acids may be referred to herein by either their generally well-known three-letter symbols or the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Similarly, nucleotides may be referred to by their generally recognized one-letter codes.

[0037] The terms "polypeptide", "peptide", and "protein" are used interchangeably herein to refer to polymers of amino acid residues, and the polymers may, in embodiments, be complexed to moieties that are not composed of amino acids. This term applies to amino acid polymers in which one or more amino acid residues are artificial chemical mimetics of the corresponding naturally occurring amino acids, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. A "fusion protein" refers to a chimeric protein that encodes two or more distinct protein sequences expressed recombinantly as a single moiety.

[0038] The "position" of an amino acid or nucleotide base is indicated by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-terminus). Due to deletions, insertions, truncations, fusions, etc. that must be considered when determining the optimal alignment, generally, the number of amino acid residues in the test sequence determined simply by counting from the N-terminus is not necessarily the same as the number of corresponding positions in the reference sequence. For example, if a variant has a deletion compared to the aligned reference sequence, there will be no amino acid in the variant corresponding to the position in the reference sequence at the deletion site. If there is an insertion in the aligned reference sequence, the insertion does not correspond to the numbered amino acid position in the reference sequence. In the case of a truncation or fusion, there may be a section of amino acids in either the reference sequence or the aligned sequence that does not correspond to any amino acid in the corresponding sequence.

[0039] When used in the context of numbering of a given amino acid or polynucleotide sequence, the terms “numbered relative to” or “corresponding to” refer to the numbering of residues of a particular reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence. Amino acid residues of a protein “correspond to” a given residue if they occupy the same essential structural position within the same protein. One of ordinary skill in the art will readily understand the identity and position of residues corresponding to a particular position in one protein (e.g., EGFR) in other proteins using different numbering systems. For example, by performing a simple sequence alignment of a protein (e.g., EGFR) with other proteins, the identity and position of residues corresponding to a particular position in that protein can be identified within the other protein sequences aligned to that protein. For example, a selected residue of a selected protein corresponds to glutamic acid at position 138 if the selected residue occupies the same essential spatial or other structural relationship as glutamic acid at position 138. In some embodiments, when the selected protein is aligned for maximum homology with the protein, the position in the aligned selected protein that aligns with glutamic acid 138 is said to correspond to glutamic acid 138. Instead of a primary sequence alignment, a three-dimensional structure alignment can also be used, e.g., aligning the structure of the selected protein for maximum match with glutamic acid at position 138 and comparing the overall structures. In this case, the amino acid occupying the same essential position as glutamic acid 138 in the structural model corresponds to the glutamic acid 138 residue.

[0040] "Conservatively modified variants" applies to both amino acid and nucleic acid sequences. With respect to a particular nucleic acid sequence, a "conservatively modified variant" refers to a nucleic acid encoding the same or essentially the same amino acid sequence. Due to the degeneracy of the genetic code, many nucleic acid sequences encode any given protein. For example, the codons GCA, GCC, GCG, and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without changing the encoded polypeptide. Such nucleic acid variations are "silent variations," which are one species of conservatively modified variations. All nucleic acid sequences herein that encode polypeptides also describe every possible silent variation of the nucleic acids. One of ordinary skill in the art will recognize that each codon in a nucleic acid (except for the AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Thus, each silent variation of a nucleic acid that encodes a polypeptide is implicitly described in each of the sequences described.

[0041] With respect to amino acid sequences, one of ordinary skill in the art will recognize that individual substitutions, deletions, or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alter, add, or delete a single amino acid or a small percentage of amino acids in the encoded sequence are "conservatively modified variants" where the alterations result in the substitution of an amino acid with a chemically similar amino acid. Tables of conserved substitutions providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to, and do not exclude, polymorphic variants, interspecies homologs, and alleles of the present disclosure.

[0042] The following eight groups each contain amino acids that are conservatively substituted for one another. 1) Alanine (A), Glycine (G) 2) Aspartic acid (D), Glutamic acid (E) 3) Asparagine (N), Glutamine (Q), 4) Arginine (R), Lysine (K), 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V), 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W), 7) Serine (S), Threonine (T), and 8) Cysteine (C), Methionine (M) (See, e.g., Creighton, Proteins (1984)).

[0043] The terms "identical" or "identity" in the context of two or more nucleic acid or polypeptide sequences refer to amino acid residues or nucleotides having a particular percentage of identity (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or more identity over a specified region when compared and aligned to maximize correspondence over a comparison window or designated region) as measured using the BLAST or BLAST 2.0 sequence comparison algorithms with the default parameters described below, or by manual alignment and visual inspection (see, e.g., the NCBI website http: / / www.ncbi.nlm.nih.gov / BLAST / , etc.). Thus, such sequences can be said to be "substantially identical." This definition may also refer to, or be applied to, the complement of a test sequence. The definition also includes sequences having deletions and / or additions, as well as sequences having substitutions. As described below, preferred algorithms can calculate gaps, etc. Preferably, identity exists over a region of at least about 25 amino acids or nucleotides in length, and more preferably over a region of 50 - 100 amino acids or nucleotides in length.

[0044] "Percentage of sequence identity" is determined by comparing two sequences optimally aligned over a comparison window, where a portion of the polynucleotide sequence or polypeptide sequence in the comparison window may include additions or deletions (i.e., gaps) as compared to the reference sequence (excluding additions or deletions) for optimal alignment of the two sequences. This percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue is present in both sequences, generating the number of matched positions, dividing the number of matched positions by the total number of positions in the comparison window, and multiplying the result by 100 to generate the percentage of sequence identity.

[0045] As used herein, "comparison window" includes, for example, any one segment of a contiguous number of positions selected from the group consisting of the full-length sequence or 20 to 600, about 50 to about 200, or about 100 to about 150 amino acids or nucleotides, and after two sequences are optimally aligned, the sequences may be compared to a reference sequence of the same number of contiguous positions. Methods for aligning sequences for comparison are well known in the art. Optimal alignment for alignment for comparison can be performed, for example, by the local homology algorithm of Smith and Waterman (1970) Adv. Appl. Math. 2:482c, by the homology alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, by Pearson and Lipman (1988) Proc. Nat’l. Acad. Sci. USA 85:2444, by computer processing of these algorithms (GAP, BESTFIT, FASTA, and TFASTA of the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by manual alignment and visual inspection (see, e.g., Ausubel et al., Current Protocols in Molecular Biology (1995, supplement)).

[0046] Examples of algorithms suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1977) Nuc. Acids Res. 25:3389-3402, and Altschul et al. (1990) J. Mol. Biol. 215:403-410, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http: / / www.ncbi.nlm.nih.gov / ). This algorithm involves identifying short words of length W in the query sequence that either match or satisfy some positive-valued threshold score T when aligned with words of the same length in the database sequence, thereby initially identifying high scoring sequence pairs (HSPs). T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits serve as seeds for initiating a search to find longer HSPs that contain them. The word hits are extended in both directions along each sequence as long as the cumulative alignment score can increase. The cumulative score is calculated using parameters M (reward score for a pair of matching residues, always >0) and N (penalty score for a mismatch residue, always >0) for nucleotide sequences, and a scoring matrix is used to calculate the cumulative score for amino acid sequences. Extension of the word hits in each direction stops when the cumulative alignment score drops by an amount X from its maximum achieved value, when the cumulative score goes to zero or below due to the accumulation of one or more negative-score residue alignments, or when the end of either sequence is reached. The W, T, and X parameters of the BLAST algorithm determine the sensitivity and speed of the alignment.The BLASTN program (for nucleotide sequences) by default uses a word length (W) of 11, an expectation value (E) of 10, M = 5, N = -4, and a comparison of both strands. For amino acid sequences, the BLASTP program by default uses a word length of 3 and an expectation value (E) of 10, the BLOSUM62 score matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89: 10915), an alignment (B) of 50, an expectation value (E) of 10, M = 5, N = -4, and a comparison of both strands by default.

[0047] The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, for example, Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90: 5873 - 5787). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability that a match between two nucleotide sequences or amino acid sequences could occur by chance. For example, in a comparison of a test nucleic acid with a reference nucleic acid, if the smallest sum probability is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001, the nucleic acid is considered to be similar to the reference sequence.

[0048] An indication that two nucleic acid sequences or polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid immunologically cross - reacts with an antibody to the polypeptide encoded by the second nucleic acid, as described below. Thus, a polypeptide is typically substantially identical to a second polypeptide, for example, when the two peptides differ only by conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that the two molecules or their complements hybridize to each other under stringent conditions, as described below. Yet another indication that two nucleic acid sequences are substantially identical is that the sequences can be amplified using the same primers.

[0049] As used herein, "CD84" refers to a protein or a variant or homolog thereof, whether recombinant or native, that has a Cluster of Differentiation 84 (CD84) complex, mediates signal transduction, and maintains CD84 complex activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to the CD84 complex). In some embodiments, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a 50-, 100-, 150-, or 200-amino acid contiguous portion) compared to the naturally occurring CD84 protein in the CD84 complex. In some embodiments, the CD84 protein is substantially identical to the protein identified by UniProt reference number Q9UIB8 or a variant or homolog having substantial identity thereto.

[0050] Antibodies are large, complex molecules with a complex internal structure (molecular weight approximately 150,000, or approximately 1320 amino acids). Natural antibody molecules contain a pair of two identical polypeptide chains, each pair having one light chain and one heavy chain. The light and heavy chains each consist of two regions in turn: a variable ("V") region involved in binding to the target antigen and a constant ("C") region that interacts with other components of the immune system. The light chain variable region and the heavy chain variable region (also referred to herein as the light chain variable (VL) domain and the heavy chain variable (VH) domain, respectively) come together in three-dimensional space to form a variable region that binds to an antigen (e.g., a receptor on the surface of a cell). Within each variable region of the light or heavy chain, there are three short segments (average 10 amino acids in length) called complementarity-determining regions ("CDRs"). The six CDRs (three from the light chain and three from the heavy chain) of the antibody variable domain are folded together in three-dimensional space to form the actual antibody binding site and dock to the target antigen. The positions and lengths of the CDRs are precisely defined by Kabat, E. et al., Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services, 1983, 1987. The portions of the variable region not included in the CDRs are called the framework ("FR") and form the surroundings of the CDRs.

[0051] As used herein, "antibody variant" refers to a polypeptide that can bind to an antigen and includes one or more structural domains of an antibody or fragment thereof (e.g., light chain variable domain, heavy chain variable domain). Non-limiting examples of antibody variants include single domain antibodies or nanobodies, monospecific Fab2, bispecific Fab2, trispecific Fab3, monovalent IgG, scFv, bispecific antibodies, bispecific diabodies, trispecific tribodies, scFv-Fc, minibodies, IgNAR, V-NAR, hcIgG, VhH, or peptibodies. As used herein, "peptibody" refers to a peptide moiety attached (via a covalent or non-covalent linker) to the Fc domain of an antibody. Further non-limiting examples of antibody variants known in the art include antibodies produced by cartilaginous fish or camels. General descriptions of antibodies and their variable regions from camels, and methods for their production, isolation, and use, can be found in International Publication Nos. WO 97 / 49805 and WO 97 / 49805, which are hereby incorporated by reference in their entirety for all purposes. Similarly, antibodies and their variable regions from cartilaginous fish, and methods for their production, isolation, and use, can be found in International Publication No. WO 2005 / 118629, which is hereby incorporated by reference in its entirety for all purposes.

[0052] As used herein, the terms "CDR L1", "CDR L2", and "CDR L3" refer to complementarity determining regions (CDRs) 1, 2, and 3 of the variable light (L) chain of an antibody. In some embodiments, the variable light chain presented herein includes CDR L1, CDR L2, and CDR L3 in the N-terminal to C-terminal direction. Similarly, as used herein, the terms "CDR H1", "CDR H2", and "CDR H3" refer to complementarity determining regions (CDRs) 1, 2, and 3 of the variable heavy (H) chain of an antibody. In some embodiments, the variable heavy chain presented herein includes CDR H1, CDR H2, and CDR H3 in the N-terminal to C-terminal direction. In some embodiments, the CDRs of the light chain are referred to as CDR1, CDR2, and CDR3 of VL, and the CDRs of the heavy chain are referred to as CDR1, CDR2, and CDR3 of VH. See, for example, the tables provided herein.

[0053] As used herein, the terms "FR L1", "FR L2", "FR L3", and "FR L4" are used according to their general meaning in the art and refer to framework regions (FRs) 1, 2, 3, and 4 of the variable light (L) chain of an antibody. In some embodiments, the variable light chain presented herein includes FR L1, FR L2, FR L3, and FR L4 in the N-terminal to C-terminal direction. Similarly, as used herein, the terms "FR H1", "FR H2", "FR H3", and "FR H4" are used according to their general meaning in the art and refer to framework regions (FRs) 1, 2, 3, and 4 of the variable heavy (H) chain of an antibody. In some embodiments, the variable heavy chain presented herein includes FR H1, FR H2, FR H3, and FR H4 in the N-terminal to C-terminal direction.

[0054] Representative immunoglobulin (antibody) structural units include tetramers. Each tetramer consists of a pair of two identical polypeptide chains, and each pair has one "light" chain (about 25 kD) and one "heavy" chain (about 50 - 70 kD). The N-terminus of each chain defines a variable region of about 100 - 110 or more amino acids that is mainly involved in antigen recognition. The terms variable light chain (VL), variable light chain (VL) domain, or light chain variable region, and variable heavy chain (VH), variable heavy chain (VH) domain, or heavy chain variable region each refer to these light chain regions and heavy chain regions, respectively. The terms variable light chain (VL), variable light chain (VL) domain, and light chain variable region referred to herein may be used interchangeably. The terms variable heavy chain (VH), variable heavy chain (VH) domain, and heavy chain variable region referred to herein may be used interchangeably. Fc (i.e., the fragment crystallizable region) is the "base" or "tail" of the immunoglobulin and typically consists of two heavy chains that contribute to two or three constant domains, depending on the class of the antibody. The Fc region ensures that each antibody elicits an appropriate immune response against a specific antigen by binding to specific proteins. The Fc region also binds to various cell receptors such as Fc receptors and other immune molecules such as complement proteins. The term "light chain" is used according to its ordinary meaning in the biological field and refers to a polypeptide formed by a variable light chain domain (VL) and a constant light chain domain (CL). Similarly, the term "heavy chain" is used according to its ordinary meaning in the biological field and refers to a polypeptide formed by a variable heavy chain domain (VH) and one or more constant heavy chain domains (CH1, CH2, CH3).

[0055] The term "antibody" is used according to its generally known meaning in the art. Antibodies exist, for example, as intact immunoglobulins or as many well-characterized fragments produced by digestion with various peptidases. Thus, for example, pepsin digests the antibody below the disulfide bond in the hinge region to produce itself, which is linked by a disulfide bond to V H -C H1Produces a dimer of Fab, which is a light chain linked to a heavy chain, and F(ab)’2. F(ab)’2 can be reduced under mild conditions to break the disulfide bonds in the hinge region, thereby converting the F(ab)’2 dimer into Fab’ monomers. Fab’ monomers are essentially Fab with a part of the hinge region (see Fundamental Immunology (Paul ed., 3d ed. 1993)). Various antibody fragments have been defined for the digestion of intact antibodies, and those skilled in the art will understand that such fragments can be synthesized de novo using chemical or recombinant DNA methodologies. Accordingly, the term "antibody" as used herein also includes antibody fragments produced by modification of whole antibodies, or antibody fragments synthesized de novo using recombinant DNA methods (e.g., single-chain Fv), or antibody fragments identified using phage display libraries (see, for example, McCafferty et al., Nature 348:552-554 (1990)). The term "antibody" referred to herein further includes antibody variants such as single-domain antibodies. Accordingly, in some embodiments, the antibody comprises a single monomeric variable antibody domain. Accordingly, in some embodiments, the antibody comprises a variable light chain (VL) domain or a variable heavy chain (VH) domain. In some embodiments, the antibody is a variable light chain (VL) domain or a variable heavy chain (VH) domain.

[0056] For the preparation of monoclonal or polyclonal antibodies, any technique known in the art can be used (see, for example, Kohler & Milstein, Nature 256:495-497 (1975)); Kozbor et al., Immunology Today 4:72 (1983); Cole et al., pp.77-96 in Monoclonal Antibodies and Cancer Therapy (1985)). A "monoclonal" antibody (mAb) refers to an antibody derived from a single clone. The technology for producing single-chain antibodies (U.S. Patent No. 4,946,778) can be adapted to produce antibodies against the polypeptides of the present invention. Alternatively, transgenic mice, or other organisms such as other mammals, may be used to express humanized antibodies. Or, phage display technology can be used to identify antibodies and Fab fragments of heteromers that specifically bind to a selected antigen (see, for example, McCafferty et al., Nature 348:552-554 (1990), Marks et al., Biotechnology 10:779-783 (1992)).

[0057] A single-chain variable fragment (scFv) is typically a fusion protein of the variable domain of the heavy chain (VH) and the variable domain of the light chain (VL) of an immunoglobulin, connected by a short linker peptide of 10 to about 25 amino acids. The linker can usually contain a lot of glycine for flexibility and a lot of serine or threonine for solubility. The linker can connect the N-terminus of VH to the C-terminus of VL, or vice versa.

[0058] The epitope of an mAb is the region of its antigen to which the mAb binds. Two antibodies bind to the same or overlapping epitopes if each competitively inhibits (blocks) the binding of the other to the antigen. That is, in the measurement of a competitive binding assay, when one antibody is present at 1-fold, 5-fold, 10-fold, 20-fold, or 100-fold excess, the binding of the other is inhibited by at least 30%, preferably 50%, 75%, 90%, or even 99% (see, e.g., Junghans et al, Cancer Res. 50:1495, 1990). Alternatively, two antibodies have the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate the binding of one antibody also reduce or eliminate the binding of the other antibody. Two antibodies have overlapping epitopes if some amino acid mutations that reduce or eliminate the binding of one antibody also reduce or eliminate the binding of the other antibody.

[0059] As used herein, the term "antigen" refers to a molecule capable of binding to an antibody-binding domain provided herein. An "antibody-binding domain" provided herein is the region of an antibody that binds to an antigen (epitope). As noted above, an antibody-binding domain generally consists of one constant domain and one variable domain (VL, VH, CL, and CH1, respectively) of each of the heavy and light chains. The paratope or antigen-binding site is formed at the N-terminus of the antibody-binding domain. The two variable domains of the antibody-binding domain typically bind to an epitope on the antigen.

[0060] For the preparation of suitable antibodies of the present invention and for use in accordance with the present invention, a number of techniques known in the art can be used, such as, for example, recombinant antibodies, monoclonal antibodies or polyclonal antibodies (see, for example: Kohler & Milstein, Nature 256:495-497 (1975)); Kozbor et al., Immunology Today 4:72 (1983), Cole et al., Monoclonal Antibodies and Cancer Therapy pp77-96, Alan R. Liss, Inc. (1985), Coligan, Current Protocols in Immunology (1991), Harlow and Lane, Antibodies, A Laboratory Manual (1988), and Goding, Monoclonal Antibodies: Principles and Practice (2d ed. 1986)). Genes encoding the heavy and light chains of the antibody of interest can be cloned from cells. For example, genes encoding monoclonal antibodies can be cloned from hybridomas and used to produce recombinant monoclonal antibodies. Gene libraries encoding the heavy and light chains of monoclonal antibodies can also be prepared from hybridomas or plasma cells. Random combinations of the heavy and light chain gene products generate a large pool of antibodies with various antigen specificities (see, for example, Kuby, Immunology (3rd ed. 1997). To generate antibodies against the polypeptides of the present invention, techniques for generating single-chain antibodies or recombinant antibodies (U.S. Patent No. 4,946,778, U.S. Patent No. 4,816,567) can be used.Alternatively, transgenic mice, or other organisms such as other mammals, may be used to express humanized antibodies or human antibodies (see, for example, U.S. Pat. Nos. 5,545,807, 5,545,806, 5,569,825, 5,625,126, 5,633,425, 5,661,016, Marks et al., Bio / Technology 10:779-783 (1992), Lonbergs et al., Nature 368:856-859 (1994), Morrison, Nature 368:812-13 (1994), Fishwild et al., Nature Biotechnology 14:845-51 (1996), Neuberger, Nature Biotechnology 14:826 (1996), and Longberg and Huszar, Intern. Rev. Immunol. 13:65-93 (1995)). Alternatively, phage display technology can be used to identify antibodies and Fab fragments of heteromers that specifically bind to a selected antigen (see, for example, McCafferty et al., Nature 348:552-554 (1990), Marks et al., Biotechnology 10:779-783 (1992)). Antibodies can also be made bispecific, i.e., capable of recognizing two different antigens (see, for example, WO93 / 08829, Traunecker et al., EMBO J. 10:10:3655-3659 (1991), and Suresh et al., Methods in Enzymology 121:210 (1986)). Antibodies may also be heteroconjugates (e.g., two covalently linked antibodies) or immunotoxins (see, for example, U.S. Pat. No. 4,676,980, International Publication Nos. 91 / 00360, 92 / 200373, and European Patent No. 03089).

[0061] Methods for humanizing or primatizing non-human antibodies are known in the art (e.g., U.S. Pat. Nos. 4,816,567, 5,530,101, 5,859,205, 5,585,089, 5,693,761, 5,693,762, 5,777,085, 6,180,370, 6,210,671, and 6,329,511; International Publication No. 87 / 02671; European Patent Application No. 0173494; Jones et al., (1986) Nature 321:522 and Verhoyen et al., (1988) Science 239:1534). Humanized antibodies are further described, for example, in Winter and Milstein (1991) Nature 349:293. In general, a humanized antibody has one or more amino acid residues introduced therein from a non-human source. These non-human amino acid residues are often called import residues and are typically obtained from the import variable domain. Humanization can be performed according to the method of Winter and co-workers by essentially replacing the rodent CDR or CDR sequences with the corresponding sequences of a human antibody (see, e.g., Morrison et al., PNAS USA, 81:6851-6855 (1984); Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Morrison and Oi, Adv. Immunol., 44:65-92 (1988); Verhoeyen et al., Science 239:1534-1536 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992); Padlan, Molec. Immunol., 28:489-498 (1991); Padlan, Molec. Immunol., 31(3):169-217 (1994)). Thus, such humanized antibodies are chimeric antibodies (U.S. Pat. No. 4,816,567) in which substantially less than the intact human variable domain is replaced by the corresponding sequences from a non-human species. In practice, a humanized antibody is typically a human antibody in which some CDR residues and perhaps some FR residues are replaced by residues from the analogous sites of a rodent antibody.For example, a polynucleotide comprising a first sequence encoding a humanized immunoglobulin framework region and a second set of sequences encoding a desired immunoglobulin complementarity determining region can be produced synthetically or by combining appropriate cDNA and genomic DNA segments. Human constant region DNA sequences can be isolated from various human cells according to well-known procedures.

[0062] A "chimeric antibody" is an antibody molecule in which (a) the constant region or a portion thereof has been modified, substituted, or exchanged such that the antigen-binding site (e.g., the variable region comprising domain VH and domain VL) is linked to a constant region of a different or modified class, effector function and / or species, or is linked to a completely different molecule, such as an enzyme, toxin, hormone, growth factor, drug, etc., that confers new properties to the chimeric antibody, or (b) the variable region or a portion thereof has been modified, substituted, or exchanged with a variable region having a different or modified antigen specificity. Preferred antibodies of the present invention, and preferred antibodies for use according to the present invention, include humanized antibodies and / or chimeric monoclonal antibodies.

[0063] The terms "specifically (or selectively) bind to" or "specifically (or selectively) immunoreact with" an antibody, when referring to a protein or peptide, most often refer to a binding reaction that determines the presence of that protein in a heterogeneous population of proteins and other biologic agents. Thus, under specified immunoassay conditions, a particular antibody binds to a particular protein at least 2-fold over background, more typically more than 10 - 100-fold over background. Specific binding to an antibody under such conditions requires an antibody selected for its specificity for a particular protein. For example, a polyclonal antibody can be selected to obtain only that subset of antibody molecules that specifically immunoreact with the selected antigen and not with other proteins. This selection may be accomplished by subtracting antibodies that cross-react with other molecules. A variety of immunoassay formats may be used to select antibodies that specifically immunoreact with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select antibodies that specifically immunoreact with a protein (see, e.g., Harlow & Lane, Using Antibodies, A Laboratory Manual (1998) for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity).

[0064] "Ligand" refers to an agent, such as a polypeptide or other molecule, that can bind to a receptor, or to an antibody, antibody variant, antibody region or fragment thereof. In some embodiments, the ligand is an antigen, fragment or portion thereof.

[0065] Techniques for conjugating therapeutic agents to antibodies are well known (see, for example, Arnon et al., “Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy”, in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery” in Controlled Drug Delivery (2 nd nd Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, “Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review” in Monoclonal Antibodies ‘84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985); and Thorpe et al., “The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates”, Immunol. Rev., 62: 119-58 (1982)). As used herein, the term “antibody-drug conjugate” or “ADC” refers to a therapeutic agent that is conjugated to an antibody or otherwise covalently bound to the antibody.

[0066] For the specific proteins described herein, the designated proteins include either the naturally occurring form of the protein, or a variant or homolog that maintains the activity of the protein transcription factor (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to the native protein). In some embodiments, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a 50-, 100-, 150-, or 200-contiguous amino acid portion) compared to the native form. In other embodiments, the protein is the protein identified by its NCBI sequence reference. In other embodiments, the protein is the protein identified by its NCBI sequence reference, its homolog, or a functional fragment thereof.

[0067] As used herein, the terms "EGFR protein" or "EGFR" include both recombinant or native forms of the epidermal growth factor receptor, also known as the proto-oncogene c-ErbB-1, receptor tyrosine-protein kinase erbB-1, ERBB, ERBB1, HER1, or a variant or homolog that maintains EGFR activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the activity compared to EGFR). In some aspects, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a 50-, 100-, 150-, or 200-contiguous amino acid portion) compared to the naturally occurring EGFR protein. In embodiments, the EGFR protein is substantially identical to the protein identified by UniProt reference number P00533, or a variant or homolog having substantial identity thereto.

[0068] The epidermal growth factor receptor, also known as EGFR, ErbB1, and HER1, is a cell surface receptor for the epidermal growth factor family of extracellular ligands. Changes in EGFR activity have been associated with certain cancers. In some embodiments, a nucleic acid sequence encoding a polypeptide that includes a membrane-distal EGF binding domain and a cytoplasmic signaling tail is removed (a "truncated EGFR," "tEGFR," or "EGFRt"), and a gene is provided that encodes an EGFR polypeptide that retains an extracellular domain IV epitope recognized by any anti-EGFR antibody (e.g., an anti-domain IV EGFR antibody), including the embodiments provided herein. In some embodiments, tEGFR does not include EGFR domain III.

[0069] The term "gene" means a segment of DNA involved in the production of a protein. This includes regions before and after the coding region (leader and trailer), as well as intervening sequences (introns) between individual coding segments (exons). The leader, trailer, and introns contain regulatory elements necessary during the transcription and translation of the gene. Further, a "protein gene product" is a protein expressed from a particular gene.

[0070] The term "episome," "vector," or "expression vector" refers to a nucleic acid molecule encoding a gene and / or regulatory elements necessary for the expression of the gene. Expression of a gene from an episome can occur either cis or trans. When a gene is expressed cis, the gene and the regulatory elements are encoded by the same episome. Trans expression refers to the case where the gene and the regulatory elements are encoded by separate episomes.

[0071] The terms "transfection," "transduction," "transfect," or "transduce" can be used interchangeably and are defined as the process of introducing nucleic acid molecules and / or proteins into cells. Nucleic acids can be introduced into cells using non-viral or viral-based methods. The nucleic acid molecule can be a gene sequence encoding a complete protein or a functional portion thereof. Non-viral transfection methods include any suitable transfection method that does not use viral DNA or viral particles as a delivery system for introducing nucleic acid molecules into cells. Representative non-viral transfection methods include calcium phosphate transfection, liposome transfection, nucleofection, sonoporation, transfection through heat shock, magnetofection, and electroporation. In some embodiments, the nucleic acid molecule is introduced into cells using electroporation according to standard procedures well known in the art. In the case of virus-based methods, any useful viral vector can be used in the methods described herein. Examples of viral vectors include, but are not limited to, retroviral vectors, adenoviral vectors, lentiviral vectors, and adeno-associated viral vectors. In some embodiments, the nucleic acid molecule is introduced into cells using a retroviral vector according to standard procedures well known in the art. The terms "transfection" or "transduction" also refer to the introduction of proteins into cells from the external environment. Typically, protein transduction or transfection relies on the attachment of a peptide or protein capable of crossing the cell membrane to the protein of interest. See, for example, Ford et al. (2001), Gene Therapy 8:1-4 and Prochiantz (2007), Nat. Methods 4:119-20.

[0072] A "label" or "detectable moiety" is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means. For example, useful labels include 32P, fluorescent dyes, high electron density reagents, enzymes (such as those commonly used in ELISA), biotin, digoxigenin, or haptens, and proteins or other substances that can be made detectable by introducing a radioactive label into a peptide or antibody having specific reactivity with, for example, a target peptide. Any suitable method well known in the art for conjugating an antibody to a label (e.g., using the methods described in Hermanson, Bioconjugate Techniques 1996, Academic Press, Inc., San Diego) may be used.

[0073] When the label or detectable moiety is a radioactive metal or paramagnetic ion, a reagent and drug having a long tail with one or more chelate groups attached thereto for binding to these ions can be reacted. The long tail can be a polymer such as polylysine, polysaccharide, or another derivatized or derivatizable chain having pendant groups to which a metal or ion can be added for binding. Examples of chelate groups that can be used in accordance with the present disclosure include, but are not limited to, groups such as ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), DOTA, NOTA, NETA, TETA, porphyrin, polyamine, crown ether, bis-thiosemicarbazone, polyoxime. The chelate is usually linked to the PSMA antibody or functional antibody fragment by the group, and the group enables the formation of a bond with this molecule while minimizing loss of immunoreactivity and minimizing aggregation and / or internal cross-linking. Even the same chelate, when complexed with a non-radioactive metal such as manganese, iron, and gadolinium, is useful in MRI when used with the antibodies and carriers described herein. Macrocyclic chelates such as NOTA, DOTA, and TETA are useful with various metals and radioactive metals including, but not limited to, radionuclides of gallium, yttrium, and copper. For RAIT 223Other cyclic chelates, such as macrocyclic polyethers, which have been noted for stably binding nuclides such as Ra, may also be used. In certain embodiments, a chelating moiety is used to attach a PET imaging agent, such as an Al- 18 F complex, to a targeting molecule for use in PET analysis.

[0074] "Contacting" is used in its ordinary and customary sense and refers to a process that enables at least two different species (e.g., an antibody and an antigen) to be close enough to react, interact, or physically touch. However, it should be understood that the resulting reaction product can be generated directly from the reaction between the added reagents or can be generated from intermediates that are derived from one or more of the added reagents and are generated in the reaction mixture.

[0075] The term "contacting" may include enabling two species to react, interact, or physically touch, where the two species can be, for example, the pharmaceutical composition provided herein and a cell. In some embodiments, contacting includes, for example, enabling the pharmaceutical composition described herein to interact with a cell.

[0076] As used herein, "cell" refers to a cell that performs sufficient metabolic or other functions to preserve or replicate its genomic DNA. Cells can be identified by methods well known in the art, including, for example, the presence of an intact membrane, staining with specific dyes, the ability to produce progeny, or, in the case of gametes, the ability to combine with a second gamete to produce viable progeny. Cells can include prokaryotic and eukaryotic cells. Prokaryotic cells include, but are not limited to, bacteria. Eukaryotic cells include, but are not limited to, yeast cells and cells derived from plants and animals, such as mammalian cells, insect cells (e.g., Spodoptera), and human cells.

[0077] The term "recombinant", when used with reference to, for example, a cell, nucleic acid, protein or vector, indicates that the cell, nucleic acid, protein or vector has been modified by the introduction of a heterologous nucleic acid or protein, or by the alteration of a native nucleic acid or protein, or that the cell is derived from a cell so modified. Thus, for example, a recombinant cell expresses a gene not found in the native (non-recombinant) form of the cell, or expresses a native gene that would otherwise be abnormally expressed, under-expressed or not expressed at all. Genetically recombinant cells and plants typically express a heterologous gene or coding sequence as a result of recombinant methods.

[0078] The term "isolated", when applied to a nucleic acid or protein, means that the nucleic acid or protein is substantially free of other cellular components with which it is associated in its natural state. This can be, for example, in a homogeneous state and can be either dry or in an aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is present as the major species in a preparation is substantially purified.

[0079] The term "heterologous", when used with reference to a portion of a nucleic acid, indicates that the nucleic acid comprises two or more subsequences that are not found in essentially the same relationship to each other. For example, a nucleic acid typically has two or more sequences from unrelated genes that are recombinantly produced and arranged to create a new functional nucleic acid, for example, a promoter from one source and a coding region from another source. Similarly, a heterologous protein indicates that the protein comprises two or more subsequences that are not found in the same relationship to each other in nature (e.g., a fusion protein).

[0080] The term "exogenous" refers to a molecule or substance (e.g., a compound, nucleic acid, or protein) that is derived from outside of a given cell or organism. For example, an "exogenous promoter" as referred to herein is a promoter that is not also derived from the cell or organism in which it is expressed. Conversely, the terms "endogenous" or "endogenous promoter" refer to a molecule or substance that is naturally present in or derived within a given cell or organism.

[0081] The term "expression" includes any stage involved in polypeptide production, including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting proteins (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0082] The term "biological sample" or "sample" refers to a material obtained from or derived from a subject or patient. Biological samples include tissue sections such as biopsy samples and autopsy samples, and frozen sections taken for histological purposes. Such samples include body fluids such as blood and blood fractions or blood products (e.g., serum, plasma, platelets, red blood cells, etc.), sputum, tissue, cultured cells (e.g., primary cultures, explants, and transformed cells), feces, urine, synovial fluid, joint tissue, immune cells, hematopoietic cells, fibroblasts, macrophages, T cells, etc. Biological samples are typically obtained from eukaryotes such as mammals (primates such as chimpanzees or humans, cows, dogs, cats, rodents such as guinea pigs, rats, mice, rabbits, or birds, reptiles, or fish, etc.).

[0083] "Control" or "standard control" refers to a reference for comparison with a test sample, measurement, or value, usually a sample, measurement, or value that functions as a well-known reference. For example, a test sample can be taken from a patient suspected of having a given disease (e.g., cancer) and compared to a well-known normal (non-afflicted) individual (e.g., the standard control subject). A standard control can also represent the average measurement or value collected from a population of similar individuals (e.g., the standard control population) without a given disease (e.g., the standard control subject), such as healthy individuals with a similar medical background, the same age, weight, etc. For example, a control can be devised for comparing therapeutic benefits based on pharmacological data (e.g., half-life) or treatment means (e.g., comparison of side effects). Controls are also useful for determining the significance of data. For example, if the value of a given parameter varies widely in the control, the variation in the test sample is not considered significant. One of ordinary skill in the art will recognize that a standard control can be designed for the evaluation of any number of parameters (e.g., RNA level, protein level, specific cell type, specific body fluid, specific tissue, etc.).

[0084] One of ordinary skill in the art will understand which standard control is most appropriate in a given situation and be able to analyze the data based on comparison to the standard control values. Standard controls are also useful for determining the significance (e.g., statistical superiority) of data. For example, if the value of a given parameter varies widely in the standard control, the variation in the test sample is not considered significant.

[0085] "Patient" or "subject in need" refers to an organism that has or is susceptible to a disease or condition that can be treated by administration of a composition or pharmaceutical composition provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient is a human.

[0086] The terms "disease" or "condition" refer to the existing state or health condition of a patient or subject that can be treated with the compounds or methods provided herein. The disease can be cancer. Cancer may refer to a solid malignant tumor. Solid malignant tumors can include malignant tumors that may lack body fluids or cysts. For example, solid malignant tumors can include breast cancer, ovarian cancer, pancreatic cancer, cervical cancer, gastric cancer, renal cancer, head and neck cancer, bone cancer, skin cancer, or prostate cancer. In some further examples, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, including solid cancers and lymphoid cancers, renal cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer, and liver cancer including hepatocellular carcinoma, B acute lymphoblastic lymphoma, non-Hodgkin lymphoma (e.g., Burkitt lymphoma, small cell lymphoma, and large cell lymphoma), Hodgkin lymphoma, lymphomas including leukemias (including acute myeloid leukemia (AML), ALL, and CML), or multiple myeloma.

[0087] As used herein, the term "cancer" refers to any type of cancer, neoplasm, or malignant tumor found in a mammal (e.g., human), including leukemia, carcinoma, and sarcoma. Exemplary cancers that can be treated with the compounds or methods provided herein include breast cancer, colon cancer, renal cancer, leukemia, lung cancer, melanoma, and ovarian cancer.

[0088] The term "modulate" is used according to its plain and ordinary meaning and refers to the action of changing or varying one or more properties. "Modulation" refers to the process of changing or varying one or more properties. For example, as applied to the effect of a modulator on a target protein, to modulate means to change by increasing or decreasing the property or function of the target molecule or the amount of the target molecule.

[0089] In the context of a substance or the activity or function of a substance associated with a disease (e.g., a protein-related disease, cancer (e.g., breast cancer, lung cancer)), the terms "associated" or "associated with" mean that the substance or the activity or function of the substance is (wholly or partly) the cause of the disease (e.g., cancer) or (wholly or partly) the cause of the symptoms of that disease. As used herein, what is described as being associated with a disease can, when it is a causative substance, be a target for the treatment of the disease.

[0090] As used herein, the term "abnormal" refers to being different from normal. When used to describe enzyme activity, abnormal refers to an activity that is greater or less than the average of a normal control or a normal non-disease control sample. Abnormal activity may refer to the amount of activity that causes a disease, and by returning the abnormal activity to a normal amount or a non-disease-related amount (e.g., by using the methods described herein), a reduction in the disease or one or more symptoms is brought about.

[0091] As used herein, a "therapeutic agent" is a composition useful for treating or preventing a disease such as cancer (e.g., leukemia). In some embodiments, the therapeutic agent is an anti-cancer agent. An "anti-cancer agent" is used in its plain ordinary meaning and refers to a composition (e.g., a compound, drug, antagonist, inhibitor, modulator) having anti-neoplastic properties or the ability to inhibit cell growth or proliferation. In embodiments, the anti-cancer agent is a chemotherapeutic agent. In embodiments, the anti-cancer agent is an agent identified herein as being useful in a method of treating cancer. In embodiments, the anti-cancer agent is an agent approved by the FDA or a similar regulatory agency in a country other than the United States for treating cancer.

[0092] As used herein, "treating" or "treatment of" a condition, disease or disorder, or a symptom associated with a condition, disease or disorder refers to an approach for obtaining a beneficial or desired result, including clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation or improvement of one or more symptoms or conditions, reduction in the degree of a condition, disorder or disease, stabilization of the state of a condition, disorder or disease, prevention of the onset of a condition, disorder or disease, prevention of the spread of a condition, disorder or disease, delay or slowing of the progression of a condition, disorder or disease, delay or slowing of the onset of a condition, disorder or disease, improvement or alleviation of the state of a condition, disorder or disease, and remission (partial or complete). "Treating" can also mean extending the survival of a subject beyond that predicted in the absence of treatment. "Treating" can also mean inhibiting the progression of a condition, disorder or disease, or temporarily delaying the progression of a condition, disorder or disease, and in some cases, can include permanently halting the progression of a condition, disorder or disease. As used herein, the terms treatment, treat, or treating refer to a method of reducing the effects of one or more symptoms of a disease or condition characterized by protease expression, or a symptom of a disease or condition characterized by protease expression. Thus, in the disclosed methods, treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an established disease, condition, or symptom of a disease or condition. For example, a method for treating a disease is considered a treatment if there is a 10% reduction in one or more symptoms of the disease in a subject compared to a control. Thus, the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction between 10% and 100% compared to the native or control level. It is understood that treatment does not necessarily refer to the cure or complete elimination of a disease, condition, or symptom of a disease or condition.Furthermore, as used herein, references to reduction, decrease, or inhibition include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to a control level, and such terms may, but do not necessarily, include complete elimination.

[0093] The terms "dosage" and "dose" are used interchangeably herein. Dosage refers to the amount of active ingredient administered to an individual at each administration. Dosage varies depending on several factors including the normal dosage range for a given treatment, frequency of administration, size and tolerance of the individual, severity of the condition, risk of side effects, and route of administration. One of ordinary skill in the art will recognize that dosage can be altered depending on the above factors or based on the progress of the treatment. The term "dosage form" refers to a specific form of a pharmaceutical or pharmaceutical composition and depends on the route of administration. For example, the dosage form can be a liquid form for nebulization (e.g., an inhalant), a tablet or liquid (e.g., for oral delivery), or saline (e.g., for injection).

[0094] A "control" sample or value refers to a sample that serves as a reference for comparison with a test sample, typically a known reference. For example, a test sample can be taken from test conditions in the presence of, for example, a test compound, and compared to a sample obtained from known conditions in the absence of the test compound (negative control) or in the presence of a known compound (positive control). The control can also represent an average value collected from several tests or results. One of ordinary skill in the art will recognize that a control can be designed for the evaluation of any number of parameters. For example, a control can be devised for comparing therapeutic benefits based on pharmacological data (e.g., half-life) or treatment means (e.g., comparison of side effects). One of ordinary skill in the art will understand which control is beneficial in a given situation and will be able to analyze data based on comparison with the control values. The control is also useful for determining the significance of data. For example, if the values of a given parameter vary widely in the control, the variation in the test sample is not considered significant.

[0095] "Patient" or "subject in need" refers to an organism that has or is susceptible to a disease or condition that can be treated by administration of a composition or pharmaceutical composition provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient is human.

[0096] The term "disease" or "condition" refers to the state of being or health state of a patient or subject that can be treated with a compound, pharmaceutical composition, or method provided herein. In some embodiments, the disease is cancer (e.g., lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia, lymphoma (Mantel cell lymphoma), head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma).

[0097] As used herein, the term "cancer" refers to all types of cancers, neoplasms, or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, melanoma, neuroendocrine tumors, carcinomas, and sarcomas. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include lymphoma (e.g., Mantel cell lymphoma, follicular lymphoma, diffuse large B cell lymphoma, marginal zone lymphoma, Burkitt lymphoma), sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., triple negative, ER positive, ER negative, chemotherapy resistant, Herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung cancer, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid, sarcoma), glioblastoma multiforme, glioma, melanoma, prostate cancer, castration-resistant prostate cancer, breast cancer, triple negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., of the head, neck or esophagus), colorectal cancer, leukemia (e.g., lymphoblastic leukemia, chronic lymphocytic leukemia, hairy cell leukemia), acute myeloid leukemia, lymphoma, B cell lymphoma, or multiple myeloma. Further examples include thyroid cancer, endocrine cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, or medulloblastoma, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, Waldenström's macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urogenital cancer, hypercalcemia of malignancy, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic neoplasms, medullary thyroid carcinoma, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget's disease of the nipple, phyllodes tumor, lobular carcinoma, ductal carcinoma, pancreatic stellate cell carcinoma, hepatic stellate cell carcinoma or prostate cancer.

[0098] The term "leukemia" broadly refers to a progressive malignant disease of the hematopoietic organs, generally characterized by the abnormal proliferation and development of white blood cells and their progenitor cells in the blood and bone marrow. Leukemias are generally clinically classified based on (1) the duration and characteristics of the disease - acute or chronic, (2) the type of cells involved, myeloid (myelogenous), lymphoid (lymphocytic), or monocytic, and (3) the increase or non-increase in the number of abnormal cells in the blood - leukemia or non-leukemia (subleukemia). The P388 leukemia model is widely accepted as predicting in vivo anti-leukemia activity. Compounds that show positive in the P388 assay are generally considered to show a certain level of anti-leukemia activity in vivo, regardless of the type of leukemia being treated. Accordingly, the present application includes methods of treating leukemia, preferably acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocythemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelogenous leukemia, cutaneous leukemia, fetal leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphocytic leukemia, lymphocytic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micro-myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelogenous leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, leader cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.

[0099] As used herein, the terms "metastasis," "metastatic," and "metastatic cancer" can be used interchangeably and refer to the spread of a proliferative disease or disorder (e.g., cancer) from one organ or another non-adjacent organ or part of the body. Cancer originates at a primary tumor site, e.g., the breast, and is referred to as a primary breast cancer. Some cancer cells at the primary tumor or site of origin acquire the ability to penetrate and invade the surrounding normal tissue in the local area and / or penetrate the walls of the lymphatic or vascular system and circulate through the system to other parts and tissues of the body. Clinically detectable secondary tumors formed from the cancer cells of the primary tumor are called metastatic or secondary tumors. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be the same as those of the original tumor. Thus, when lung cancer metastasizes to the breast, the secondary tumor at the breast site consists of abnormal lung cells and not abnormal breast cells. The secondary tumor in the breast is called metastatic lung cancer. Thus, the phrase "metastatic cancer" refers to a disease in which a subject has one or more secondary tumors that had or have a primary tumor. The phrase "subject having a non-metastatic cancer or a cancer that is not metastatic" refers to a disease in which a subject has a primary tumor but no one or more secondary tumors. For example, metastatic lung cancer refers to a disease in a subject who has a history of a primary lung tumor and has one or more secondary tumors at a second site or multiple sites, e.g., the breast.

[0100] In the context of a substance or the activity or function of a substance associated with a disease (e.g., cancer), the terms "associated" or "associated with" mean that the substance or the activity or function of the substance is (wholly or partially) the cause of the disease (e.g., cancer) or (wholly or partially) the cause of the symptoms of that disease.

[0101] As used herein, the terms "treatment" or "treating" or "palliating" or "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results, including but not limited to therapeutic and / or prophylactic benefits. "Therapeutic benefit" means eradication or amelioration of the underlying disease being treated. Also, a therapeutic benefit is achieved by eradication or alleviation of one or more of the physiological symptoms associated with the underlying disease such that an improvement is observed in the patient, even though the patient may still be afflicted with the underlying disease. For prophylactic benefit, the compositions can be administered to a patient at risk of developing a particular disease or to a patient reporting one or more physiological symptoms of a disease, even though no diagnosis of this disease has been made. Treatment includes preventing a disease, i.e., causing the clinical symptoms of a disease not to develop by administering a protective composition prior to the induction of the disease, suppressing a disease, i.e., causing the clinical symptoms of a disease not to develop by administering a protective composition after an inciting event but prior to the clinical appearance or reappearance of the disease, inhibiting a disease, i.e., preventing the expression of the disease by administering a protective composition after the clinical symptoms have first appeared, preventing recurrence of a disease, and / or alleviating a disease, i.e., causing regression of the disease by administering a protective composition after the clinical symptoms have first appeared. For example, certain methods herein are for treating cancer (e.g., lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma). For example, certain methods herein treat cancer by reducing or decreasing or preventing the development, growth, metastasis or progression of cancer or by alleviating the symptoms of cancer.The symptoms of cancer (e.g., lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma) are those that would be known to those skilled in the art or can be determined by those skilled in the art.

[0102] As used herein, the terms "treatment", "treat", or "treating" refer to a method of reducing one or more symptoms of a disease or condition characterized by the expression of a protease, or the effect of the symptoms of a disease or condition characterized by the expression of a protease. Thus, in the disclosed methods, treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an established disease, condition, or symptoms of a disease or condition. For example, a method for treating a disease is considered a treatment if there is a 10% reduction in one or more symptoms of the disease in a subject compared to a control. Thus, the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction between 10% and 100% compared to the native or control level. It is understood that treatment does not necessarily refer to the cure or complete elimination of a disease, condition, or symptoms of a disease or condition. Further, as used herein, references to decrease, reduction, or inhibition include a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater change compared to the control level, and such terms can include, but do not necessarily include, complete elimination.

[0103] The terms "dosage" and "dose" are used interchangeably herein. Dosage refers to the amount of active ingredient given to an individual in each administration. Dosage varies according to several factors including the normal dosage range for a given treatment, frequency of administration, size and tolerance of the individual, severity of the condition, risk of side effects, and route of administration. One of ordinary skill in the art will recognize that the dosage can be altered depending on the above factors or based on the progression of the treatment. The term "dosage form" refers to a specific form of a medicament or pharmaceutical composition and depends on the route of administration. For example, the dosage form can be a liquid form for nebulization (e.g., inhalant), a tablet or liquid (e.g., for oral delivery), or saline (e.g., for injection).

[0104] As used herein, "therapeutically effective dosage or amount" means a dosage that produces the effect for which it is administered (e.g., treatment or prevention of a disease). Its exact dosage and formulation will depend on the purpose of the treatment and can be elucidated by one of ordinary skill in the art using well-known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992), Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999), Remington: The Science and Practice of Pharmacy, 20th Edition, Gennaro, Editor (2003), and Pickar, Dosage Calculations (1999)). For example, for a given parameter, the therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic effectiveness can also be expressed as an increase or decrease of "~-fold". For example, the therapeutically effective amount can be at least 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effective than the control. A therapeutically effective dosage or amount can improve one or more symptoms of a disease. A therapeutically effective dosage or amount can prevent or delay the onset of a disease or one or more symptoms of a disease if the effect for which it is administered is to treat a person at risk of developing the disease.

[0105] "Effective amount" means an amount sufficient to achieve the stated purpose (e.g., to achieve the effect for which it is administered, to treat a disease, to reduce enzyme activity, to reduce one or more symptoms of a disease or condition, etc.). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or alleviation of the symptoms of a disease, which may also be referred to as a "therapeutically effective amount". "Alleviation" (and grammatical equivalents of this phrase) of a symptom(s) means a decrease in the severity or frequency of the symptom(s), or the elimination of the symptom(s). A "prophylactically effective amount" of a drug, when administered to a subject, is an amount of the drug that is expected to result in the intended prophylactic effect, e.g., to prevent (or delay) the onset (or recurrence) of an injury, disease, disorder, or condition, or to reduce the likelihood of the onset (or recurrence) of an injury, disease, lesion, or condition, or their symptoms. A complete prophylactic effect does not necessarily occur upon administration of a single dose and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. As used herein, an "amount that reduces activity" refers to the amount of an antagonist required to reduce the activity of an enzyme or protein as compared to the absence of the antagonist. As used herein, an "amount that interferes with function" refers to the amount of an antagonist required to interfere with the function of an enzyme or protein as compared to the absence of the antagonist. Guidelines can be found in the literature regarding the appropriate dosage of a given class of pharmaceuticals. For example, for a given parameter, an effective amount may show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Efficacy can also be expressed as an increase or decrease in "fold". For example, a therapeutically effective amount may be at least 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effective than a control.The exact amount will depend on the purpose of treatment and will be ascertainable by those skilled in the art using techniques known to them (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992), Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999), Pickar, Dosage Calculations (1999), and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0106] As used herein, the term "administering" means oral administration to a subject, administration as a suppository, topical contact, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intranasal administration or subcutaneous administration, or implantation of a sustained release device, such as a small osmotic pump. Administration can be by any route, including parenteral and transmucosal (e.g., oral, sublingual, palatal, gingival, nasal, vaginal, rectal or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, arteriolar, intradermal, subcutaneous, intraperitoneal, intracerebroventricular and intracranial. Other delivery modes include, but are not limited to, the use of liposomal formulations, intravenous infusions, transdermal patches, etc. "Concurrent administration" means administering the compositions described herein either simultaneously with, immediately before, or immediately after the administration of one or more additional therapies, such as cancer therapies like chemotherapy, hormone therapy, radiation therapy or immunotherapy. The compounds of the invention can be administered alone or concurrently with a patient. Concurrent administration is intended to include co - administration or sequential administration of the compounds, either individually or in combination (two or more compounds). For this reason, the preparation can be combined with other active substances, if desired (e.g., to reduce metabolic degradation). The compositions of the invention can also be formulated for transdermal delivery, delivery by topical route, and can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, nanoparticles, pastes, jellies, paints, powders, and aerosols.

[0107] In some embodiments, the method further comprises administering an additional therapeutic agent to the subject. As noted above, the therapeutic agent is a composition useful for treating or preventing a disease such as cancer. In some embodiments, the additional therapeutic agent is an anti - cancer agent.

[0108] Xamoterone), finasteride, aromatase inhibitor, gonadotropin-releasing hormone agonist (GnRH), for example, goserelin or leuprolide, adrenal corticosteroid (e.g., prednisone), progestin (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogen (e.g., diethylstilbestrol, ethinyl estradiol), anti-estrogen (e.g., tamoxifen), androgen (e.g., testosterone propionate, fluoxymesterone), anti-androgen (e.g., flutamide), immunostimulant (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibody (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibody), immunotoxin (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., anti-CD20 monoclonal antibody conjugated to 111In, 90Y, or 131I, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, seribastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitor, epidermal growth factor receptor (EGFR) targeted therapy or therapeutic agent (e.g., gefitinib (Iressa (trademark)), erlotinib (Tarceva (trademark)), cetuximab (Erbitux (trademark)), lapatinib (Tykerb (trademark)), panitumumab (Vectibix (trademark)), vandetanib (Caprelsa (trademark)), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OSI-420 / desmethyl erlotinib, AZD8931, AEE788,Examples include, but are not limited to, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, etc.

[0109] Formulations suitable for oral administration may be (a) a liquid solution such as an effective amount of an antibody provided herein suspended in a diluent such as water, physiological saline or PEG400, (b) capsules, cachets or tablets each containing a predetermined amount of the active ingredient as a liquid, solid, granule or gelatin, (c) a suspension using a suitable liquid, and (d) a suitable emulsion. Tablet forms can include one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphate, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, coloring agents, bulking agents, binders, diluents, buffers, wetting agents, preservatives, flavoring agents, dyes, disintegrants, and pharmaceutically compatible carriers. Troche forms can include the active ingredient in a flavoring agent (e.g., sucrose), and can include troches containing the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia emulsion, gel, etc., and containing a carrier known in the art in addition to the active ingredient.

[0110] The pharmaceutical composition may also include macromolecules with large molecular weights and slow metabolism, such as proteins, polysaccharides such as chitosan, polylactic acid, polyglycolic acid and copolymers (such as latex-functionalized sepharose (trademark), agarose, cellulose, etc.), polymeric amino acids, amino acid copolymers, and lipid aggregates (such as oil droplets and liposomes, etc.). Furthermore, these carriers can function as immunostimulants (i.e., adjuvants).

[0111] Examples of formulations suitable for rectal administration include, for example, suppositories composed of nucleic acids encapsulated in a suppository base. Suitable suppository bases include natural or synthetic triglycerides or paraffin hydrocarbons. Furthermore, it is also possible to use gelatin rectal capsules composed of a combination of the selected compound and a base containing, for example, liquid triglycerides, polyethylene glycol, and paraffin hydrocarbons.

[0112] Examples of formulations suitable for parenteral administration by, for example, intra-articular (intra-articular), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, and subcutaneous routes include aqueous and non-aqueous isotonic sterile injection solutions, which may include antioxidants, buffers, bacteriostatic agents, solutes that make the formulation isotonic with the blood of the recipient for whom the formulation is intended, and may include aqueous and non-aqueous sterile suspensions that may contain suspending agents, solubilizing agents, thickening agents, stabilizers, and preservatives. In the practice of the present invention, the composition can be administered, for example, by intravenous infusion, orally, topically, intraperitoneally, intravesically, or intrathecally. Parenteral administration, oral administration, and intravenous administration are preferred routes of administration. The formulation of the compound can be provided in sealed containers of unit dose or multiple doses such as ampoules and vials.

[0113] Injection solutions and injection suspensions can be prepared from sterile powders, granules, and tablets as described above. Cells transfected with nucleic acids for ex vivo therapy can also be administered intravenously or parenterally as described above.

[0114] Pharmaceutical preparations are preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form can be a packaged formulation, and the package can include individual amounts of the formulation such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or a form in which any of these are appropriately packaged in a number. The above composition can also optionally include other compatible therapeutic agents.

[0115] Combined administration contemplates co - administration using separate formulations or a single pharmaceutical formulation, and sequential administration in either order, where preferably there is a period during which both (or all) of the active agents exert their biological activity simultaneously.

[0116] The effective amount of the compositions provided herein can vary depending on a number of diverse factors including the means of administration, the target site, the physiological state of the patient, whether the patient is human or an animal, other drugs being administered, and whether the treatment is for prophylactic or therapeutic purposes. However, one of ordinary skill in the art will readily appreciate an appropriate and / or equivalent dosage by looking at the dosages of approved compositions for treating and preventing cancer as a guide.

[0117] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that can be included in the compositions of the present invention that assist in the administration of the active agent to the subject and its absorption by the subject without causing significant adverse toxic effects to the patient. Non - limiting examples of pharmaceutically acceptable excipients include water, NaCl, standard physiological saline aqueous solutions, lactated Ringer's solution, standard sucrose, standard glucose, binders, fillers, disintegrants, lubricants, coating agents, sweetening agents, flavoring agents, saline solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations may be sterilized and, if necessary, may be mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifying agents, salts for influencing osmotic pressure, buffering agents, coloring agents and / or aromatic substances that do not show an adverse reaction with the compounds of the present invention. One of ordinary skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0118] The term "pharmaceutically acceptable salt" is derived from various organic and inorganic counterions well-known in the art, and by way of example only, refers to salts such as sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and when the molecule contains a basic functional group, refers to salts of organic acids or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc.

[0119] The term "formulation" is intended to include a combination of an active compound and a capsule encapsulation material as a carrier providing the capsule, and the active ingredient, whether or not containing other carriers in the capsule, is surrounded by and thus associated with the carrier. Similarly, cachets and troches are included. Tablets, powders, capsules, pills, cachets, and troches can be used as solid dosage forms suitable for oral administration.

[0120] Pharmaceutical formulations are preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of the active constituent. The unit dosage form can be a packaged formulation, and the package contains individual amounts of the formulation such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be the capsule, tablet, cachet, or troche itself, or a form in which any of these are packaged in appropriate numbers. The unit dosage form can be that of a frozen dispersion.

[0121] The composition of the present invention may further comprise components for providing sustained release and / or comfort. Such components include high molecular weight anionic mucoadhesive polymers, gelling polysaccharides, and finely divided drug carrier matrices. These components are discussed in more detail in U.S. Patent Nos. 4,911,920, 5,403,841, 5,212,162, and 4,861,760. The entire contents of these patents are hereby incorporated by reference in their entirety for all purposes. The composition of the present invention can also be delivered as microspheres for sustained release in the body. For example, the microspheres can be administered by intradermal injection of drug-containing microspheres for subcutaneous sustained release (see Rao, J. Biomater Sci. Polym. Ed. 7: 623-645, 1995), as biodegradable injectable gel formulations (e.g., see Gao Pharm. Res. 12: 857-863, 1995), or as microspheres for oral administration (e.g., see Eyles, J. Pharm. Pharmacol. 49: 669-674, 1997). In some embodiments, the formulation of the composition of the present invention can be delivered by the use of liposomes that fuse with cell membranes or are endocytosed, i.e., by using receptor ligands that are attached to the liposomes and bind to cell surface membrane protein receptors that cause endocytosis. In particular, when the liposome surface carries receptor ligands specific for target cells or is preferentially directed to specific organs, the use of liposomes can concentrate the delivery of the composition of the present invention to target cells in vivo. (See, for example, Al-Muhammed, J. Microencapsul. 13: 293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6: 698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46: 1576-1587, 1989). The composition of the present invention can also be delivered as nanoparticles.

[0122] The examples and embodiments described in this specification are for illustrative purposes only, and it is understood that various modifications or changes contemplated thereby would be suggested to those skilled in the art and should be within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

[0123] The examples and embodiments described in this specification are for illustrative purposes only, and it is understood that various modifications or changes contemplated thereby would be suggested to those skilled in the art and should be within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

[0124] Anti-CD84 antibody In particular, antibodies that can bind to the differentiation antigen cluster 84 (CD84: Cluster of Differentiation 84) are provided herein. The antibodies provided herein include novel light chain and heavy chain sequences and bind to CD84 with high efficiency and specificity. Based on these binding characteristics, the antibodies provided herein can effectively mediate antibody-dependent cell cytotoxicity (ADCC) in the cancer microenvironment, which triggers cell-mediated immune defense, whereby effector cells of the immune system actively lyse CD84-expressing cancer cells. Thus, CD84 antibodies, including the embodiments provided herein, are useful for the purpose of anti-cancer treatment.

[0125] In one aspect, there is provided an anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 75, CDR H2 set forth in SEQ ID NO: 76, and CDR H3 set forth in SEQ ID NO: 77, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 78, CDR L2 set forth in SEQ ID NO: 79, and CDR L3 set forth in SEQ ID NO: 80.

[0126] In another aspect, provided is an anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 comprising the sequence set forth in SEQ ID NO: 75, CDR H2 comprising the sequence set forth in SEQ ID NO: 76, and CDR H3 comprising the sequence set forth in SEQ ID NO: 77, and the light chain variable domain comprises CDR L1 comprising the sequence set forth in SEQ ID NO: 78, CDR L2 comprising the sequence set forth in SEQ ID NO: 79, and CDR L3 comprising the sequence set forth in SEQ ID NO: 80.

[0127] In some embodiments, the anti-CD84 antibody is a chimeric antibody. In some embodiments, the anti-CD84 antibody is a humanized antibody.

[0128] In some embodiments, the heavy chain variable domain comprises FR H1 set forth in SEQ ID NO: 81, FR H2 set forth in SEQ ID NO: 82, FR H3 set forth in SEQ ID NO: 83, and FR H4 set forth in SEQ ID NO: 84. In some embodiments, the light chain variable domain comprises FR L1 set forth in SEQ ID NO: 85, FR L2 set forth in SEQ ID NO: 86, FR L3 set forth in SEQ ID NO: 87, and FR L4 set forth in SEQ ID NO: 88.

[0129] In some embodiments, the heavy chain variable domain comprises FR H1 comprising the sequence set forth in SEQ ID NO: 81, FR H2 comprising the sequence set forth in SEQ ID NO: 82, FR H3 comprising the sequence set forth in SEQ ID NO: 83, and FR H4 comprising the sequence set forth in SEQ ID NO: 84. In some embodiments, the light chain variable domain comprises FR L1 comprising the sequence set forth in SEQ ID NO: 85, FR L2 comprising the sequence set forth in SEQ ID NO: 86, FR L3 comprising the sequence set forth in SEQ ID NO: 87, and FR L4 comprising the sequence set forth in SEQ ID NO: 88.

[0130] In some embodiments, the heavy chain variable domain comprises the sequence of SEQ ID NO: 89. In some embodiments, the heavy chain variable domain has the sequence of SEQ ID NO: 89. In some embodiments, the light chain variable domain comprises the sequence of SEQ ID NO: 90. In some embodiments, the light chain variable domain has the sequence of SEQ ID NO: 90.

[0131] In some embodiments, the anti-CD84 antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 91. In some embodiments, the anti-CD84 antibody comprises a heavy chain having the sequence of SEQ ID NO: 91. In some embodiments, the anti-CD84 antibody comprises a light chain comprising the sequence of SEQ ID NO: 92. In some embodiments, the anti-CD84 antibody comprises a light chain having the sequence of SEQ ID NO: 92. In some embodiments, the anti-CD84 antibody is referred to herein as clone 7D2.

[0132] In another aspect, provided is an anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 19, CDR H2 set forth in SEQ ID NO: 20, and CDR H3 set forth in SEQ ID NO: 21, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 22, CDR L2 set forth in SEQ ID NO: 23, and CDR L3 set forth in SEQ ID NO: 24.

[0133] In another aspect, provided is an anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 comprising the sequence set forth in SEQ ID NO: 19, CDR H2 comprising the sequence set forth in SEQ ID NO: 20, and CDR H3 comprising the sequence set forth in SEQ ID NO: 21, and the light chain variable domain comprises CDR L1 comprising the sequence set forth in SEQ ID NO: 22, CDR L2 comprising the sequence set forth in SEQ ID NO: 23, and CDR L3 comprising the sequence set forth in SEQ ID NO: 24.

[0134] In some embodiments, the anti-CD84 antibody is a humanized antibody. In some embodiments, the antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 37. In some embodiments, the antibody comprises a heavy chain having the sequence of SEQ ID NO: 37. In some embodiments, the antibody comprises a light chain comprising the sequence of SEQ ID NO: 38. In some embodiments, the antibody comprises a light chain having the sequence of SEQ ID NO: 38.

[0135] In some embodiments, the anti-CD84 antibody is a chimeric antibody. In some embodiments, the heavy chain variable domain comprises FR H1 as set forth in SEQ ID NO: 25, FR H2 as set forth in SEQ ID NO: 26, FR H3 as set forth in SEQ ID NO: 27, and FR H4 as set forth in SEQ ID NO: 28. In some embodiments, the light chain variable domain comprises FR L1 as set forth in SEQ ID NO: 29, FR L2 as set forth in SEQ ID NO: 30, FR L3 as set forth in SEQ ID NO: 31, and FR L4 as set forth in SEQ ID NO: 32. In some embodiments, the heavy chain variable domain comprises FR H1 comprising the sequence set forth in SEQ ID NO: 25, FR H2 comprising the sequence set forth in SEQ ID NO: 26, FR H3 comprising the sequence set forth in SEQ ID NO: 27, and FR H4 comprising the sequence set forth in SEQ ID NO: 28. In some embodiments, the light chain variable domain comprises FR L1 comprising the sequence set forth in SEQ ID NO: 29, FR L2 comprising the sequence set forth in SEQ ID NO: 30, FR L3 comprising the sequence set forth in SEQ ID NO: 31, and FR L4 comprising the sequence set forth in SEQ ID NO: 32.

[0136] In some embodiments, the heavy chain variable domain comprises the sequence of SEQ ID NO: 33. In some embodiments, the heavy chain variable domain has the sequence of SEQ ID NO: 33. In some embodiments, the light chain variable domain comprises the sequence of SEQ ID NO: 34. In some embodiments, the light chain variable domain has the sequence of SEQ ID NO: 34. In some embodiments, the antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 35. In some embodiments, the antibody comprises a heavy chain having the sequence of SEQ ID NO: 35. In some embodiments, the antibody comprises a light chain comprising the sequence of SEQ ID NO: 36. In some embodiments, the antibody comprises a light chain having the sequence of SEQ ID NO: 36. In some embodiments, the anti-CD84 antibody is referred to herein as clone 13D11.

[0137] In another aspect, there is provided an anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 39, CDR H2 set forth in SEQ ID NO: 40, and CDR H3 set forth in SEQ ID NO: 41, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 42, CDR L2 set forth in SEQ ID NO: 43, and CDR L3 set forth in SEQ ID NO: 44.

[0138] In another aspect, there is provided an anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 comprising the sequence set forth in SEQ ID NO: 39, CDR H2 comprising the sequence set forth in SEQ ID NO: 40, and CDR H3 comprising the sequence set forth in SEQ ID NO: 41, and the light chain variable domain comprises CDR L1 comprising the sequence set forth in SEQ ID NO: 42, CDR L2 comprising the sequence set forth in SEQ ID NO: 43, and CDR L3 comprising the sequence set forth in SEQ ID NO: 44.

[0139] In some embodiments, the anti-CD84 antibody is a chimeric antibody. In some embodiments, the anti-CD84 antibody is a humanized antibody. In some embodiments, the heavy chain variable domain comprises FR H1 set forth in SEQ ID NO: 45, FR H2 set forth in SEQ ID NO: 46, FR H3 set forth in SEQ ID NO: 47, and FR H4 set forth in SEQ ID NO: 48. In some embodiments, the light chain variable domain comprises FR L1 set forth in SEQ ID NO: 49, FR L2 set forth in SEQ ID NO: 50, FR L3 set forth in SEQ ID NO: 51, and FR L4 set forth in SEQ ID NO: 52. In some embodiments, the heavy chain variable domain comprises FR H1 comprising the sequence set forth in SEQ ID NO: 45, FR H2 comprising the sequence set forth in SEQ ID NO: 46, FR H3 comprising the sequence set forth in SEQ ID NO: 47, and FR H4 comprising the sequence set forth in SEQ ID NO: 48. In some embodiments, the light chain variable domain comprises FR L1 comprising the sequence set forth in SEQ ID NO: 49, FR L2 comprising the sequence set forth in SEQ ID NO: 50, FR L3 comprising the sequence set forth in SEQ ID NO: 51, and FR L4 comprising the sequence set forth in SEQ ID NO: 52.

[0140] In some embodiments, the heavy chain variable domain comprises the sequence of SEQ ID NO: 53. In some embodiments, the heavy chain variable domain has the sequence of SEQ ID NO: 53. In some embodiments, the light chain variable domain comprises the sequence of SEQ ID NO: 54. In some embodiments, the light chain variable domain has the sequence of SEQ ID NO: 54. In some embodiments, the anti-CD84 antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 55. In some embodiments, the anti-CD84 antibody comprises a heavy chain having the sequence of SEQ ID NO: 55. In some embodiments, the anti-CD84 antibody comprises a light chain comprising the sequence of SEQ ID NO: 56. In some embodiments, the anti-CD84 antibody comprises a light chain having the sequence of SEQ ID NO: 56. In some embodiments, the anti-CD84 antibody is referred to herein as clone 2H7.

[0141] In another aspect, there is provided an anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 57, CDR H2 set forth in SEQ ID NO: 58, and CDR H3 set forth in SEQ ID NO: 59, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 60, CDR L2 set forth in SEQ ID NO: 61, and CDR L3 set forth in SEQ ID NO: 62.

[0142] In another aspect, there is provided an anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 comprising the sequence set forth in SEQ ID NO: 57, CDR H2 comprising the sequence set forth in SEQ ID NO: 58, and CDR H3 comprising the sequence set forth in SEQ ID NO: 59, and the light chain variable domain comprises CDR L1 comprising the sequence set forth in SEQ ID NO: 60, CDR L2 comprising the sequence set forth in SEQ ID NO: 61, and CDR L3 comprising the sequence set forth in SEQ ID NO: 62.

[0143] In some embodiments, the anti-CD84 antibody is a chimeric antibody. In some embodiments, the anti-CD84 antibody is a humanized antibody. In some embodiments, the heavy chain variable domain comprises FR H1 set forth in SEQ ID NO: 63, FR H2 set forth in SEQ ID NO: 64, FR H3 set forth in SEQ ID NO: 65, and FR H4 set forth in SEQ ID NO: 66. In some embodiments, the light chain variable domain comprises FR L1 set forth in SEQ ID NO: 67, FR L2 set forth in SEQ ID NO: 68, FR L3 set forth in SEQ ID NO: 69, and FR L4 set forth in SEQ ID NO: 70. In some embodiments, the heavy chain variable domain comprises FR H1 comprising the sequence set forth in SEQ ID NO: 63, FR H2 comprising the sequence set forth in SEQ ID NO: 64, FR H3 comprising the sequence set forth in SEQ ID NO: 65, and FR H4 comprising the sequence set forth in SEQ ID NO: 66. In some embodiments, the light chain variable domain comprises FR L1 comprising the sequence set forth in SEQ ID NO: 67, FR L2 comprising the sequence set forth in SEQ ID NO: 68, FR L3 comprising the sequence set forth in SEQ ID NO: 69, and FR L4 comprising the sequence set forth in SEQ ID NO: 70.

[0144] In some embodiments, the heavy chain variable domain comprises the sequence of SEQ ID NO: 71. In some embodiments, the heavy chain variable domain has the sequence of SEQ ID NO: 71. In some embodiments, the light chain variable domain comprises the sequence of SEQ ID NO: 72. In some embodiments, the light chain variable domain has the sequence of SEQ ID NO: 72. In some embodiments, the anti-CD84 antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 73. In some embodiments, the anti-CD84 antibody comprises a heavy chain having the sequence of SEQ ID NO: 73. In some embodiments, the anti-CD84 antibody comprises a light chain comprising the sequence of SEQ ID NO: 74. In some embodiments, the anti-CD84 antibody comprises a light chain having the sequence of SEQ ID NO: 74. In some embodiments, the anti-CD84 antibody is referred to herein as clone 5C6.

[0145] In another aspect, provided is an anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 93, CDR H2 set forth in SEQ ID NO: 94, and CDR H3 set forth in SEQ ID NO: 95, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 96, CDR L2 set forth in SEQ ID NO: 97, and CDR L3 set forth in SEQ ID NO: 98.

[0146] In another aspect, provided is an anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 comprising the sequence set forth in SEQ ID NO: 93, CDR H2 comprising the sequence set forth in SEQ ID NO: 94, and CDR H3 comprising the sequence set forth in SEQ ID NO: 95, and the light chain variable domain comprises CDR L1 comprising the sequence set forth in SEQ ID NO: 96, CDR L2 comprising the sequence set forth in SEQ ID NO: 97, and CDR L3 comprising the sequence set forth in SEQ ID NO: 98.

[0147] In some embodiments, the anti-CD84 antibody is a chimeric antibody. In some embodiments, the anti-CD84 antibody is a humanized antibody. In some embodiments, the heavy chain variable domain comprises FR H1 set forth in SEQ ID NO: 99, FR H2 set forth in SEQ ID NO: 100, FR H3 set forth in SEQ ID NO: 101, and FR H4 set forth in SEQ ID NO: 102. In some embodiments, the light chain variable domain comprises FR L1 set forth in SEQ ID NO: 103, FR L2 set forth in SEQ ID NO: 104, FR L3 set forth in SEQ ID NO: 105, and FR L4 set forth in SEQ ID NO: 106. In some embodiments, the heavy chain variable domain comprises FR H1 comprising the sequence set forth in SEQ ID NO: 99, FR H2 comprising the sequence set forth in SEQ ID NO: 100, FR H3 comprising the sequence set forth in SEQ ID NO: 101, and FR H4 comprising the sequence set forth in SEQ ID NO: 102. In some embodiments, the light chain variable domain comprises FR L1 comprising the sequence set forth in SEQ ID NO: 103, FR L2 comprising the sequence set forth in SEQ ID NO: 104, FR L3 comprising the sequence set forth in SEQ ID NO: 105, and FR L4 comprising the sequence set forth in SEQ ID NO: 106.

[0148] In some embodiments, the heavy chain variable domain comprises the sequence of SEQ ID NO: 107. In some embodiments, the heavy chain variable domain has the sequence of SEQ ID NO: 107. In some embodiments, the light chain variable domain comprises the sequence of SEQ ID NO: 108. In some embodiments, the light chain variable domain has the sequence of SEQ ID NO: 108. In some embodiments, the anti-CD84 antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 109. In some embodiments, the anti-CD84 antibody comprises a heavy chain having the sequence of SEQ ID NO: 109. In some embodiments, the anti-CD84 antibody comprises a light chain comprising the sequence of SEQ ID NO: 110. In some embodiments, the anti-CD84 antibody comprises a light chain having the sequence of SEQ ID NO: 110. In some embodiments, the anti-CD84 antibody is referred to herein as clone 8A5.

[0149] In another aspect, there is provided an anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 1, CDR H2 set forth in SEQ ID NO: 2, and CDR H3 set forth in SEQ ID NO: 3, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 4, CDR L2 set forth in SEQ ID NO: 5, and CDR L3 set forth in SEQ ID NO: 6.

[0150] In another aspect, there is provided an anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 comprising the sequence set forth in SEQ ID NO: 1, CDR H2 comprising the sequence set forth in SEQ ID NO: 2, and CDR H3 comprising the sequence set forth in SEQ ID NO: 3, and the light chain variable domain comprises CDR L1 comprising the sequence set forth in SEQ ID NO: 4, CDR L2 comprising the sequence set forth in SEQ ID NO: 5, and CDR L3 comprising the sequence set forth in SEQ ID NO: 6.

[0151] In some embodiments, the anti-CD84 antibody is a chimeric antibody. In some embodiments, the anti-CD84 antibody is a humanized antibody. In some embodiments, the heavy chain variable domain comprises FR H1 set forth in SEQ ID NO: 7, FR H2 set forth in SEQ ID NO: 8, FR H3 set forth in SEQ ID NO: 9, and FR H4 set forth in SEQ ID NO: 10. In some embodiments, the light chain variable domain comprises FR L1 set forth in SEQ ID NO: 11, FR L2 set forth in SEQ ID NO: 12, FR L3 set forth in SEQ ID NO: 13, and FR L4 set forth in SEQ ID NO: 14. In some embodiments, the heavy chain variable domain comprises FR H1 comprising the sequence set forth in SEQ ID NO: 7, FR H2 comprising the sequence set forth in SEQ ID NO: 8, FR H3 comprising the sequence set forth in SEQ ID NO: 9, and FR H4 comprising the sequence set forth in SEQ ID NO: 10. In some embodiments, the light chain variable domain comprises FR L1 comprising the sequence set forth in SEQ ID NO: 11, FR L2 comprising the sequence set forth in SEQ ID NO: 12, FR L3 comprising the sequence set forth in SEQ ID NO: 13, and FR L4 comprising the sequence set forth in SEQ ID NO: 14.

[0152] In some embodiments, the heavy chain variable domain comprises the sequence of SEQ ID NO: 15. In some embodiments, the heavy chain variable domain has the sequence of SEQ ID NO: 15. In some embodiments, the light chain variable domain comprises the sequence of SEQ ID NO: 16. In some embodiments, the light chain variable domain has the sequence of SEQ ID NO: 16. In some embodiments, the anti-CD84 antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 17. In some embodiments, the anti-CD84 antibody comprises a heavy chain having the sequence of SEQ ID NO: 17. In some embodiments, the anti-CD84 antibody comprises a light chain comprising the sequence of SEQ ID NO: 18. In some embodiments, the anti-CD84 antibody comprises a light chain having the sequence of SEQ ID NO: 18. In some embodiments, the anti-CD84 antibody is referred to herein as clone 4B11.

[0153] In some embodiments, the anti-CD84 antibody is a Fab’ fragment. In an embodiment, the anti-CD84 antibody is IgG. In some embodiments, the anti-CD84 antibody is IgG1, IgG2, IgG3 or IgG4. In an embodiment, the anti-CD84 antibody is IgG1. In an embodiment, the anti-CD84 antibody is IgG2. In an embodiment, the anti-CD84 antibody is IgG3. In an embodiment, the anti-CD84 antibody is IgG4. In some embodiments, the light chain variable domain and the heavy chain variable domain form part of an scFv.

[0154] In some embodiments, the anti-CD84 antibody can bind to the CD84 protein. In some embodiments, the anti-CD84 antibody is bound to the CD84 protein. In some embodiments, the CD84 protein is a human CD84 protein. In some embodiments, the CD84 protein forms part of a cell. In some embodiments, the CD84 protein is expressed on the surface of a cell. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is a leukemia cancer cell, a myeloid cancer cell, or a lymphoma cancer cell. In some embodiments, the cancer cell is a leukemia cancer cell. In some embodiments, the cancer cell is a myeloid cancer cell. In some embodiments, the cancer cell is a lymphoma cancer cell.

[0155] In another aspect, there is provided an anti-CD84 antibody that binds to the same epitope as an antibody comprising a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 19, CDR H2 set forth in SEQ ID NO: 20, and CDR H3 set forth in SEQ ID NO: 21, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 22, CDR L2 set forth in SEQ ID NO: 23, and CDR L3 set forth in SEQ ID NO: 24.

[0156] In another aspect, there is provided an anti-CD84 antibody that binds to the same epitope as an antibody comprising a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 39, CDR H2 set forth in SEQ ID NO: 40, and CDR H3 set forth in SEQ ID NO: 41, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 42, CDR L2 set forth in SEQ ID NO: 43, and CDR L3 set forth in SEQ ID NO: 44.

[0157] In another aspect, there is provided an anti-CD84 antibody that comprises a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 57, CDR H2 set forth in SEQ ID NO: 58, and CDR H3 set forth in SEQ ID NO: 59, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 60, CDR L2 set forth in SEQ ID NO: 61, and CDR L3 set forth in SEQ ID NO: 62, and an anti-CD84 antibody that binds to the same epitope.

[0158] In another aspect, there is provided an anti-CD84 antibody that comprises a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 75, CDR H2 set forth in SEQ ID NO: 76, and CDR H3 set forth in SEQ ID NO: 77, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 78, CDR L2 set forth in SEQ ID NO: 79, and CDR L3 set forth in SEQ ID NO: 80, and an anti-CD84 antibody that binds to the same epitope.

[0159] In another aspect, there is provided an anti-CD84 antibody that comprises a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 93, CDR H2 set forth in SEQ ID NO: 94, and CDR H3 set forth in SEQ ID NO: 95, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 96, CDR L2 set forth in SEQ ID NO: 97, and CDR L3 set forth in SEQ ID NO: 98, and an anti-CD84 antibody that binds to the same epitope.

[0160] In another aspect, there is provided an anti-CD84 antibody that comprises a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 1, CDR H2 set forth in SEQ ID NO: 2, and CDR H3 set forth in SEQ ID NO: 3, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 4, CDR L2 set forth in SEQ ID NO: 5, and CDR L3 set forth in SEQ ID NO: 6, and an anti-CD84 antibody that binds to the same epitope.

[0161] In some embodiments, the anti-CD84 antibody is conjugated to a therapeutic moiety or a diagnostic moiety. In some embodiments, the anti-CD84 antibody is conjugated to a therapeutic moiety. In some embodiments, the anti-CD84 antibody is conjugated to a diagnostic moiety. In some embodiments, the therapeutic moiety is an anti-cancer moiety.

[0162] As described above, the "light chain variable (VL) domain" provided herein forms part of the variable region of the light chain of an antibody, antibody variant, or fragment thereof. Similarly, the "heavy chain variable (VH) domain" provided herein forms part of the variable region of the heavy chain of an antibody, antibody variant, or fragment thereof. The light chain variable domain and the heavy chain variable domain together form a paratope, which binds to an antigen (epitope). The paratope or antigen-binding site is formed at the N-terminus of the antibody, antibody variant, or fragment thereof. In some embodiments, the light chain variable (VL) domain comprises CDR L1, CDR L2, CDR L3 of the antibody light chain, as well as FR L1, FR L2, FR L3, and FR L4 (framework regions). In some embodiments, the heavy chain variable (VH) domain comprises CDR H1, CDR H2, CDR H3 of the antibody heavy chain, as well as FR H1, FR H2, FR H3, and FR H4 (framework regions). In some embodiments, the light chain variable (VL) domain and the light chain constant (CL) domain form part of the antibody light chain. In some embodiments, the heavy chain variable (VH) domain and the heavy chain constant (CH1) domain form part of the antibody heavy chain. In some embodiments, the heavy chain variable (VH) domain and one or more heavy chain constant (CH1, CH2, or CH3) domains form part of the antibody heavy chain. Thus, in some embodiments, the light chain variable (VL) domain forms part of an antibody. In some embodiments, the heavy chain variable (VH) domain forms part of an antibody. In some embodiments, the light chain variable (VL) domain forms part of a therapeutic antibody. In some embodiments, the heavy chain variable (VH) domain forms part of a therapeutic antibody. In some embodiments, the light chain variable (VL) domain forms part of a human antibody. In some embodiments, the heavy chain variable (VH) domain forms part of a human antibody. In some embodiments, the light chain variable (VL) domain forms part of a humanized antibody. In some embodiments, the heavy chain variable (VH) domain forms part of a humanized antibody. In some embodiments, the light chain variable (VL) domain forms part of a chimeric antibody. In some embodiments, the heavy chain variable (VH) domain forms part of a chimeric antibody.In some embodiments, the light chain variable (VL) domain forms part of an antibody fragment. In some embodiments, the heavy chain variable (VH) domain forms part of an antibody fragment. In some embodiments, the light chain variable (VL) domain forms part of an antibody variant. In some embodiments, the heavy chain variable (VH) domain forms part of an antibody variant. In some embodiments, the light chain variable (VL) domain forms part of a Fab. In some embodiments, the heavy chain variable (VH) domain forms part of a Fab. In some embodiments, the light chain variable (VL) domain forms part of a scFv. In some embodiments, the heavy chain variable (VH) domain forms part of a scFv. In some embodiments, the light chain variable (VL) domain forms part of a single domain antibody. In some embodiments, the heavy chain variable (VH) domain forms part of a single domain antibody.

[0163] In one embodiment, the heavy chain variable domain has the sequence of SEQ ID NO: 15, and the light chain variable domain has the sequence of SEQ ID NO: 16. In one embodiment, the anti-CD84 antibody has a heavy chain of SEQ ID NO: 17 and a light chain of SEQ ID NO: 18. In one further embodiment, the antibody is 4B11.

[0164] In one embodiment, the heavy chain variable domain has the sequence of SEQ ID NO: 33, and the light chain variable domain has the sequence of SEQ ID NO: 34. In one embodiment, the anti-CD84 antibody has a heavy chain of SEQ ID NO: 35 and a light chain of SEQ ID NO: 36. In one further embodiment, the antibody is 13D11.

[0165] In one embodiment, the anti-CD84 antibody has a heavy chain of SEQ ID NO: 37 and a light chain of SEQ ID NO: 38. In one further embodiment, the antibody is 13D11Hu.

[0166] In one embodiment, the heavy chain variable domain has the sequence of SEQ ID NO: 53, and the light chain variable domain has the sequence of SEQ ID NO: 54. In one embodiment, the anti-CD84 antibody has a heavy chain of SEQ ID NO: 55 and a light chain of SEQ ID NO: 56. In one further embodiment, the antibody is 2H7.

[0167] In one embodiment, the heavy chain variable domain has the sequence of SEQ ID NO: 71, and the light chain variable domain has the sequence of SEQ ID NO: 72. In one embodiment, the anti-CD84 antibody has a heavy chain of SEQ ID NO: 73 and a light chain of SEQ ID NO: 74. In one further embodiment, the antibody is 5C6.

[0168] In one embodiment, the heavy chain variable domain has the sequence of SEQ ID NO: 89, and the light chain variable domain has the sequence of SEQ ID NO: 90. In one embodiment, the anti-CD84 antibody has a heavy chain of SEQ ID NO: 91 and a light chain of SEQ ID NO: 92. In one further embodiment, the antibody is 7D2.

[0169] In one embodiment, the heavy chain variable domain has the sequence of SEQ ID NO: 107, and the light chain variable domain has the sequence of SEQ ID NO: 108. In one embodiment, the anti-CD84 antibody has a heavy chain of SEQ ID NO: 109 and a light chain of SEQ ID NO: 110. In one further embodiment, the antibody is 8A5.

[0170] CD84 epitope Antibodies, including the embodiments provided herein, can specifically bind to a CD84 epitope. In some embodiments, the epitope is a human CD84 protein.

[0171] In some embodiments, the epitope interacts with the heavy chain of the anti-CD84 antibody. In some embodiments, the epitope has Val at the position corresponding to position 21 of SEQ ID NO: 111, Asn at the position corresponding to position 22 of SEQ ID NO: 111, Ile at the position corresponding to position 23 of SEQ ID NO: 111, Gln at the position corresponding to position 24 of SEQ ID NO: 111, Glu at the position corresponding to position 25 of SEQ ID NO: 111, Pro at the position corresponding to position 26 of SEQ ID NO: 111, Arg at the position corresponding to position 27 of SEQ ID NO: 111, Gln at the position corresponding to position 28 of SEQ ID NO: 111, Ser at the position corresponding to position 48 of SEQ ID NO: 111, Glu at the position corresponding to position 49 of SEQ ID NO: 111, Pro at the position corresponding to position 70 of SEQ ID NO: 111, Tyr at the position corresponding to position 72 of SEQ ID NO: 111, Ala at the position corresponding to position 95 of SEQ ID NO: 111, Asp at the position corresponding to position 96 of SEQ ID NO: 111, Pro at the position corresponding to position 97 of SEQ ID NO: 111, Tyr at the position corresponding to position 98 of SEQ ID NO: 111, Thr at the position corresponding to position 100 of SEQ ID NO: 111, or Lys at the position corresponding to position 102 of SEQ ID NO: 111.

[0172] In some embodiments, the epitope contains Val at a position corresponding to position 21 of SEQ ID NO: 111. In some embodiments, the epitope contains Asn at a position corresponding to position 22 of SEQ ID NO: 111. In some embodiments, the epitope contains Ile at a position corresponding to position 23 of SEQ ID NO: 111. In some embodiments, the epitope contains Gln at a position corresponding to position 24 of SEQ ID NO: 111. In some embodiments, the epitope contains Glu at a position corresponding to position 25 of SEQ ID NO: 111. In some embodiments, the epitope contains Pro at a position corresponding to position 26 of SEQ ID NO: 111. In some embodiments, the epitope contains Arg at a position corresponding to position 27 of SEQ ID NO: 111. In some embodiments, the epitope contains Gln at a position corresponding to position 28 of SEQ ID NO: 111. In some embodiments, the epitope contains Ser at a position corresponding to position 48 of SEQ ID NO: 111. In some embodiments, the epitope contains Glu at a position corresponding to position 49 of SEQ ID NO: 111. In some embodiments, the epitope contains Pro at a position corresponding to position 70 of SEQ ID NO: 111. In some embodiments, the epitope contains Tyr at a position corresponding to position 72 of SEQ ID NO: 111. In some embodiments, the epitope contains Ala at a position corresponding to position 95 of SEQ ID NO: 111. In some embodiments, the epitope contains Asp at a position corresponding to position 96 of SEQ ID NO: 111. In some embodiments, the epitope contains Pro at a position corresponding to position 97 of SEQ ID NO: 111. In some embodiments, the epitope contains Tyr at a position corresponding to position 98 of SEQ ID NO: 111. In some embodiments, the epitope contains Thr at a position corresponding to position 100 of SEQ ID NO: 111. In some embodiments, the epitope contains Lys at a position corresponding to position 102 of SEQ ID NO: 111.

[0173] In some embodiments, the epitope comprises Val at a position corresponding to position 21 of SEQ ID NO: 111, Asn at a position corresponding to position 22 of SEQ ID NO: 111, Ile at a position corresponding to position 23 of SEQ ID NO: 111, Gln at a position corresponding to position 24 of SEQ ID NO: 111, Glu at a position corresponding to position 25 of SEQ ID NO: 111, Pro at a position corresponding to position 26 of SEQ ID NO: 111, Arg at a position corresponding to position 27 of SEQ ID NO: 111, Gln at a position corresponding to position 28 of SEQ ID NO: 111, Ser at a position corresponding to position 48 of SEQ ID NO: 111, Glu at a position corresponding to position 49 of SEQ ID NO: 111, Pro at a position corresponding to position 70 of SEQ ID NO: 111, Tyr at a position corresponding to position 72 of SEQ ID NO: 111, Ala at a position corresponding to position 95 of SEQ ID NO: 111, Asp at a position corresponding to position 96 of SEQ ID NO: 111, Pro at a position corresponding to position 97 of SEQ ID NO: 111, Tyr at a position corresponding to position 98 of SEQ ID NO: 111, Thr at a position corresponding to position 100 of SEQ ID NO: 111, and Lys at a position corresponding to position 102 of SEQ ID NO: 111.

[0174] In one embodiment, the heavy chain of the anti-CD84 antibody binds to the epitope with Thr at the position corresponding to position 30 of SEQ ID NO: 109, Thr at the position corresponding to position 31 of SEQ ID NO: 109, Tyr at the position corresponding to position 32 of SEQ ID NO: 109, Ser at the position corresponding to position 33 of SEQ ID NO: 109, His at the position corresponding to position 35 of SEQ ID NO: 109, Trp at the position corresponding to position 47 of SEQ ID NO: 109, Trp at the position corresponding to position 50 of SEQ ID NO: 109, Asp at the position corresponding to position 52 of SEQ ID NO: 109, Thr at the position corresponding to position 53 of SEQ ID NO: 109, Ala at the position corresponding to position 54 of SEQ ID NO: 109, Thr at the position corresponding to position 55 of SEQ ID NO: 109, Glu at the position corresponding to position 57 of SEQ ID NO: 109, Pro at the position corresponding to position 58 of SEQ ID NO: 109, Thr at the position corresponding to position 59 of SEQ ID NO: 109, Tyr at the position corresponding to position 60 of SEQ ID NO: 109, Ala at the position corresponding to position 61 of SEQ ID NO: 109, Lys at the position corresponding to position 65 of SEQ ID NO: 109, Ser at the position corresponding to position 99 of SEQ ID NO: 109, Tyr at the position corresponding to position 101 of SEQ ID NO: 109, Trp at the position corresponding to position 102 of SEQ ID NO: 109, Tyr at the position corresponding to position 103 of SEQ ID NO: 109, or Phe at the position corresponding to position 104 of SEQ ID NO: 109.

[0175] In one further embodiment, the heavy chain of the anti-CD84 antibody binds to the epitope with Thr at the position corresponding to position 30 of SEQ ID NO: 109, Thr at the position corresponding to position 31 of SEQ ID NO: 109, Tyr at the position corresponding to position 32 of SEQ ID NO: 109, Ser at the position corresponding to position 33 of SEQ ID NO: 109, His at the position corresponding to position 35 of SEQ ID NO: 109, Trp at the position corresponding to position 47 of SEQ ID NO: 109, Trp at the position corresponding to position 50 of SEQ ID NO: 109, Asp at the position corresponding to position 52 of SEQ ID NO: 109, Thr at the position corresponding to position 53 of SEQ ID NO: 109, Ala at the position corresponding to position 54 of SEQ ID NO: 109, Thr at the position corresponding to position 55 of SEQ ID NO: 109, Glu at the position corresponding to position 57 of SEQ ID NO: 109, Pro at the position corresponding to position 58 of SEQ ID NO: 109, Thr at the position corresponding to position 59 of SEQ ID NO: 109, Tyr at the position corresponding to position 60 of SEQ ID NO: 109, Ala at the position corresponding to position 61 of SEQ ID NO: 109, Lys at the position corresponding to position 65 of SEQ ID NO: 109, Ser at the position corresponding to position 99 of SEQ ID NO: 109, Tyr at the position corresponding to position 101 of SEQ ID NO: 109, Trp at the position corresponding to position 102 of SEQ ID NO: 109, Tyr at the position corresponding to position 103 of SEQ ID NO: 109, and Phe at the position corresponding to position 104 of SEQ ID NO: 109.

[0176] In one embodiment, the heavy chain of the anti-CD84 antibody binds to Gln at the position corresponding to position 24 of SEQ ID NO: 111 with Ser at the position corresponding to position 99 of SEQ ID NO: 109. In one embodiment, the heavy chain of the anti-CD84 antibody binds to Gln at the position corresponding to position 24 of SEQ ID NO: 111 with Thr at the position corresponding to position 53 of SEQ ID NO: 109. In one embodiment, the heavy chain of the anti-CD84 antibody binds to Glu at the position corresponding to position 25 of SEQ ID NO: 111 with Ser at the position corresponding to position 33 of SEQ ID NO: 109. In one embodiment, the heavy chain of the anti-CD84 antibody binds to Gln at the position corresponding to position 24 of SEQ ID NO: 111 with Thr at the position corresponding to position 30 of SEQ ID NO: 109.

[0177] In some embodiments, the epitope interacts with the light chain of the anti-CD84 antibody. In some embodiments, the epitope comprises Glu at a position corresponding to position 25 of SEQ ID NO: 111, Arg at a position corresponding to position 27 of SEQ ID NO: 111, Gln at a position corresponding to position 28 of SEQ ID NO: 111, Val at a position corresponding to position 29 of SEQ ID NO: 111, Lys at a position corresponding to position 30 of SEQ ID NO: 111, Pro at a position corresponding to position 45 of SEQ ID NO: 111, Gly at a position corresponding to position 46 of SEQ ID NO: 111, Ser at a position corresponding to position 48 of SEQ ID NO: 111, Glu at a position corresponding to position 49 of SEQ ID NO: 111, Gln at a position corresponding to position 94 of SEQ ID NO: 111, or Ala at a position corresponding to position 95 of SEQ ID NO: 111.

[0178] In some embodiments, the epitope comprises Glu at a position corresponding to position 25 of SEQ ID NO: 111. In some embodiments, the epitope comprises Arg at a position corresponding to position 27 of SEQ ID NO: 111. In some embodiments, the epitope comprises Gln at a position corresponding to position 28 of SEQ ID NO: 111. In some embodiments, the epitope comprises Val at a position corresponding to position 29 of SEQ ID NO: 111. In some embodiments, the epitope comprises Lys at a position corresponding to position 30 of SEQ ID NO: 111. In some embodiments, the epitope comprises Pro at a position corresponding to position 45 of SEQ ID NO: 111. In some embodiments, the epitope comprises Gly at a position corresponding to position 46 of SEQ ID NO: 111. In some embodiments, the epitope comprises Ser at a position corresponding to position 48 of SEQ ID NO: 111. In some embodiments, the epitope comprises Glu at a position corresponding to position 49 of SEQ ID NO: 111. In some embodiments, the epitope comprises Gln at a position corresponding to position 94 of SEQ ID NO: 111. In some embodiments, the epitope comprises Ala at a position corresponding to position 95 of SEQ ID NO: 111.

[0179] In some embodiments, the epitope comprises Glu at a position corresponding to position 25 of SEQ ID NO: 111, Arg at a position corresponding to position 27 of SEQ ID NO: 111, Gln at a position corresponding to position 28 of SEQ ID NO: 111, Val at a position corresponding to position 29 of SEQ ID NO: 111, Lys at a position corresponding to position 30 of SEQ ID NO: 111, Pro at a position corresponding to position 45 of SEQ ID NO: 111, Gly at a position corresponding to position 46 of SEQ ID NO: 111, Ser at a position corresponding to position 48 of SEQ ID NO: 111, Glu at a position corresponding to position 49 of SEQ ID NO: 111, Gln at a position corresponding to position 94 of SEQ ID NO: 111, and Ala at a position corresponding to position 95 of SEQ ID NO: 111.

[0180] In one embodiment, the light chain of the anti-CD84 antibody binds to the epitope with His at a position corresponding to position 31 of SEQ ID NO: 110, Ile at a position corresponding to position 32 of SEQ ID NO: 110, Asn at a position corresponding to position 33 of SEQ ID NO: 110, Gly at a position corresponding to position 34 of SEQ ID NO: 110, Asn at a position corresponding to position 35 of SEQ ID NO: 110, Tyr at a position corresponding to position 37 of SEQ ID NO: 110, Glu at a position corresponding to position 39 of SEQ ID NO: 110, Lys at a position corresponding to position 55 of SEQ ID NO: 110, Phe at a position corresponding to position 94 of SEQ ID NO: 110, Gly at a position corresponding to position 96 of SEQ ID NO: 110, Ser at a position corresponding to position 97 of SEQ ID NO: 110, His at a position corresponding to position 98 of SEQ ID NO: 110, Val at a position corresponding to position 99 of SEQ ID NO: 110, or Trp at a position corresponding to position 101 of SEQ ID NO: 110.

[0181] In one embodiment, the light chain of the anti-CD84 antibody binds to the epitope with His at the position corresponding to position 31 of SEQ ID NO: 110, Ile at the position corresponding to position 32 of SEQ ID NO: 110, Asn at the position corresponding to position 33 of SEQ ID NO: 110, Gly at the position corresponding to position 34 of SEQ ID NO: 110, Asn at the position corresponding to position 35 of SEQ ID NO: 110, Tyr at the position corresponding to position 37 of SEQ ID NO: 110, Glu at the position corresponding to position 39 of SEQ ID NO: 110, Lys at the position corresponding to position 55 of SEQ ID NO: 110, Phe at the position corresponding to position 94 of SEQ ID NO: 110, Gly at the position corresponding to position 96 of SEQ ID NO: 110, Ser at the position corresponding to position 97 of SEQ ID NO: 110, His at the position corresponding to position 98 of SEQ ID NO: 110, Val at the position corresponding to position 99 of SEQ ID NO: 110, and Trp at the position corresponding to position 101 of SEQ ID NO: 110.

[0182] In one embodiment, the light chain of the anti-CD84 antibody binds to Ser at the position corresponding to position 48 of SEQ ID NO: 111 with Asn at the position corresponding to position 33 of SEQ ID NO: 110. In one embodiment, the light chain of the anti-CD84 antibody binds to Glu at the position corresponding to position 49 of SEQ ID NO: 111 with Lys at the position corresponding to position 55 of SEQ ID NO: 110. In one embodiment, the light chain of the anti-CD84 antibody binds to Arg at the position corresponding to position 27 of SEQ ID NO: 111 with Gly at the position corresponding to position 96 of SEQ ID NO: 110. In one embodiment, the light chain of the anti-CD84 antibody binds to Ser at the position corresponding to position 48 of SEQ ID NO: 111 with Asn at the position corresponding to position 35 of SEQ ID NO: 110. In one embodiment, the light chain of the anti-CD84 antibody binds to Glu at the position corresponding to position 49 of SEQ ID NO: 111 with Lys at the position corresponding to position 55 of SEQ ID NO: 110. In one embodiment, the light chain of the anti-CD84 antibody binds to Arg at the position corresponding to position 27 of SEQ ID NO: 111 with Glu at the position corresponding to position 39 of SEQ ID NO: 110.

[0183] Nucleic acid composition The compositions provided herein include nucleic acid molecules encoding an anti-CD84 antibody or a portion thereof, including the embodiments provided herein. Throughout this application (including the above description and the Examples section), the antibodies encoded by the isolated nucleic acids provided herein are described in detail. Thus, in one aspect, an isolated nucleic acid encoding an anti-CD84 antibody, including the embodiments provided herein, is provided.

[0184] Cell composition In another aspect, a cell is provided that includes an anti-CD84 antibody, including the embodiments provided herein, or a nucleic acid, including the embodiments provided herein.

[0185] Pharmaceutical composition The compositions provided herein include a pharmaceutical composition comprising an anti-CD84 antibody or a portion thereof, including the embodiments provided herein. In one aspect, a pharmaceutical composition is provided that includes a therapeutically effective amount of an antibody, including the embodiments provided herein, and a pharmaceutically acceptable excipient.

[0186] Method for producing an antibody In one aspect, a method for generating an antibody capable of binding to CD84 is provided, the method comprising immunizing a mammal with a peptide comprising the sequence of SEQ ID NO: 111.

[0187] Treatment method The compositions provided herein (e.g., anti-CD84 antibodies), including their various embodiments, are contemplated to provide effective treatment for diseases such as cancer (e.g., acute myeloid leukemia). Thus, in one aspect, a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-CD84 antibody including the various embodiments provided herein or a pharmaceutical composition including the various embodiments provided herein, thereby treating the subject's cancer, is provided. In some embodiments, the cancer is lymphoma, myeloma, and / or leukemia. In some embodiments, the cancer is lymphoma, myeloma, and leukemia. In an embodiment, the cancer is lymphoma. In some embodiments, the cancer is myeloma. In an embodiment, the cancer is leukemia. In some embodiments, the cancer is acute myeloid leukemia (AML).

[0188] In some embodiments, the anti-CD84 antibody is administered in an amount less than the amount of an anti-cancer antibody typically administered to treat cancer. In some embodiments, the amount is 1 / 2, 1 / 5, 1 / 10, 1 / 100, 1 / 200, 1 / 500, 1 / 1000, or 1 / 10000 of the amount of the anti-cancer antibody. In some embodiments, the amount is 1 / 2 of the amount of the anti-cancer antibody. In some embodiments, the amount is 1 / 5 of the amount of the anti-cancer antibody. In some embodiments, the amount is 1 / 10 of the amount of the anti-cancer antibody. In some embodiments, the amount is 1 / 100 of the amount of the anti-cancer antibody. In some embodiments, the amount is 1 / 200 of the amount of the anti-cancer antibody. In some embodiments, the amount is 1 / 500 of the amount of the anti-cancer antibody. In some embodiments, the amount is 1 / 1000 of the amount of the anti-cancer antibody. In some embodiments, the amount is 1 / 10000 of the amount of the anti-cancer antibody.

[0189] In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 1 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 1.5 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 2 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 2.5 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 3 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 3.5 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 4 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 4.5 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 5 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 5.5 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 6 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 6.5 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 7 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 7.5 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 8 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 8.5 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 9 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 9.5 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 10 mg / kg to about 20 mg / kg.

[0190] In some embodiments, the anti-CD84 antibody is administered in an amount of about 10.5 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 11 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 11.5 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 12 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 12.5 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 13 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 13.5 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 14 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 14.5 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 15 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 15.5 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 6 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 16.5 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 17 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 17.5 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 18 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 18.5 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 19 mg / kg to about 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 19.5 mg / kg to about 20 mg / kg.

[0191] In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 8.5 mg / kg, 9 mg / kg, 9.5 mg / kg, 10 mg / kg, 10.5 mg / kg, 11 mg / kg, 11.5 mg / kg, 12 mg / kg, 12.5 mg / kg, 13 mg / kg, 13.5 mg / kg, 14 mg / kg, 14.5 mg / kg, 15 mg / kg, 15.5 mg / kg, 16 mg / kg, 16.5 mg / kg, 17 mg / kg, 17.5 mg / kg, 18 mg / kg, 18.5 mg / kg, 19 mg / kg, 19.5 mg / kg or 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 1 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 1.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 2 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 2.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 3 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 3.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 4 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 4.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 5.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 6 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 6.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 7 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 7.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 8 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 8.5 mg / kg.In some embodiments, the anti-CD84 antibody is administered in an amount of about 9 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 9.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 10 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 10.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 11 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 11.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 12 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 12.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 13 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 13.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 14 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 14.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 15 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 15.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 16 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 16.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 17 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 17.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 18 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 18.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 19 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 19.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 20 mg / kg.

[0192] In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 1 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 1.5 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 2 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 2.5 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 3 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 3.5 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 4 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 4.5 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 5 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 5.5 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 6 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 6.5 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 7 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 7.5 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 8 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 8.5 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 9 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 9.5 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 10 mg / kg to 20 mg / kg.

[0193] In some embodiments, the anti-CD84 antibody is administered in an amount of 10.5 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 11 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 11.5 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 12 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 12.5 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 13 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 13.5 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 14 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 14.5 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 15 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 15.5 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 6 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 16.5 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 17 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 17.5 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 18 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 18.5 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 19 mg / kg to 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 19.5 mg / kg to 20 mg / kg.

[0194] In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 8.5 mg / kg, 9 mg / kg, 9.5 mg / kg, 10 mg / kg, 10.5 mg / kg, 11 mg / kg, 11.5 mg / kg, 12 mg / kg, 12.5 mg / kg, 13 mg / kg, 13.5 mg / kg, 14 mg / kg, 14.5 mg / kg, 15 mg / kg, 15.5 mg / kg, 16 mg / kg, 16.5 mg / kg, 17 mg / kg, 17.5 mg / kg, 18 mg / kg, 18.5 mg / kg, 19 mg / kg, 19.5 mg / kg or 20 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 1 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 1.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 2 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 2.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 3 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 3.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 4 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 4.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 5.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 6 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 6.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 7 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 7.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 8 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 8.5 mg / kg.In some embodiments, the anti-CD84 antibody is administered in an amount of about 9 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 9.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 10 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 10.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 11 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 11.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 12 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 12.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 13 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 13.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 14 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 14.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 15 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 15.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 16 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 16.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 17 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 17.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 18 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 18.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 19 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 19.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 20 mg / kg. As used herein, the term "mg / kg" refers to the number of mg of the anti-CD84 antibody or a salt thereof per 1 kg of body weight.

[0195] In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 19.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 19 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 18.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 18 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 17.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 17 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 16.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 16 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 15.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 15 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 14.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 14 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 13.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 13 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 12.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 12 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 11.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 11 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 10.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 10 mg / kg.

[0196] In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 9.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 9 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 8.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 8 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 7.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 7 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 6.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 6 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 5.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 4.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 4 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 3.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 3 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 2.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 2 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 1.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of about 0.5 mg / kg to about 1 mg / kg.

[0197] In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 19.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 19 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 18.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 18 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 17.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 17 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 16.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 16 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 15.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 15 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 14.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 14 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 13.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 13 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 12.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 12 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 11.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 11 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 10.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 10 mg / kg.

[0198] In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 9.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 9 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 8.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 8 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 7.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 7 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 6.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 6 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 5.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 4.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 4 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 3.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 3 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 2.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 2 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 1.5 mg / kg. In some embodiments, the anti-CD84 antibody is administered in an amount of 0.5 mg / kg to 1 mg / kg.

Example

[0199] Example 1: Preparation of Recombinant Human CD84 Protein To construct the recombinant CD84 protein, the extracellular domain (ECD) of human CD84 was fused with mouse IgG2a.Fc or human IgA1.Fc, respectively (Figure 1). The recombinant DNAs encoding these two proteins were synthesized by the manufacturer (Twist Bioscience) and cloned into a mammalian expression vector. DNA was prepared using the ZymoPURE™ II Plasmid Maxiprep Kit (Zymo Research). The CD84 fusion proteins were produced using the ExpiCHO expression system (Thermo Fisher Scientific). The procedure was followed according to the manufacturer's manual. Briefly, 24 hours before DNA transfection, CHO cells were seeded at 3 - 4×10 6 cells / mL in fresh ExpiCHO expression medium. On the day of transfection, the cells were at 6×10 6Adjusted to cells / mL. For 100 mL of transfection, 80 mg of DNA was diluted with 4 mL of OptiPRO™ SFM and then mixed with 320 mL of ExpiFectamine™ diluted with 3.7 mL of OptiPRO™ SFM. The mixture was slowly added to the cell culture while gently rotating. The cells were then cultured at 37 °C. After 16 - 22 hours, 6 mL of ExpiCHO™ Enhancer and 24 mL of ExpiCHO™ Feed were added to the cell culture and the cells were continued to be cultured at 32 °C for 10 days. The culture supernatant was recovered by centrifuging at 4000 × g for 30 minutes and passed through a 0.22 mm filter for protein purification. CD84-IgG2a and CD84-IgA1 were purified using Protein A resin (GE Healthcare) and CaptureSelect™ IgA Affinity Matrix (Thermo Fisher Scientific), respectively. The purification procedure followed the manufacturer's manual. The purified proteins were electrophoresed using Mini-PROTEAN® TGX Stain-Free® Precast Gels (Bio-Rad) for reducing SDS-PAGE and analyzed using a Superdex 200 Increase 10 / 300 GL column (GE Healthcare) with PBS (Figure 2).

[0200] Example 2: Preparation of Anti-CD84 Hybridoma All animal experiments were conducted under the approval of the Institutional Animal Care and Use Committee of City of Hope (IUCAC numbers #19070 and #19023). For mouse immunization, recombinant CD84-IgG2a protein was emulsified with complete Freund's adjuvant (Sigma Aldrich) and subcutaneously injected into 10 Balb / c mice (The Jackson Laboratory). Each mouse was injected with 50 micrograms of the protein. Three weeks later, 50 mg of CD84-IgG2a emulsified with incomplete Freund's adjuvant (Sigma Aldrich) was subcutaneously injected into the mice twice at two-week intervals. Three days before spleen collection, 10 mg of CD84-IgG2a was injected into the mice via the tail vein. Spleen cells were collected for fusion with the mouse myeloma cell line FO (ATCC) using PEG1500 (Roche). The cell fusion procedure followed the manufacturer's manual. After fusion, the cells were selected in complete DMEM medium containing hypoxanthine / aminopterin / thymidine (Thermo Fisher Scientific) and 10% UltraCruz® Hybridoma Cloning Supplement (Santa Cruz) for 10 - 12 days. The hybridoma culture supernatants were screened for reactivity against CD84-IgA1 protein using ELISA. For ELISA screening, 50 μL of CD84-IgA1 diluted to a concentration of 1 mg / mL with carbonate / bicarbonate buffer (pH 9.6) was added to the microwells and incubated overnight at 4°C. The wells were washed three times with PBS containing 0.1% Tween 20 (PBST) and blocked with 200 μL of PBS containing 1% bovine serum albumin. After incubation for 1 hour at room temperature and washing three times with PBST, 50 μL of the culture supernatant was added to the wells and incubated for 1 hour at room temperature. After washing, 50 μL of 1:10,000 diluted goat anti-mouse IgG.Fc-HRP (Jackson ImmunoResearch) was added to the wells and incubated for 1 hour at room temperature.After washing six times, 50 mL of TMB substrate (Thermo Fisher Scientific) was added to the wells to develop color. The reaction was stopped by adding 50 mL of 1 N HCl. The wells were read at an absorbance of 450 nm using a Synergy 4 microplate reader (BioTek). In the results of ELISA screening, 71 hybridoma clones showed a strong binding signal to the CD84-IgA1 protein.

[0201] Example 3: Flow Cytometry of Anti-CD84 Hybridoma Clones Hybridoma clones selected from ELISA screening were subjected to flow cytometry analysis using NS0, a mouse myeloma cell line (ECACC) expressing human CD84, by lentiviral transduction. 500,000 transduced cells were incubated on ice for 30 minutes with 100 mL of hybridoma culture supernatant and washed with cold PBS containing 1% fetal bovine serum and 0.1% sodium azide. The cells were then incubated on ice for 30 minutes with 100 mL of 1:400 diluted Alexa Fluor® 488 AffiniPure goat anti-mouse IgG (Jackson ImmunoResearch) for analysis by an Accuri C6 flow cytometer (BD) and washed. From the results, it was found that 16 clones were able to bind to human CD84 on the cell surface (Figure 3). For six clones with strong staining signals, namely 2H7, 4B11, 5C6, 7D2, 8A5, and 13D11 (Table 1), their binding to human myeloma cell line HL-60, T cell line Jurkat, lymphoma cell line K-562, and breast cancer cell line SKBR3 (ATCC) was further tested. A commercially available mouse anti-human CD84 monoclonal antibody (aCD84, BioLegend) was used as a positive control. From the results, it was found that these anti-CD84 antibodies, like the positive control, specifically bound to CD84-expressing cells without reacting with CD84-negative cells (Figure 4).

[0202] [Table 1]

[0203] Example 4: VH / VL Isotyping and Cloning of Anti-CD84 Antibodies To determine the Ig isotype of mouse antibodies, CD84-IgA1 protein was used as the immobilized antigen for incubation with hybridoma culture supernatants in ELISA. Antibody isotypes were detected using HRP-conjugated goat anti-mouse Igg1, Igg2a, Igg2b, Igg3, Igk, and Igl (SouthernBiotech) and developed with TMB substrate. All six of these antibodies were of the g1 and kappa isotypes (Figure 5). To clone VH / VL sequences from the hybridomas, mRNA was extracted using the Quick-RNA Microprep Kit (Zymo Research). First-strand cDNA was synthesized using the SuperScript III First-Strand Synthesis System (Thermo Fisher Scientific). VH and VL fragments were amplified by PCR using the Mouse Ig-Primer Set (Millipore Sigma) and OneTaq 2X Master Mix (NEB). The amplified DNA fragments were purified using the DNA Clean-up Kit (Zymo Research) and ligated into the pGEM-T vector (Promega) for sequencing.

[0204] Example 5: CD84 Is Overexpressed in AML and Is Required for the Proliferation of Human AML Cells Based on a dataset of gene expression profiling including a large cohort of AML patients (GSE9476 and GSE13159), the inventors observed that the bone marrow mononuclear cells of AML specimens showed a significant increase in CD84 mRNA levels compared to those of normal healthy donors (Figure 11A, left panel). In particular, higher CD84 expression was observed in patients with myelomonocytic leukemia and monoblastic leukemia with t(11q23) and inv(16) abnormalities compared to other AML subtypes (highlighted in the right panel of Figure 11A). The inventors further confirmed that surface CD84 was overexpressed in AML cell lines (n = 6) and primary cells (n = 4) compared to that in healthy donors (Figure 11B). Furthermore, the inventors also found that in AML patients (GSE10358), the higher the CD84 expression, the shorter the overall survival (OS) (Figure 11C).

[0205] To investigate the role of CD84 in AML, both gain-of-function and loss-of-function assays were performed. In AML cell lines, CD84 knockdown by small hairpin RNA (shRNA) caused significant inhibition of cell proliferation and apoptosis (Figure 12A, left and right panels respectively). In primary AML cells, the inventors found that CD84 knockdown dramatically induced cell apoptosis and suppressed the colony number (Figure 12B, left and right panels respectively).

[0206] Furthermore, the inventors knocked down CD84 in luciferase-expressing THP1 cells and then transplanted the selected cells into immunodeficient NSG mice. In mice transplanted with CD84 knockdown cells, a reduction in tumor burden (Figure 12C, left panel) and an extension of survival time (Figure 12C, right panel) were observed compared to control mice.

[0207] Example 6: Depletion of CD84 expression impairs AML cell repopulation and AML maintenance To understand the functional involvement of CD84 in leukemia induction, the inventors knocked down the expression of CD84 (shCD84-1 and shCD84-2) using an shRNA system based on a lentiviral vector in mouse MLL-AF9-HSPC pre-LSCs (Leukemia Stem Cells) generated by transducing lentiviruses encoding the MLL-AF9 fusion oncogene into mouse HSPCs (hematopoietic stem / progenitor cells). As shown in Fig. 13A, the cell proliferation rate of MLL-AF9-HSPC pre-LSCs transduced with shCD84 (CD84 KD) was slower (Fig. 13B). As expected, in the colony formation assay (CFA: colony formation assay), stable CD84 KD by both shRNAs was shown to significantly reduce the number of colonies of transduced MLL-AF9-HSPC cells (Fig. 13C). To evaluate the role of CD84 in leukemia induction in vivo, the inventors performed a mouse bone marrow transplantation assay in sub-lethally irradiated C57BL / 6 syngeneic recipient mice. The inventors found that in mice transplanted with CD84 KD MLL-AF9-HSPC cells, the bone marrow and spleen tumors were reduced compared to recipient mice transplanted with MLL-AF9 cells transduced with an sh-control vector (Figs. 13D - 13E).

[0208] The inventors next performed in vivo transplantation to evaluate the potential of CD84 in the maintenance of human AML. The inventors transfected AML primary patient cells with CD84 shRNA (sh-CD84-2) and control shRNA. Also in this case, the inventors observed that the AML burden in the BM, spleen and peripheral blood (PB) of recipient mice transplanted with primary CD84 knockdown AML cells was significantly lower compared to mice transplanted with sh-control AML cells (Figure 14A). The inventors also found that the spleen weight of CD84 knockdown mice was decreased (Figure 14B). Taken together, the inventors' data suggest that CD84 is required for the maintenance of AML.

[0209] Example 7: CD84 is a survival receptor in AML and anti-CD84 antibody potently induces ADCC in AML cell lines To efficiently target CD84-expressing AML cells in vivo, the inventors generated three mouse anti-human chimeric monoclonal antibodies (anti-CD84 antibodies) against CD84, including in particular monoclonal antibodies 5C6, 7D2, and 8A5. From an antibody-dependent cellular cytotoxicity (ADCC) assay, it was found that the anti-CD84 7D2 antibody induced higher cytotoxicity in CD84-high-expressing cells THP1, but not in CD84-none / low-expressing cells MM1S (Figure 15A). The inventors used the anti-CD84 7D2 antibody in further tests. As expected, the anti-CD84 7D2 antibody strongly induced ADCC in THP1 cells in the presence of effector cells (E), total peripheral blood mononuclear cells (PBMC) or purified NK cells, which was shown to depend on the effector-to-target cell ratio and the antibody dosage (Figure 15B). In particular, in luciferase-expressing THP1 xenograft NSG mice, a decrease in tumor burden and an extension of survival were observed after treatment with the anti-CD84 7D2 antibody (Figure 16A). On the other hand, the inventors maintained the same treatment strategy in the U937-Luc+ xenograft mouse model. Mice treated with the anti-CD84 antibody showed a significant extension of survival and a significant decrease in disease burden by bioluminescence compared to mice treated with IgG (Figure 16B). Consistently, in a patient-derived xenograft (PDX) model of AML, the inventors found a decrease in engraftment in the bone marrow, spleen, and peripheral blood (indicated by human CD45 / CD33), and splenomegaly was reduced after 3 weeks of anti-CD84 antibody treatment (Figure 17). Overall, the inventors' results suggest that CD84 is a survival receptor in AML and that anti-CD84 antibodies are a promising treatment for AML patients.

[0210] Example 8: Interface between CD84 and 8A5 Using the PISA (Proteins, Interfaces, Structures and Assemblies) tool, the buried surface area of the CD84 / 8A5 structure was calculated. The interface area between the human heavy chain (HC) and CD84 (calculated in Å2 as half of the difference in the total accessible surface area of the separated and interacting structures) is 684 Å2. There are several hydrogen bonds within the interface, including Ser99 (HC)-Gln24 (CD84), Thr53 (HC)-Gln24 (CD84), Ser33 (HC)-Glu25 (CD84); Thr30 (HC)-Gln24 (CD84) and the salt bridge His25 (HC)Glu25 (CD84).

[0211] The list of CD84 residues buried at the HC-CD84 interface is Val21, Asn22, ILe23, Gln24, Glu25, Pro26, Arg27, Gln28, Ser48, Glu49 Pro70, Tyr72, Ala95, Asp96, Pro97, Tyr98, Thr100, Lys102

[0212] The list of 8A5 residues of HC is Thr30, Thr31, Tyr32, Ser33, His35, Trp47, Trp50, Asp52, Thr53, Ala54, Thr55, Glu57, Pro58, Thr59, Tyr60, Ala61, Lys65, Ser99, Tyr101, Trp102, Tyr103, Phe104

[0213] The interface between the human light chain (LC) and CD84 is 472 Å2. There are several hydrogen bonds within the interface, including Asn33 (LC)-Ser48 (CD84), Lys55 (LC)-Glu49 (CD84), Gly96 (LC)-Arg27 (CD84) and Asn35 (LC)-Ser48 (CD84), as well as the salt bridges Lys55 (LC)-Glu49 (CD84) and Glu39 (LC)-Arg27 (CD84).

[0214] The list of CD84 residues buried at the LC-CD84 interface is Glu25, Arg27, Gln28, Val29, Lys30, Pro45, Gly46, Ssp47, Ser48, Glu49, Gln94, and Ala95.

[0215] The list of residues of 8A5 of LC is His31, Ile32, Asn33, Gly34, Asn35, Tyr37, Glu39, Lys55, Phe94, Gly96, Ser97, His98, Vla99, Trp101.

[0216] Unofficial Sequence Listing

[0217] [Table 2-1]

[0218] [Table 2-2]

[0219] [Table 2-3]

[0220] [Table 2-4]

[0221] P Embodiment P Embodiment 1. An anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 75, CDR H2 set forth in SEQ ID NO: 76, and CDR H3 set forth in SEQ ID NO: 77, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 78, CDR L2 set forth in SEQ ID NO: 79, and CDR L3 set forth in SEQ ID NO: 80.

[0222] P Embodiment 2. The anti-CD84 antibody according to P Embodiment 1, wherein the anti-CD84 antibody is a chimeric antibody.

[0223] P Embodiment 3. The anti-CD84 antibody according to P Embodiment 1 or 2, wherein the heavy chain variable domain comprises FR H1 described in SEQ ID NO: 81, FR H2 described in SEQ ID NO: 82, FR H3 described in SEQ ID NO: 83, and FR H4 described in SEQ ID NO: 84.

[0224] P Embodiment 4. The anti-CD84 antibody according to any one of P Embodiments 1 to 3, wherein the light chain variable domain comprises FR L1 described in SEQ ID NO: 85, FR L2 described in SEQ ID NO: 86, FR L3 described in SEQ ID NO: 87, and FR L4 described in SEQ ID NO: 88.

[0225] P Embodiment 5. The anti-CD84 antibody according to any one of P Embodiments 1 to 4, wherein the heavy chain variable domain comprises the sequence of SEQ ID NO: 89.

[0226] P Embodiment 6. The anti-CD84 antibody according to any one of P Embodiments 1 to 5, wherein the light chain variable domain comprises the sequence of SEQ ID NO: 90.

[0227] P Embodiment 7. The anti-CD84 antibody according to any one of P Embodiments 1 to 6, wherein the anti-CD84 antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 91.

[0228] P Embodiment 8. The anti-CD84 antibody according to any one of P Embodiments 1 to 7, wherein the anti-CD84 antibody comprises a light chain comprising the sequence of SEQ ID NO: 92.

[0229] P Embodiment 9. An anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 described in SEQ ID NO: 19, CDR H2 described in SEQ ID NO: 20, and CDR H3 described in SEQ ID NO: 21, and the light chain variable domain comprises CDR L1 described in SEQ ID NO: 22, CDR L2 described in SEQ ID NO: 23, and CDR L3 described in SEQ ID NO: 24.

[0230] Embodiment P10. The anti-CD84 antibody according to Embodiment P9, wherein the anti-CD84 antibody is a humanized antibody.

[0231] Embodiment P11. The anti-CD84 antibody according to any one of Embodiments P9 or P10, wherein the antibody comprises a light chain containing the sequence of SEQ ID NO: 37.

[0232] Embodiment P12. The anti-CD84 antibody according to any one of Embodiments P9 to P11, wherein the antibody comprises a heavy chain containing the sequence of SEQ ID NO: 38.

[0233] Embodiment P13. The anti-CD84 antibody according to Embodiment P9, wherein the anti-CD84 antibody is a chimeric antibody.

[0234] Embodiment P14. The anti-CD84 antibody according to Embodiment P9 or P13, wherein the heavy chain variable domain comprises FR H1 described in SEQ ID NO: 25, FR H2 described in SEQ ID NO: 26, FR H3 described in SEQ ID NO: 27, and FR H4 described in SEQ ID NO: 28.

[0235] Embodiment P15. The anti-CD84 antibody according to Embodiment P9 or any one of Embodiments P13 to P14, wherein the light chain variable domain comprises FR L1 described in SEQ ID NO: 29, FR L2 described in SEQ ID NO: 30, FR L3 described in SEQ ID NO: 31, and FR L4 described in SEQ ID NO: 32.

[0236] Embodiment P16. The anti-CD84 antibody according to Embodiment P9 or any one of Embodiments P13 to P15, wherein the heavy chain variable domain comprises the sequence of SEQ ID NO: 33.

[0237] Embodiment P17. The anti-CD84 antibody according to Embodiment P9 or any one of Embodiments P13 to P16, wherein the light chain variable domain comprises the sequence of SEQ ID NO: 34.

[0238] Embodiment P18. The anti-CD84 antibody according to Embodiment P9 or any one of Embodiments P13 to P17, wherein the anti-CD84 antibody comprises a heavy chain containing the sequence of SEQ ID NO: 35.

[0239] P Embodiment 19. The anti-CD84 antibody according to any one of Embodiments 9 or 13 to 18, wherein the anti-CD84 antibody comprises a light chain containing the sequence of SEQ ID NO: 36.

[0240] P Embodiment 20. An anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 39, CDR H2 set forth in SEQ ID NO: 40, and CDR H3 set forth in SEQ ID NO: 41, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 42, CDR L2 set forth in SEQ ID NO: 43, and CDR L3 set forth in SEQ ID NO: 44.

[0241] P Embodiment 21. The anti-CD84 antibody according to P Embodiment 20, wherein the anti-CD84 antibody is a chimeric antibody.

[0242] P Embodiment 22. The anti-CD84 antibody according to P Embodiment 20 or 21, wherein the heavy chain variable domain comprises FR H1 set forth in SEQ ID NO: 45, FR H2 set forth in SEQ ID NO: 46, FR H3 set forth in SEQ ID NO: 47, and FR H4 set forth in SEQ ID NO: 48.

[0243] P Embodiment 23. The anti-CD84 antibody according to any one of P Embodiments 20 to 22, wherein the light chain variable domain comprises FR L1 set forth in SEQ ID NO: 49, FR L2 set forth in SEQ ID NO: 50, FR L3 set forth in SEQ ID NO: 51, and FR L4 set forth in SEQ ID NO: 52.

[0244] P Embodiment 24. The anti-CD84 antibody according to any one of P Embodiments 20 to 23, wherein the heavy chain variable domain comprises the sequence of SEQ ID NO: 53.

[0245] P Embodiment 25. The anti-CD84 antibody according to any one of P Embodiments 20 to 24, wherein the light chain variable domain comprises the sequence of SEQ ID NO: 54.

[0246] P Embodiment 26. The anti-CD84 antibody according to any one of P Embodiments 20 to 25, wherein the anti-CD84 antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 55.

[0247] P Embodiment 27. The anti-CD84 antibody according to any one of P Embodiments 20 to 26, wherein the anti-CD84 antibody comprises a light chain comprising the sequence of SEQ ID NO: 56.

[0248] P Embodiment 28. An anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 57, CDR H2 set forth in SEQ ID NO: 58, and CDR H3 set forth in SEQ ID NO: 59, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 60, CDR L2 set forth in SEQ ID NO: 61, and CDR L3 set forth in SEQ ID NO: 62.

[0249] P Embodiment 29. The anti-CD84 antibody according to P Embodiment 28, wherein the anti-CD84 antibody is a chimeric antibody.

[0250] P Embodiment 30. The anti-CD84 antibody according to P Embodiment 28 or 29, wherein the heavy chain variable domain comprises FR H1 set forth in SEQ ID NO: 63, FR H2 set forth in SEQ ID NO: 64, FR H3 set forth in SEQ ID NO: 65, and FR H4 set forth in SEQ ID NO: 66.

[0251] P Embodiment 31. The anti-CD84 antibody according to any one of P Embodiments 28 to 30, wherein the light chain variable domain comprises FR L1 set forth in SEQ ID NO: 67, FR L2 set forth in SEQ ID NO: 68, FR L3 set forth in SEQ ID NO: 69, and FR L4 set forth in SEQ ID NO: 70.

[0252] P Embodiment 32. The anti-CD84 antibody according to any one of P Embodiments 28 to 31, wherein the heavy chain variable domain comprises the sequence of SEQ ID NO: 71.

[0253] P Embodiment 33. The anti-CD84 antibody according to any one of P Embodiments 28 to 32, wherein the light chain variable domain comprises the sequence of SEQ ID NO: 72.

[0254] P Embodiment 34. The anti-CD84 antibody according to any one of P Embodiments 28 to 33, wherein the anti-CD84 antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 73.

[0255] P Embodiment 35. The anti-CD84 antibody according to any one of P Embodiments 28 to 34, wherein the anti-CD84 antibody comprises a light chain comprising the sequence of SEQ ID NO: 74.

[0256] P Embodiment 36. An anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 93, CDR H2 set forth in SEQ ID NO: 94, and CDR H3 set forth in SEQ ID NO: 95, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 96, CDR L2 set forth in SEQ ID NO: 97, and CDR L3 set forth in SEQ ID NO: 98.

[0257] P Embodiment 37. The anti-CD84 antibody according to P Embodiment 36, wherein the anti-CD84 antibody is a chimeric antibody.

[0258] P Embodiment 38. The anti-CD84 antibody according to P Embodiment 36 or 37, wherein the heavy chain variable domain comprises FR H1 set forth in SEQ ID NO: 99, FR H2 set forth in SEQ ID NO: 100, FR H3 set forth in SEQ ID NO: 101, and FR H4 set forth in SEQ ID NO: 102.

[0259] P Embodiment 39. The anti-CD84 antibody according to any one of P Embodiments 36 to 38, wherein the light chain variable domain comprises FR L1 set forth in SEQ ID NO: 103, FR L2 set forth in SEQ ID NO: 104, FR L3 set forth in SEQ ID NO: 105, and FR L4 set forth in SEQ ID NO: 106.

[0260] P Embodiment 40. The anti-CD84 antibody according to any one of P Embodiments 36 to 39, wherein the heavy chain variable domain contains the sequence of SEQ ID NO: 107.

[0261] P Embodiment 41. The anti-CD84 antibody according to any one of P Embodiments 36 to 40, wherein the light chain variable domain contains the sequence of SEQ ID NO: 108.

[0262] P Embodiment 42. The anti-CD84 antibody according to any one of P Embodiments 36 to 41, wherein the anti-CD84 antibody contains a heavy chain containing the sequence of SEQ ID NO: 109.

[0263] P Embodiment 43. The anti-CD84 antibody according to any one of P Embodiments 36 to 42, wherein the anti-CD84 antibody contains a light chain containing the sequence of SEQ ID NO: 110.

[0264] P Embodiment 44. The anti-CD84 antibody according to any one of P Embodiments 1 to 43, wherein the anti-CD84 antibody is a Fab' fragment.

[0265] P Embodiment 45. The anti-CD84 antibody according to any one of P Embodiments 1 to 44, wherein the anti-CD84 antibody is IgG.

[0266] P Embodiment 46. The anti-CD84 antibody according to any one of P Embodiment 1, P Embodiments 3 to 6, P Embodiment 9, P Embodiments 14 to 17, P Embodiment 20, P Embodiments 22 to 25, P Embodiment 28, P Embodiments 30 to 33, or P Embodiment 36, or P Embodiments 38 to 41, wherein the light chain variable domain and the heavy chain variable domain form part of an scFv.

[0267] P Embodiment 47. The anti-CD84 antibody according to any one of P Embodiments 1 to 46, wherein the anti-CD84 antibody can bind to the CD84 protein.

[0268] P Embodiment 48. The anti-CD84 antibody according to any one of P Embodiments 1 to 47, wherein the anti-CD84 antibody is bound to the CD84 protein.

[0269] The anti-CD84 antibody according to P embodiment 47, wherein the CD84 protein is a human CD84 protein.

[0270] The anti-CD84 antibody according to P embodiment 48 or 49, wherein the CD84 protein forms part of a cell.

[0271] The anti-CD84 antibody according to any one of embodiments 47 to 50, wherein the CD84 protein is expressed on the surface of a cell.

[0272] The anti-CD84 antibody according to P embodiment 50 or 51, wherein the cell is a cancer cell.

[0273] The anti-CD84 antibody according to P embodiment 52, wherein the cancer cell is a leukemia cancer cell, a myeloid cancer cell or a lymphoma cancer cell.

[0274] An anti-CD84 antibody comprising a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 19, CDR H2 set forth in SEQ ID NO: 20, and CDR H3 set forth in SEQ ID NO: 21, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 22, CDR L2 set forth in SEQ ID NO: 23, and CDR L3 set forth in SEQ ID NO: 24, and an anti-CD84 antibody that binds to the same epitope.

[0275] An anti-CD84 antibody comprising a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 39, CDR H2 set forth in SEQ ID NO: 40, and CDR H3 set forth in SEQ ID NO: 41, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 42, CDR L2 set forth in SEQ ID NO: 43, and CDR L3 set forth in SEQ ID NO: 44, and an anti-CD84 antibody that binds to the same epitope.

[0276] P Embodiment 56. An anti-CD84 antibody comprising a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 57, CDR H2 set forth in SEQ ID NO: 58, and CDR H3 set forth in SEQ ID NO: 59, and an antibody comprising a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 60, CDR L2 set forth in SEQ ID NO: 61, and CDR L3 set forth in SEQ ID NO: 62, and an anti-CD84 antibody that binds to the same epitope.

[0277] P Embodiment 57. An anti-CD84 antibody comprising a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 75, CDR H2 set forth in SEQ ID NO: 76, and CDR H3 set forth in SEQ ID NO: 77, and an antibody comprising a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 78, CDR L2 set forth in SEQ ID NO: 79, and CDR L3 set forth in SEQ ID NO: 80, and an anti-CD84 antibody that binds to the same epitope.

[0278] P Embodiment 58. An anti-CD84 antibody comprising a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 93, CDR H2 set forth in SEQ ID NO: 94, and CDR H3 set forth in SEQ ID NO: 95, and an antibody comprising a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 96, CDR L2 set forth in SEQ ID NO: 97, and CDR L3 set forth in SEQ ID NO: 98, and an anti-CD84 antibody that binds to the same epitope.

[0279] P Embodiment 59. The anti-CD84 antibody according to any one of P Embodiments 1 to 58, wherein the anti-CD84 antibody is bound to a therapeutic moiety or a diagnostic moiety.

[0280] P Embodiment 60. The anti-CD84 antibody according to P Embodiment 59, wherein the therapeutic moiety is an anti-cancer moiety.

[0281] P Embodiment 61. An isolated nucleic acid encoding the anti-CD84 antibody according to any one of P Embodiments 1 to 60.

[0282] A cell comprising the anti-CD84 antibody according to any one of claims 1 to 60, or the nucleic acid according to P embodiment 61.

[0283] P embodiment 63. A pharmaceutical composition comprising a therapeutically effective amount of the antibody according to any one of P embodiments 1 to 60 and a pharmaceutically acceptable excipient.

[0284] P embodiment 64. A method for generating an antibody capable of binding to CD84, the method comprising immunizing a mammal with a peptide comprising the sequence of SEQ ID NO: 111.

[0285] P embodiment 65. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the anti-CD84 antibody according to any one of P embodiments 1 to 60 or the pharmaceutical composition according to P embodiment 63, thereby treating the cancer in the subject.

[0286] P embodiment 66. The method for treating cancer according to P embodiment 65, wherein the cancer is lymphoma, myeloma or leukemia.

[0287] P embodiment 67. The method for treating cancer according to P embodiment 65 or 66, wherein the cancer is acute myeloid leukemia (AML).

Claims

**Claim 1** An anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 75, CDR H2 set forth in SEQ ID NO: 76, and CDR H3 set forth in SEQ ID NO: 77, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 78, CDR L2 set forth in SEQ ID NO: 79, and CDR L3 set forth in SEQ ID NO:

80. An anti-CD84 antibody. **Claim 2** The anti-CD84 antibody according to claim 1, wherein the anti-CD84 antibody is a chimeric antibody. **Claim 3** The anti-CD84 antibody according to claim 1, wherein the heavy chain variable domain comprises FR H1 set forth in SEQ ID NO: 81, FR H2 set forth in SEQ ID NO: 82, FR H3 set forth in SEQ ID NO: 83, and FR H4 set forth in SEQ ID NO:

84. **Claim 4** The anti-CD84 antibody according to claim 1, wherein the light chain variable domain comprises FR L1 set forth in SEQ ID NO: 85, FR L2 set forth in SEQ ID NO: 86, FR L3 set forth in SEQ ID NO: 87, and FR L4 set forth in SEQ ID NO:

88. **Claim 5** The anti-CD84 antibody according to claim 1, wherein the heavy chain variable domain comprises the sequence of SEQ ID NO:

89. **Claim 6** The anti-CD84 antibody according to claim 1, wherein the light chain variable domain comprises the sequence of SEQ ID NO:

90. **Claim 7** The anti-CD84 antibody according to claim 1, wherein the anti-CD84 antibody comprises a heavy chain comprising the sequence of SEQ ID NO:

91. **Claim 8** The anti-CD84 antibody according to claim 1, wherein the anti-CD84 antibody comprises a light chain comprising the sequence of SEQ ID NO:

92. **Claim 9** An anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 19, CDR H2 set forth in SEQ ID NO: 20, and CDR H3 set forth in SEQ ID NO: 21, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 22, CDR L2 set forth in SEQ ID NO: 23, and CDR L3 set forth in SEQ ID NO:

24. An anti-CD84 antibody. **Claim 10** The anti-CD84 antibody according to claim 9, wherein the anti-CD84 antibody is a humanized antibody. **Claim 11** The anti-CD84 antibody according to claim 9, wherein the antibody comprises a light chain comprising the sequence of SEQ ID NO:

37. **Claim 12** The anti-CD84 antibody according to claim 9, wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO:

38. **Claim 13** The anti-CD84 antibody according to claim 9, wherein the anti-CD84 antibody is a chimeric antibody.

14. The anti-CD84 antibody according to claim 9, wherein the heavy chain variable domain comprises FR H1 described in SEQ ID NO: 25, FR H2 described in SEQ ID NO: 26, FR H3 described in SEQ ID NO: 27, and FR H4 described in SEQ ID NO:

28.

15. The anti-CD84 antibody according to claim 9, wherein the light chain variable domain comprises FR L1 described in SEQ ID NO: 29, FR L2 described in SEQ ID NO: 30, FR L3 described in SEQ ID NO: 31, and FR L4 described in SEQ ID NO:

32.

16. The anti-CD84 antibody according to claim 9, wherein the heavy chain variable domain comprises the sequence of SEQ ID NO:

33.

17. The anti-CD84 antibody according to claim 9, wherein the light chain variable domain comprises the sequence of SEQ ID NO:

34.

18. The anti-CD84 antibody according to claim 9, wherein the anti-CD84 antibody comprises a heavy chain comprising the sequence of SEQ ID NO:

35.

19. The anti-CD84 antibody according to claim 9, wherein the anti-CD84 antibody comprises a light chain comprising the sequence of SEQ ID NO:

36.

20. An anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 described in SEQ ID NO: 39, CDR H2 described in SEQ ID NO: 40, and CDR H3 described in SEQ ID NO: 41, and the light chain variable domain comprises CDR L1 described in SEQ ID NO: 42, CDR L2 described in SEQ ID NO: 43, and CDR L3 described in SEQ ID NO:

44.

21. The anti-CD84 antibody according to claim 20, wherein the anti-CD84 antibody is a chimeric antibody.

22. The anti-CD84 antibody according to claim 20, wherein the heavy chain variable domain comprises FR H1 described in SEQ ID NO: 45, FR H2 described in SEQ ID NO: 46, FR H3 described in SEQ ID NO: 47, and FR H4 described in SEQ ID NO:

48.

23. The anti-CD84 antibody according to claim 20, wherein the light chain variable domain comprises FR L1 described in SEQ ID NO: 49, FR L2 described in SEQ ID NO: 50, FR L3 described in SEQ ID NO: 51, and FR L4 described in SEQ ID NO:

52.

24. The anti-CD84 antibody according to claim 20, wherein the heavy chain variable domain comprises the sequence of SEQ ID NO:

53.

25. The anti-CD84 antibody according to claim 20, wherein the light chain variable domain comprises the sequence of SEQ ID NO:

54.

26. The anti-CD84 antibody according to claim 20, wherein the anti-CD84 antibody comprises a heavy chain comprising the sequence of SEQ ID NO:

55.

27. The anti-CD84 antibody according to claim 20, wherein the anti-CD84 antibody comprises a light chain comprising the sequence of SEQ ID NO:

56.

28. An anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 57, CDR H2 set forth in SEQ ID NO: 58, and CDR H3 set forth in SEQ ID NO: 59, and the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 60, CDR L2 set forth in SEQ ID NO: 61, and CDR L3 set forth in SEQ ID NO:

62.

29. The anti-CD84 antibody according to claim 28, wherein the anti-CD84 antibody is a chimeric antibody.

30. The anti-CD84 antibody according to claim 28, wherein the heavy chain variable domain comprises FR H1 set forth in SEQ ID NO: 63, FR H2 set forth in SEQ ID NO: 64, FR H3 set forth in SEQ ID NO: 65, and FR H4 set forth in SEQ ID NO:

66.

31. The anti-CD84 antibody according to claim 28, wherein the light chain variable domain comprises FR L1 set forth in SEQ ID NO: 67, FR L2 set forth in SEQ ID NO: 68, FR L3 set forth in SEQ ID NO: 69, and FR L4 set forth in SEQ ID NO:

70.

32. The anti-CD84 antibody according to claim 28, wherein the heavy chain variable domain comprises the sequence of SEQ ID NO:

71.

33. The anti-CD84 antibody according to claim 28, wherein the light chain variable domain comprises the sequence of SEQ ID NO:

72.

34. The anti-CD84 antibody according to claim 28, wherein the anti-CD84 antibody comprises a heavy chain comprising the sequence of SEQ ID NO:

73.

35. The anti-CD84 antibody according to claim 28, wherein the anti-CD84 antibody comprises a light chain comprising the sequence of SEQ ID NO:

74.

36. An anti-CD84 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises CDR H1 set forth in SEQ ID NO: 93, CDR H2 set forth in SEQ ID NO: 94, and CDR H3 set forth in SEQ ID NO: 95, An anti-CD84 antibody, wherein the light chain variable domain comprises CDR L1 set forth in SEQ ID NO: 96, CDR L2 set forth in SEQ ID NO: 97, and CDR L3 set forth in SEQ ID NO:

98.

37. The anti-CD84 antibody according to claim 36, wherein the anti-CD84 antibody is a chimeric antibody.

38. The anti-CD84 antibody according to claim 36, wherein the heavy chain variable domain comprises FR H1 set forth in SEQ ID NO: 99, FR H2 set forth in SEQ ID NO: 100, FR H3 set forth in SEQ ID NO: 101, and FR H4 set forth in SEQ ID NO:

102.

39. The anti-CD84 antibody according to claim 36, wherein the light chain variable domain comprises FR L1 set forth in SEQ ID NO: 103, FR L2 set forth in SEQ ID NO: 104, FR L3 set forth in SEQ ID NO: 105, and FR L4 set forth in SEQ ID NO:

106.

40. The anti-CD84 antibody according to claim 36, wherein the heavy chain variable domain comprises the sequence of SEQ ID NO:

107.

41. The anti-CD84 antibody according to claim 36, wherein the light chain variable domain comprises the sequence of SEQ ID NO:

108.

42. The anti-CD84 antibody according to claim 36, wherein the anti-CD84 antibody comprises a heavy chain comprising the sequence of SEQ ID NO:

109.

43. The anti-CD84 antibody according to claim 36, wherein the anti-CD84 antibody comprises a light chain comprising the sequence of SEQ ID NO:

110.

44. The anti-CD84 antibody according to any one of claims 1, 9, 20, 28 or 36, wherein the anti-CD84 antibody is a Fab' fragment.

45. The anti-CD84 antibody according to any one of claims 1, 9, 20, 28 or 36, wherein the anti-CD84 antibody is IgG.

46. The anti-CD84 antibody according to any one of claims 1, 9, 20, 28 or 36, wherein the light chain variable domain and the heavy chain variable domain form part of an scFv.

47. The anti-CD84 antibody according to any one of claims 1, 9, 20, 28 or 36, wherein the anti-CD84 antibody is capable of binding to a CD84 protein.

48. The anti-CD84 antibody according to any one of claims 1, 9, 20, 28 or 36, wherein the anti-CD84 antibody is bound to a CD84 protein.

49. The anti-CD84 antibody according to claim 47, wherein the CD84 protein is a human CD84 protein.

50. The anti-CD84 antibody according to claim 48, wherein the CD84 protein forms part of a cell. **Claim 51** The anti-CD84 antibody according to claim 47, wherein the CD84 protein is expressed on the surface of a cell. **Claim 52** The anti-CD84 antibody according to claim 50, wherein the cell is a cancer cell. **Claim 53** The anti-CD84 antibody according to claim 52, wherein the cancer cell is a leukemia cancer cell, a myeloid cancer cell or a lymphoma cancer cell. **Claim 54** An anti-CD84 antibody, comprising a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 19, CDR H2 set forth in SEQ ID NO: 20, and CDR H3 set forth in SEQ ID NO: 21, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 22, CDR L2 set forth in SEQ ID NO: 23, and CDR L3 set forth in SEQ ID NO: 24, and an antibody that binds to the same epitope. **Claim 55** An anti-CD84 antibody, comprising a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 39, CDR H2 set forth in SEQ ID NO: 40, and CDR H3 set forth in SEQ ID NO: 41, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 42, CDR L2 set forth in SEQ ID NO: 43, and CDR L3 set forth in SEQ ID NO: 44, and an antibody that binds to the same epitope. **Claim 56** An anti-CD84 antibody, comprising a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 57, CDR H2 set forth in SEQ ID NO: 58, and CDR H3 set forth in SEQ ID NO: 59, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 60, CDR L2 set forth in SEQ ID NO: 61, and CDR L3 set forth in SEQ ID NO: 62, and an antibody that binds to the same epitope. **Claim 57** An anti-CD84 antibody, comprising a heavy chain variable domain comprising CDR H1 set forth in SEQ ID NO: 75, CDR H2 set forth in SEQ ID NO: 76, and CDR H3 set forth in SEQ ID NO: 77, and a light chain variable domain comprising CDR L1 set forth in SEQ ID NO: 78, CDR L2 set forth in SEQ ID NO: 79, and CDR L3 set forth in SEQ ID NO: 80, and an antibody that binds to the same epitope. **Claim 58** An anti-CD84 antibody comprising a heavy chain variable domain containing CDR H1 set forth in SEQ ID NO: 93, CDR H2 set forth in SEQ ID NO: 94, and CDR H3 set forth in SEQ ID NO: 95, and a light chain variable domain containing CDR L1 set forth in SEQ ID NO: 96, CDR L2 set forth in SEQ ID NO: 97, and CDR L3 set forth in SEQ ID NO: 98, and an anti-CD84 antibody that binds to the same epitope.

59. The anti-CD84 antibody according to any one of claims 1, 9, 20, 28, 36, 54, 55, 56, 57 or 58, wherein the anti-CD84 antibody is bound to a therapeutic moiety or a diagnostic moiety.

60. The anti-CD84 antibody according to claim 59, wherein the therapeutic moiety is an anti-cancer moiety.

61. An isolated nucleic acid encoding the anti-CD84 antibody according to any one of claims 1, 9, 20, 28, 36, 54, 55, 56, 57 or 58.

62. A cell comprising the anti-CD84 antibody according to any one of claims 1, 9, 20, 28, 36, 54, 55, 56, 57 or 58, or the nucleic acid according to claim 61.

63. A pharmaceutical composition comprising a therapeutically effective amount of the antibody according to any one of claims 1, 9, 20, 28, 36, 54, 55, 56, 57 or 58 and a pharmaceutically acceptable excipient.

64. A method for generating an antibody capable of binding to CD84, the method comprising immunizing a mammal with a peptide comprising the sequence of SEQ ID NO:

111.

65. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the anti-CD84 antibody according to any one of claims 1, 9, 20, 28, 36, 54, 55, 56, 57 or 58, or the pharmaceutical composition according to claim 63, thereby treating the cancer in the subject.

66. The method for treating cancer according to claim 65, wherein the cancer is lymphoma, myeloma or leukemia.

67. The method for treating cancer according to claim 65, wherein the cancer is acute myeloid leukemia (AML).

Images