Engineered platelets for targeted delivery of a therapeutic agent

Abstract

The present invention provides engineered platelets with chimeric platelet receptors (CPR) with a desired target specificity. Additionally, the engineered platelets may comprise cargo which may be released upon activation of the platelet. Additionally, the platelets may be generated in vitro from megakaryocytes engineered to generate non-thrombogemc platelets.

Description

SEQUENCE LISTING

[0001] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing file, entitled SEQLIST.txt, was created on December 14, 2020, and is 46,300 bytes in size. The information in electronic format of the Sequence Listing is incorporated herein by reference in its entirety. FIELD OF THE INVENTION

[0002] The invention relates to engineered platelets for targeted therapeutic delivery systems. BACKGROUND OF THE INVENTION

[0003] Platelets are small and enucleated and cannot divide or reproduce. In the human body, they perform the important function of recognising injured tissue and releasing their contents to reduce or prevent bleeding. Thrombopoietin from the kidneys and liver contact a myeloid stem cell causing differentiation into a megakaryoblasorphant, and additional signals result in differentiation of the megakaryoblast into a progenitor megakaryocyte. Progenitor megakaryocytes are large cells with platelet precursor extensions that bud off fragments as they divide and proliferate to create platelets.

[0004] Mitochondria, microtubules, and vesicles are contained within the platelets, and the platelets have a life span of about 10 days before clearance by macrophages. Platelets have a volume of about 7pnF and a diameter of 300nm. They are metabolically active and can alter gene expression through post-transcriptional control of preloaded mRNA expression (e.g. by miRNAs). On activation, granulation is stimulated to alter the shape and release the contents of the intracellular vesicles.

[0005] Platelets respond to a variety of extra cellular signals through a diverse set of signaling pathway receptors. Receptors act both to trigger intracellular signaling cascades resulting in platelet degranulation and effector release and to cause platelet aggregation and adhesion, glycoprotein VI platelet (GPVI) signaling functions analogously to many immune cell receptors - such as the TCR. Interestingly, platelets also express toll-like receptors (TLRs) and can mediated targeted killing of bacteria via peptide secretion and immune system activation.

[0006] A huge variety of products are released on platelet degranulation. Vesicles are released by exocytosis. Platelets contain three primary subtypes of vesicles: a-granules (50 to 80 per platelet), dense granules (3 to 8 per platelet), and large dense core vesicles (LDCV) (about 10,000 per platelet). Different mutations can selectively disrupt the biogenesis of each vesicle subtype.

[0007] a-granules have a diameter of about 200 to 500nm and make up about 10% of the platelet’s volume. Most effector proteins are found in a-granules. For example, effector proteins released from a-granules include: integral membrane proteins, such as P-selectin, allbp, and GPIba; coagulants / anticoagulants and fibrinolytic proteins, such as factor V, factor IX, and plasminogen; adhesion proteins, such as fibrinogen and von Willebrand Factor (vWF); chemokines, such as CXCL4 (cytokine (C-X-C motif) ligand 4), also known as platelet factor 4 or PF4, and CXCL12 (cytokine (C-X-C motif) ligand 12), also known as stromal cell-derived factor 1 alpha or SDF-la; growth factors, such as elongation growth factor (EGF) and insulin-like growth factor 1 (IGF); angiogenic factors / inhibitors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and angiostatins; and immune mediators, such as immunoglobulin G (IgG) and complement precursors.

[0008] Dense granules have a diameter of about 150nm and make up about 1% of the platelet’s volume. Effector proteins released from dense granules include cations, such as Ca2” and Mg2+; polyphosphates; bioactive amines, such as serotonin and histamine; and nucleotides, such as adenosine diphosphate (ADP) and adenosine triphosphate (ATP).

[0009] LDCVs have a diameter in the range of about 150nm to about 300nm and make up about 13.5% of the platelet’s volume. Effector proteins released from LDCVs include structural proteins (e.g., granins and glycoproteins); vascoregulators (e.g., cateholammes, vasostatins, reninangiotensin); paracrine signaling factors (e.g., guanylin, neurotensin, chromogranin B); immune mediators (e.g., enkelytin and ubiquitin); opiods (e.g., enkephalins and endorphins); ions (e.g., Ca2+, Na+, C1-), and nucleotides and polyphosphates (e.g., adenosine monophosphate (AMP), guanosine diphosphate (GDP), uridine-5'-triphosphate (DTP)).

[0010] Current cell therapies based on engineered chimeric antigen receptor T cells (CAR-T cells) have shown promise treating cancer; however, concerns regarding their safety, specifically oncogenic transformation in the patient, and the limited ability to generate a generic or universal therapeutic product have restricted their use to a small number of patients. There is a long felt need in the art for a new? type of therapy with the potential to treat cancer, autoimmune conditions, and infections, free from the safety, cost, and patient matching issues which plague current cell therapeutic products. SUMMARY OF THE INVENTION

[0011] Various embodiments of the invention described herein provide a chimeric platelet receptor (CPR) comprising: a) an intracellular domain that is a platelet stimulation domain and comprises domains from an immunoreceptor tyrosine-based activation motif (ITAM) receptor; and b) a heterologous targeting domain that recognizes and binds a target. By a heterologous targeting domain we mean that the targeting domain is heterologous to the intracellular platelet stimulation domain i.e. the targeting domain is not the usual extracellular domain associated with the intracellular domain. The heterologous targeting domain may bind to an endogenous target, for example may bind to a tumour antigen that is endogenous to a subject but, by virtue of the CPR being chimeric, the targeting domain is heterologous to the internal platelet stimulation domain.

[0012] The invention described herein also provides a chimeric platelet receptor (CPR) comprising: a first region encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NO: 1-19, 24-47, and 52-55; and a second region selected from the group consisting of: (i) a linker or a targeting domain encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NO: 48-51; (li) at least a portion of a protein selected from the group consisting of: myelin oligodendrocyte glycoprotein (MOG), glutamic acid decarboxylase 2 (GAD65), myelin associated glycoprotein (MAG), peripheral myelin protein 22 (PMP22), thyroid peroxidase (TPO), voltagegated potassium channel (VGKC), proteolipid protein (PLP), acetylcholine receptor (AChR), tribbles pseudokinase 2 (TRIB2), N-methyl-D-aspartate (NMDA)-type glutamate receptor (GluR), glutamate decarboxylase 2 (GAD2), Armadillo repeat containing 9 (ARMC9), Cytochrome P450 Family 21 Subfamily .A Member 2 (CYP21A2), calcium sensing receptor (CASR), nuclear autoantigenic sperm protein (NASP), insulin, thyroid stimulating hormone receptor (TSHR), thyroperoxidase, asioglycoprotein receptor, Cytochrome P450 Family 2 Subfamily D Member 6 (CYP2D6), lactoferrin (LF), tissue trans-glutaminase (TTG), 11 K ATP-ase, Factor XIII (F8), beta2- glycoprotein I (Beta2-GPI), erythrocyte 1 / 1, B2 integrin (ITGB2), granulocyte-colony stimulating factor (G-CSF), glycoprotein (GP) Hb Ha. collagen II (COLII), fibrinogen (FBG) pa, myeloperoxidase (MPO), cardiac myosin (CYO), proteinase 3 (PRTN3), trichohyalin (TCHH), bullous pemphigoid associated (BP), glycoprotein 1 (GP1), laminin-332 (LM332), transglutaminase (TGM), type VII collagen (COL VII), P80 Coilin (COIL), Desmoglein I (DSG1), Desmoglein III (DSG3), SRY-Box 10 (SOX10), small nuclear ribonucleoprotein Ui subunit (70SNRNP70), S-antigen (SAG), and Collagen alpha-3(IV) chain (a3(IV)NCl collagen); (iii) an antibody or an antibody fragment selected from the group consisting of: 3F8, 8H9, Abagovomab, Abciximab, Abituzumab, Abrezekimab, Abrilumab, Actoxumab, Adalimumab, Adecatumumab, Atidortoxumab, Aducanumab, Afasevikumab, Afelimomab, Alacizumab pego, Alemtuzumab, Alirocumab, Altumomab pentetate, Amatuximab, Anatumomab mafenatox, Andecaliximab, Anetumab ravtansine, Anifrolumab, Anrukinzumab, Apolizumab, Aprutumab ixadotin, Arcitumomab, Ascrinvacumab, Aselizumab, Atezolizumab, Atinumab, Atorolimumab, Avelumab, Azintuxizumab vedotin, Bapineuzumab, Basiliximab, Bavituximab, BCD-100, Bectumomab, Begelomab, Belantamab mafodotin, Belimumab, Bemarituzumab, Benralizumab, Berlimatoxumab, Bermekimab, Bersanlimab, Bertilimumab, Besilesomab, Bevacizumab, Bezlotoxumab, Biciromab, Bimagrumab, Bimekizumab, Birtamimab, Bivatuzumab mertansine, Bleselumab, Blinatumomab, Blontuvetmab, Blosozumab, Bococizumab, Brazikumab, Brentuximab vedotin, Briakinumab, Brodalumab, Brolucizumab, Brontictuzumab, Burosumab, Cabiralizumab, Camidanlumab tesirine, Camrelizumab, Canakinumab, Cantuzumab mertansine, Cantuzumab ravtansine, Caplacizumab, Capromab pendetide, Carlumab, Carotuximab, Catumaxomab, cBR96-doxorubicin immunoconjugate, Cedelizumab, Cemiplimab, Cergutuzumab amunaleukin, Certolizumab pegol, Cetrelimab, Cetuximab, Cibisatamab, Cirmtuzumab, Citatuzumab bogatox, Cixutumumab, Clazakizumab, Clenoliximab, Clivatuzumab tetraxetan, Codrituzumab, Cofetuzumab pelidotin, Coltuximab ravtansine, Conatumumab, Concizumab, Cosfroviximab, Crenezumab, Crizanlizumab, Crotedumab, CR6261, Cusatuzumab, Dacetuzumab, Daclizumab, Dalotuzumab, Dapirolizumab pegol, Daratumumab, Dectrekumab, Demcizumab, Denintuzumab mafodotin, Denosumab, Depatuxizumab mafodotin, Derlotuximab biotin, Detumomab, Dezamizumab, Dinutuximab, Diridavumab, Domagrozumab, Dorlimomab aritox, Dostarlimab, Drozitumab, DS-8201, Duligotuzumab, Dupilumab, Durvalumab, Dusigitumab, Duvortuxizumab, Ecromeximab, Eculizumab, Edobacomab, Edrecolomab, Efalizumab, Efungumab, Eldelumab, Elezanumab, Elgemtumab, Elotuzumab, Elsihmomab, Emactuzumab, Emapalumab, Emibetuzumab, Emicizumab, Enapotamab vedotin, Enavatuzumab, Enfortumab vedotin, Enlimomab pegol, Enoblituzumab, Enokizumab, Enoticumab, Ensituximab, Epitumomab cituxetan, Epratuzumab, Eptinezumab, Erenumab, Erlizumab, Ertumaxomab, Etaracizumab, Etigilimab, Etrolizumab, Evinacumab, Evolocumab, Exbivirumab, Fanolesomab, Faralimomab, Faricimab, Farletuzumab, Fasinumab, FBTA05, Felvizumab, Fezakinumab, Fibatuzumab, Ficlatuzumab, Figitumumab, Firivumab, Flanvotumab, Fletikumab, Flotetuzumab, Fontolizumab, Foralumab, Foravirumab, Fremanezumab, Fresolimumab, Frovocimab, Frunevetmab, Fulranumab, Futuximab, Galcanezumab, Galiximab, Gancotamab, Ganitumab, Gantenerumab, Gatipotuzumab, Gavilimomab, Gedivumab, Gemtuzumab ozogamicin, Gevokizumab, Gilvetmab, Gimsilumab, Girentuximab, Glembatumumab vedotin, Golimumab, Gomiliximab, Gosuranemab, Guselkumab, lanalumab, Ibalizumab, IBI308, Ibritumomab tiuxetan, Icrucumab, Idarucizumab, Ifabotuzumab, Igovomab, Iladatuzumab vedotin, IMAB362, Imalumab, Imaprelimab, Imciromab, Imgatuzumab, Inclacumab, Indatuximab ravtansine, Indusatumab vedotin, Inebilizumab, Infliximab, Intetumumab, Inolimomab, Inotuzumab ozogamicin, Ipilimumab, lomab-B, Iratumumab, Isatuximab, Iscalimab, Istiratumab, Itolizumab, Ixekizumab, Keliximab, Labetuzumab, Lacnotuzumab, Ladiratuzumab vedotin, Lampalizumab, Lanadelumab, Landogrozumab, Laprituximab emtansine, Larcaviximab, Lebrikizumab, Lemalesomab, Lendalizumab, Lenvervimab, Lenzilumab, Lerdelimumab, Leronlimab, Lesofavumab, Letolizumab, Lexatumumab, Libivirumab, Lifastuzumab vedotin, Ligelizumab, Loncastuximab tesinne, Losatuxizumab vedotin, Lilotomab satetraxetan, Lintuzumab, Lirilumab, Lodelcizumab, Lokivetmab, Lorvotuzumab mertansine, Lucatumumab, Lulizumab pegol, Lumiliximab, Lumretuzumab, Lupartumab amadotin, Lutikizumab, Mapatumumab, Margetuximab, Marstacimab, Maslimomab, Mavrilimumab, Matuzumab, Mepolizumab, Metelimumab, Milatuzumab, Minretumomab, Mirikizumab, Mirvetuximab soravtansine, Mitumomab, Modotuximab, Mogamulizumab, Monalizumab, Morolimumab, Mosunetuzumab, Motavizumab, Moxetumomab pasudotox, Muromonab-CD3, Nacolomab tafenatox, Namilumab, Naptumomab estafenatox, Naratuximab emtansine, Narnatumab, Natalizumab, Navicixizumab, Navivumab, Naxitamab, Nebacumab, Necitumumab, Nemolizumab, NEOD001, Nerelimomab, Nesvacumab, Netakimab, Nimotuzumab, Nirsevimab, Nivolumab, Nofetumomab merpentan, Obiltoxaximab, Obinutuzumab, Ocaratuzumab, Ocrelizumab, Odulimomab, Ofatumumab, Olaratumab, Oleclumab, Olendalizumab, Olokizumab, Omalizumab, Omburtamab, OMS721, Onartuzumab, Ontuxizumab, Onvatilimab, Opicinumab, Oportuzumab monatox, Oregovomab, Orticumab, Otelixizumab, Otilimab, Otlertuzumab, Oxelumab, Ozanezumab, Ozoralizumab, Pagibaximab, Palivizumab, Pamrevlumab, Panitumumab, Pankomab, Panobacumab, Parsatuzumab, Pascolizumab, Pasotuxizumab, Pateclizumab, Patritumab, PDR001, Pembrolizumab, Pemtumomab, Perakizumab, Pertuzumab, Pexelizumab, Pidilizumab, Pinatuzumab vedotin, Pintumomab, Placulumab, Plozalizumab, Pogalizumab, Polatuzumab vedotin, Ponezumab, Porgaviximab, Prasinezumab, Prezalizumab, Priliximab, Pritoxaximab, Pritumumab, PRO 140, Quilizumab, Racotumomab, Radretumab, Rafivirumab, Ralpancizumab, Ramucirumab, Ranevetmab, Ranibizumab, Raxibacumab, Ravagalimab, Ravulizumab, Refanezumab, Regavirumab, Reiatlimab, Remtolumab, Reslizumab, Rilotumumab, Rinucumab, Risankizumab, Rituximab, Rivabazumab pegol, Robatumumab, Rmab, Roledumab, Romilkimab, Romosozumab, Rontalizumab, Rosmantuzumab, Rovalpituzumab tesirine, Rovelizumab, Rozanolixizumab, Ruplizumab, SA237, Sacituzumab govitecan, Samalizumab, Samrotamab vedotin, Sarilumab, Satralizumab, Satumomab pendetide, Secukinumab, Selicrelumab, Seribantumab, Setoxaximab, Setrusumab, Sevirumab, Sibrotuzumab, SGN-CD19A, SHP647, Sifalimumab, Siltuximab, Simtuzumab, Siplizumab, Sirtratumab vedotin, Sirukumab, Sofituzumab vedotin, Solanezumab, Solitomab, Sonepcizumab, Sontuzumab, Spartalizumab, Stamulumab, Sulesomab, Suptavumab, Sutimlimab, Suvizumab, Suvratoxumab, Tabalumab, Tacatuzumab tetraxetan, Tadocizumab, Talacotuzumab, Talizumab, Tamtuvetmab, Tanezumab, Taplitumomab paptox, Tarextumab, Tavolimab, Tefibazumab, Telimomab aritox, Telisotuzumab vedotin, Tenatumomab, Teneliximab, Teplizumab, Tepoditamab, Teprotumumab, Tesidolumab, Tetulomab, Tezepelumab, TGN1412, Tibulizumab, Tildrakizumab, Tigatuzumab, Timigutuzumab, Timolumab, Tiragotumab, Tislelizumab, Tisotumab vedotin, TNX-650, Tocilizumab, Tomuzotuximab, Toralizumab, Tosatoxumab, Tositumomab, Tovetumab, Tralokinumab, Trastuzumab, Trastuzumab emtansine, TRBS07, Tregalizumab, Tremelimumab, Trevogrumab, Tucotuzumab celmoleukin, Tuvirumab, Ublituximab, Ulocuplumab, Urelumab, Urtoxazumab, Ustekinumab, Utomilumab, Vadastuximab talirme, Vanatimab, Vandortuzumab vedotin, Vantictumab, Vanucizumab, Vapaliximab, Varisacumab, Varlilumab, Vatelizumab, Vedolizumab, Veltuzumab, Vepalimomab, Vesencumab, Visilizumab, Vobarilizumab, Volociximab, Vonlerolizumab, Vopratelimab, Vorsetuzumab mafodotin, Votumumab, Vunakizumab, Xentuzumab, XMAB-5574, Zalutumumab, Zanolimumab, Zatuximab, Zenocutuzumab, Ziralimumab, Zolbetuximab, Zolimomab aritox; and (iv) a major histocompatibility complex (MHC) class I receptor or a major histocompatibility complex (MHC) class 2 receptor, wherein the MHC class 1 receptor is bound to a peptide derived from a tumor antigen, a neoantigen, or an autoantigen or the MHC class 2 receptor is bound to a peptide derived from a tumor antigen, a neoantigen, or an autoantigen.

[0013] In some embodiments, the chimeric platelet receptor binds at least one antigen. In some embodiments, the chimeric platelet receptor binds a tissue in the body of a subject. In some embodiments, the chimeric platelet receptor inhibits platelet activation. In some embodiments, the chimeric platelet receptor is an ITIM-containing receptor. In some embodiments, the chimeric platelet receptor stimulates platelet activation. In some embodiments, the chimeric platelet receptor is an ITAM-containing receptor. In some embodiments the chimeric platelet receptor binds to at least one antigen that is an endogenous antigen, for example is an endogenous host or subject antigen. By an endogenous host or subject antigen we include the meaning that the antigen is present within a host or subject into which the chimeric platelet receptor is administered or into which cells such as megakaryocytes or platelets that comprise the CPR of the invention are administered. For example the antigen may be an antigen that is present on tissue, or on a particular subset of tissue, or in plasma or blood of a subject, for example a human subject. The antigen may be an antigen that is expressed at abnormal levels, for example at abnormally high levels, on a tissue that does not normally express a high level of the antigen, or that does not normally express the antigen at all. In some embodiments, the chimeric platelet receptor is not, or does not comprise, a GPCR or a protease-acti vated receptor. The invention also provides a nucleic acid encoding the chimeric platelet receptor of the invention. In preferred instances, the chimeric platelet receptor is not a naturally occurring receptor, and so the nucleic acid encoding said receptor is not a naturally occurring nucleic acid. In some embodiments the nucleic acid encodes the CPR of the invention and also comprises a heterologous nucleic acid sequence. In some instances the nucleic acid is operatively linked to an expression control sequence. Expression control sequences are considered to include component such as enhancers and promoters. In one embodiment the nucleic acid of the invention comprises a heterologous promoter. In the same or different embodiment the nucleic acid of the invention comprises a heterologous enhancer sequence. In some embodiments the nucleic acid is DNA. In some embodiments the nucleic acid is RNA for example is an mRNA. In some embodiments the nucleic acid comprises a megakaryocyte-specific promoter or a platelet-specific promoter. The terms megakaryocyte-specific promoter and plateletspecific promoter are used synonymously. The skilled person will understand what is meant by the terms megakaryocyte-specific promoter and platelet-specific promoter. The invention also provides a vector that comprises a nucleic acid that encodes the CPR. By vector we include the meaning of plasmid. In some embodiments the vector also comprises a heterologous nucleic acid. In some embodiments the vector comprises a megakaryocyte-specific promoter. In some embodiments the vector comprises a platelet-specific promoter. The invention also provides a viral particle, or viral vector, comprising any one or more of the nucleic acids of the invention. The invention also provides a nucleic acid encoding a cargo protein or peptide which comprises sequences suitable for driving expression in a megakaryocyte and / or platelet. For example, in some embodiments the nucleic acid encoding the cargo protein, cargo peptide or cargo RNA is operatively linked to a heterologous expression control sequence such as a promoter. In some embodiments the nucleic acid encodes a cargo protein or peptide and also comprises a megakaryocyte specific promoter or a platelet specific promoter. In some embodiments the nucleic acid encodes a cargo protein or peptide and comprises a heterologous sequence, such as a megakaryocyte specific promoter or a platelet specific promoter.

[0014]

[0015] Various embodiments of the invention described herein provide a therapeutic delivery system comprising: an engineered platelet presenting the chimeric platelet receptor previously described; and at least one therapeutic agent selected from the group consisting of: a toxin, a protein, a small molecule drug, and a nucleic acid packaged within a vesicle inside the platelet.

[0016] In some embodiments, the engineered platelet is produced from an iPSC progenitor. In some embodiments, the nucleic acid is a mRNA, a miRNA, shRNA, and a clustered regularly interspaced short palindromic repeats (CRISPR) sequence. In some embodiments, the protein is selected from the group consisting of an antibody, an enzyme, a cytokine, and a CRISPR associated protein 9 (Cas9). In an aspect, the enzyme is a nuclease. 10017] In some embodiments, the nuclease is a transcription activator-like effector nuclease (TALEN). In some embodiments, the antibody binds a target such as, but not limited to, a tumor antigen or a neoantigen. In some embodiments, the therapeutic agent is released from the platelet following activation of the platelet by an antigen recognized by the chimeric platelet receptor.

[0018] Various methods are provided for delivering a cargo to a subject in need thereof. As described herein, the cargo may be a therapeutic drug or a toxin. The cargo may be a protein or peptide, or may be a nucleic acid such as a therapeutic RNA or an mRNA. Preferences for the cargo are as described elsewhere herein. The invention provides a method of delivering a cargo comprising administering an effective amount of any one or more of an engineered megakaryocyte, engineered platelet, and / or CPR according to any of the preceding claims. The invention also provides a therapeutic delivery' system. The invention also provides a non-therapeutic delivery system. The invention also provides a method of targeted cargo delivery to a target tissue or site in the body wherein the method comprises administering an effecti ve amount of any one or more of an engineered megakaryocyte, engineered platelet, and / or CPR according to any of the preceding claims wherein the targeting domain of the CPR binds to the target tissue or site m the body. Various embodiments of the invention described herein provide a method of treating a disease, disorder, or condition in a subject, the method comprising: administering to the subject the previously described therapeutic delivery system, wherein the chimeric receptor is specific to an antigen associated with the disease, disorder, or condition.

[0019] In some embodiments, the disease, disorder, or condition may be, but is not limited to, a cancer, an autoimmunity, and an infection. In some embodiments, the cancer is selected from the group consisting of: Acute granulocytic leukemia, Acute lymphocytic leukemia, Acute myelogenous leukemia, Adenocarcinoma, Adenosarcoma, Adrenal cancer, Adrenocortical carcinoma, Anal cancer, Anaplastic astrocytoma, Angiosarcoma, Appendix cancer, Astrocytoma, Basal cell carcinoma, B-Cell lymphoma), Bile duct cancer, Bladder cancer, Bone cancer, Bowel cancer, Bram cancer, Brain stem glioma, Brain tumor, Breast cancer, Carcinoid tumors, Cervical cancer, Cholangiocarcmoma, Chondrosarcoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Colon cancer, Colorectal cancer, Craniopharyngioma, Cutaneous lymphoma, Cutaneous melanoma, Diffuse astrocytoma, Ductal carcinoma in situ, Endometrial cancer, Ependymoma, Epithelioid sarcoma, Esophageal cancer, Ewing sarcoma, Extrahepatic bile duct cancer, Eye cancer, Fallopian tube cancer, Fibrosarcoma, Gallbladder cancer, Gastric cancer, Gastrointestinal cancer, Gastrointestinal carcinoid cancer, Gastrointestinal stromal tumors, General, Germ cell tumor, Glioblastoma multiforme, Glioma, Hairy cell leukemia, Head and neck cancer, Hemangioendothelioma, Hodgkin lymphoma, Hodgkin's disease, Hodgkin's lymphoma, Hypopharyngeal cancer, Infiltrating ductal carcinoma, Infiltrating lobular carcinoma, Inflammatory breast cancer, Intestinal Cancer, Intrahepatic bile duct cancer, Invasive / infiltrating breast cancer, Islet cell cancer, Jaw cancer, Kaposi sarcoma, Kidney cancer, Laryngeal cancer, Leiomyosarcoma, Leptomeningeal metastases, Leukemia, Lip cancer, Liposarcoma, Liver cancer, Lobular carcinoma in situ, Low-grade astrocytoma, Lung cancer, Lymph node cancer, Lymphoma, Male breast cancer, Medullary carcinoma, Medulloblastoma, Melanoma, Meningioma, Merkel cell carcinoma, Mesenchymal chondrosarcoma, Mesenchymous, Mesothelioma, Metastatic breast cancer, Metastatic melanoma, Metastatic squamous neck cancer. Mixed gliomas, Mouth cancer, Mucinous carcinoma, Mucosal melanoma, Multiple myeloma, Nasal cavity cancer, Nasopharyngeal cancer. Neck cancer, Neuroblastoma, Neuroendocrine tumors, Non-Hodgkin lymphoma, Non-Hodgkin's lymphoma. Nonsmall cell lung cancer, Oat cell cancer, Ocular cancer, Ocular melanoma, Oligodendroglioma, Oral cancer, Oral cavity cancer, Oropharyngeal cancer, Osteogenic sarcoma, Osteosarcoma, Ovarian cancer, Ovarian epithelial cancer, Ovarian germ cell tumor, Ovarian primary peritoneal carcinoma, Ovarian sex cord stromal tumor, Paget's disease, Pancreatic cancer, Papillary carcinoma. Paranasal sinus cancer, Parathyroid cancer, Pelvic cancer, Penile cancer, Peripheral nerve cancer, Peritoneal cancer, Pharyngeal cancer, Pheochromocytoma, Pilocytic astrocytoma, Pineal region tumor, Pineoblastoma, Pituitary gland cancer, Primary central nervous system lymphoma, Prostate cancer, Rectal cancer, Renal cell cancer, Renal pelvis cancer, Rhabdomyosarcoma, Salivary gland cancer, Sarcoma, Sarcoma, bone, Sarcoma, soft tissue, Sarcoma, uterine, Sinus cancer, Skm cancer, Small cell lung cancer, Small intestine cancer, Soft tissue sarcoma, Spinal cancer, Spinal column cancer, Spinal cord cancer, Spinal tumor, Squamous cell carcinoma, Stomach cancer, Synovial sarcoma, T-cell lymphoma), Testicular cancer, Throat cancer, Thymoma / thymic carcinoma, Thyroid cancer, Tongue cancer, Tonsil cancer, Transitional cell cancer, Transitional cell cancer, Transitional cell cancer, Triple-negative breast cancer, Tubal cancer, Tubular carcinoma, Ureteral cancer, Ureteral cancer, Urethral cancer, Uterine adenocarcinoma, Uterine cancer, Uterine sarcoma, Vaginal cancer, and Vulvar cancer.

[0020] In some embodiments, the method further comprises incubating the engineered platelet with the at least one therapeutic agent such as, but not limited to, a toxin, a protein, and a small molecule drug to produce the therapeutic delivery system. In some embodiments, the nucleic acid may be, but is not limited to, a mRNA, a miRNA, shRNA, and a clustered regularly interspaced short palindromic repeats (CRISPR) sequence. In some embodiments, the protein may be, but is not limited to, an antibody, an enzyme, and a CRISPR associated protein 9 (Cas9). In some embodiments, the enzyme is a nuclease. In some embodiments, the nuclease is a transcription activator-like effector nuclease (TALEN). In some embodiments, incubating occurs prior to administering. In some embodiments, the disease, disorder, or condition is an autoimmunity such as, but not limited to, Autoimmune disseminated encephalomyelitis, Autoimmune inner ear disease, Batten disease / Neuronal Ceroid Lipofuscinoses, Chronic inflammatory demyelinating polyneuropathy, Encephalitis lethargica, Anti-basal ganglia, Guillain-Barre syndrome, Hashimoto's Encephalopathy, Anti-TPO, Isaac's syndrome / acquired neuromyotonia, Miller Fisher syndrome Morvan's syndrome, Multiple sclerosis, Myasthenia gravis, Narcolepsy PANDAS, Rasmussen's encephalitis, Stiff-person syndrome, Vogt-Koyanagi-Harada syndrome, Addison's disease, Autoimmune hypoparathyroidism, Autoimmune hypophysitis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune polyglandular syndrome I (APECED), Autoimmune polyglandular syndrome IT, Autoimmune polyglandular syndrome HI, Diabetes mellitus, type 1, Graves' disease, Hashimoto's autoimmune thyroiditis, Immunodysregulation, polyendocrinopathy, enteropathy, X-linked, Autoimmune hepatitis type 1, Autoimmune hepatitis type 2, Autoimmune pancreatitis, Coeliac disease, Crohn's disease, Pernicious anemia / atrophic gastritis, Primary biliary-cirrhosis, Primary sclerosing cholangitis, Ulcerative colitis, Acquired hemophilia A, Antiphospholipid syndrome, Autoimmune hemolytic anemia, Autoimmune lymphoproliferative syndrome, Autoimmune neutropenia, Evans syndrome, Felty's syndrome, Immune thrombocytopenic purpura, Polymyositis / dermatomyositis, Relapsing polychondritis, Rheumatoid arthritis, Still's disease, Alopecia areata, Bullous pemphigoid, Cicatricial pemphigoid, Dermatitis herpetiformis, Discoid lupus erythematosus, Epidermolysis bullosa acquisita, Linear morphea, Pemphigus foliaceus. Pemphigus vulgaris, Vitiligo, Behcet disease, Churg-Strauss syndrome, Cogan's syndrome, CREST syndrome, Anti-fibrillarin, Essential mixed cryoglobulinemia, Mixed connective tissue disease, POEMS syndrome, Scleroderma, Sjogren's syndrome, Systemic lupus erythematosus, Erythema elevatum diutinum, Kawasaki disease, Microscopic polyangiitis, Polyarteritis nodosa, Rheumatic fever, Takayasu arteritis Temporal arteritis, Wegener's granulomatosis, HLA-B27-associated acute anterior uveitis, Sympathetic ophthalmia, and Goodpasture's disease. The invention also provides non-therapeutic methods of delivering a cargo to a subject in need or desirous thereof. For example the invention provides a non-therapeutic method of delivering cargo to a subject in need thereof. In such non-therapeutic methods, the cargo may be a cosmetic agent. In some embodiments the invention provides a non-therapeutic method of targeted delivery of a cargo to a subject in need thereof.

[0021] Various embodiments of the invention described herein provide an engineered platelet produced from a megakaryocyte comprising a mutation in the nucleic acid sequence resulting in disruption of a vesicle biogenesis pathway or a vesicle release pathway in the platelet, expression of a toxin, or expression of for exampl e a cargo that is a protein or peptide or a RNA for example an mRNA, for example a therapeutic agent or imaging agent, or deletion of a platelet receptor, mediator, or signal transduction protein compared to a platelet produced from a megakaryocyte without the mutation.

[0022] In some embodiments, the megakaryocyte is differentiated from an iPSC progenitor or the megakaryocyte is immortalized. In some embodiments, the mutation occurs in a gene encoding a component of the vesicle biogenesis pathway or a vesicle release pathway of the engineered platelet such as, but not limited to, a-granules, dense granules, and large dense-core vesicle. In some embodiments, the mutation is an insertion of a gene encoding a major histocompatibility complex (MHC) molecule. In some embodiments, the deletion is of at least one gene such as, but not limited to, RAB27a (RAS oncogene), HPS (haptoglobin) genes, integrin AHbB3. GPlb-IX-V (Glycoprotein lb complexed with glycoprotein IX), Pari (protease activated receptor I), Par4 (protease activated receptor 4), P2Y1 (purinergic receptor P2Y1), P2Y12 (purinergic receptor P2YI2), IP (PGI2R or prostaglandin 12 receptor), TP (TxA2R or Thromboxane A2 Receptor), TLR (toll-like receptor), GPVI, a2Bl (type I collagen receptor), GPIIblllA (Glycoprotein lib Platelet Subunit Alpha), CLEC-2 (C-type lectinlike receptor 2), MyD88 (Myeloid Differentiation Primary Response 88), Galphaq (G-protein alpha pathway q), LIMK1 (LIMDomain Kinase I), vWF (von Willebrand), Fibrinogen, PDGF (platelet derived growth factor), VEGF (vascular endothelial growth factor), Factor V, Factor VIII, Factor XI, Factor XIII, PF4 (platelet factor 4), NAP2 (Nucleosome Assembly Protein 2), Prothrombin, High Molecular Weight Kininogens, Plasminogen activator inhibitor 1, a2-antiplasmin, plasminogen, P-Selectin, CXCL4 (C-X-C motif chemokine ligand 4), CXCL7 (C-X-C motif chemokine ligand 7), FGF (fibroblast growth factor), EGF (elongation growth factor), HGF (hepatocyte growth factor), IGF (insulin-like growth factor), Angipoetin, Thromboxane synthase, PAF (platelet activating factor), cPLA2a, Thromospondin, CD40L, SglII (Secretogranin III), Endostatin, TGF-0 (transforming growth factor beta), Talinl, Kindlins, and Anoctamin 6.

[0023] In some embodiments, the mutation is a deletion which is a knock-out of a gene encoding a pro-thrombotic factor. In some embodiments, the gene is a p2 microglobulin gene, wherein the deletion results in endogenous MHC class 1 disruption and the generation of a non-immunogenic platelet. In some embodiments, the mutation reduces the thrombogenic potential of the engineered platelet compared to a platelet produced from a megakaryocyte without the mutation.

[0024] Various embodiments of the invention described herein provide a method of reducing activity in the immune system of a subject, the method comprising: administering to the subject an engineered platelet presenting at least one receptor expressing a major histocompatibility complex (MHC) molecule bound to a peptide derived from a tumor antigen, a neoantigen, or an autoantigen.

[0025] In some embodiments, the receptor expresses a MHC class I molecule. In some embodiments, the receptor expresses a MHC class II molecule. In some embodiments, wherein the MHC molecule stimulates an immune response to an antigen. In some embodiments, the antigen is associated with at least one disease, disorder, or condition selected from the group consisting of: a cancer, an autoimmunity, and an infection.

[0026] Various embodiments of the invention described herein provide a method of in vitro production of platelets, the method comprising: transfecting a plurality7 of induced pluripotent stem cell (iPSC) progenitors with an expression system, wherein the expression system is induced by an agent not found in an iPSC; establishing a megakaryocyte progenitor cell line by contacting the expression system with the agent to expand megakaryocytes; engineering the megakaryocyte to have at least one mutation such as, but not limited to, insertion of a nucleic sequence encoding a chimeric platelet receptor previously7 described, insertion of a nucleic acid sequence encoding a toxin, or for example encoding a cargo that is a protein or peptide or a RNA for example an mRNA, for example a therapeutic agent or imaging agent, and deletion of a nucleic acid sequence encoding a platelet receptor; and removing the agent from the expression system to induce differentiation of the megakaryocytes into platelets.

[0027] In some embodiments, the mutation results in platelets with less immunogenicity compared to platelets from human donors. In some embodiments, the platelet does not function analogously to platelets derived from a human donor. In some embodiments, the deletion prevents toxin release or prevents cargo release in response to platelet activation signals. In some embodiments, the toxin or cargo is attached to an a-granule localization signal. In some embodiments, the a-granule localization signal. In some embodiments, the method of platelet production further comprising contacting the platelets with at least one of a cargo for example a cargo that is a protein or peptide or a RNA for example an mRNA, for example a therapeutic agent or imaging agent or a small molecule; a toxin; and a small molecule drug under conditions to facilitate absorption by the platelet. In some embodiments, the expression system further comprises a platelet-specific promoter.

[0028] Various embodiments of the invention described herein provide a method of in vivo gene editing or gene therapy in a subject, the method comprising: administering to the subject an engineered platelet comprising a chimeric platelet receptor described herein specific to a tissue to be edited, wherein the engineered platelet is cloaking an adenovirus loaded with genome engineering machinery; and releasing the genome machinery at the tissue. In some embodiments, the genome machinery is a CRISPR / Cas gene editing system.

[0029] Various embodiments of the invention described herein provide a use of the therapeutic delivery system previously described, wherein the chimeric receptor is specific to an antigen associated with the disease, disorder, or condition in treating a disease, disorder, or condition in a subject. In some embodiments of the use described herein, the disease, disorder, or condition is selected from the group consisting of: a cancer, an autoimmunity, and an infection.

[0030] In some embodiments of the use described herein, the cancer may be, but is not limited to, Acute granulocytic leukemia, Acute lymphocytic leukemia, Acute myelogenous leukemia, Adenocarcinoma, Adenosarcoma, Adrenal cancer, Adrenocortical carcinoma, Anal cancer, Anaplastic astrocytoma, Angiosarcoma, Appendix cancer, Astrocytoma, Basal cell carcinoma, B-Cell lymphoma), Bile duct cancer, Bladder cancer, Bone cancer, Bowel cancer, Brain cancer, Brain stem glioma, Brain tumor, Breast cancer, Carcinoid tumors, Cervical cancer, Cholangiocarcinoma, Chondrosarcoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Colon cancer, Colorectal cancer, Craniopharyngioma, Cutaneous lymphoma, Cutaneous melanoma, Diffuse astrocytoma, Ductal carcinoma in situ, Endometrial cancer, Ependymoma, Epithelioid sarcoma, Esophageal cancer, Ewing sarcoma, Extrahepatic bile duct cancer, Eye cancer, Fallopian tube cancer, Fibrosarcoma, Gallbladder cancer, Gastric cancer, Gastrointestinal cancer, Gastrointestinal carcinoid cancer, Gastrointestinal stromal tumors, General, Germ cell tumor, Glioblastoma multiforme, Glioma, Hairy cell leukemia, Head and neck cancer, Hemangioendothelioma, Hodgkin lymphoma, Hodgkin’s disease, Hodgkin's lymphoma, Hypopharyngeal cancer, Infiltrating ductal carcinoma, Infiltrating lobular carcinoma, Inflammatory breast cancer, Intestinal Cancer, Intrahepatic bile duct cancer, Invasive / infiltrating breast cancer, Islet cell cancer, Jaw cancer, Kaposi sarcoma, Kidney cancer, Laryngeal cancer, Leiomyosarcoma, Leptomeningeal metastases, Leukemia, Lip cancer, Liposarcoma, Liver cancer, Lobular carcinoma in situ, Low-grade astrocytoma, Lung cancer, Lymph node cancer, Lymphoma, Male breast cancer, Medullary carcinoma, Medulloblastoma, Melanoma, Meningioma, Merkel cell carcinoma, Mesenchymal chondrosarcoma, Mesenchymous, Mesothelioma, Metastatic breast cancer, Metastatic melanoma, Metastatic squamous neck cancer, Mixed gliomas, Mouth cancer, Mucinous carcinoma, Mucosal melanoma, Multiple myeloma, Nasal cavity cancer, Nasopharyngeal cancer, Neck cancer, Neuroblastoma, Neuroendocrine tumors, Non-Hodgkin lymphoma, Non-Hodgkin's lymphoma, Nonsmall cell lung cancer, Oat cell cancer, Ocular cancer, Ocular melanoma, Oligodendroglioma, Oral cancer, Oral cavity cancer, Oropharyngeal cancer, Osteogenic sarcoma, Osteosarcoma, Ovarian cancer, Ovarian epithelial cancer, Ovarian germ cell tumor, Ovarian primary peritoneal carcinoma, Ovarian sex cord stromal tumor, Paget's disease, Pancreatic cancer, Papillary carcinoma, Paranasal sinus cancer, Parathyroid cancer, Pelvic cancer, Penile cancer, Peripheral nerve cancer, Peritoneal cancer, Pharyngeal cancer, Pheochromocytoma, Pilocytic astrocytoma, Pineal region tumor, Pineoblastoma, Pituitary gland cancer, Primary central nervous system lymphoma, Prostate cancer, Rectal cancer, Renal cell cancer, Renal pelvis cancer, Rhabdomyosarcoma, Salivary gland cancer, Sarcoma, Sarcoma, bone, Sarcoma, soft tissue, Sarcoma, uterine, Sinus cancer, Skin cancer, Small cell lung cancer, Small intestine cancer, Soft tissue sarcoma, Spinal cancer, Spinal column cancer, Spinal cord cancer, Spinal tumor, Squamous cell carcinoma, Stomach cancer, Synovial sarcoma, T-cell lymphoma), Testicular cancer, Throat cancer, Thymoma / thymic carcinoma, Thyroid cancer, Tongue cancer, Tonsil cancer, Transitional cell cancer, Transitional cell cancer, Transitional cell cancer, Triple-negative breast cancer, Tubal cancer, Tubular carcinoma, Ureteral cancer, Ureteral cancer, Urethral cancer, Uterine adenocarcinoma, Uterine cancer, Uterine sarcoma, Vaginal cancer, and Vulvar cancer.

[0031] In some embodiments of the use described herein, the disease, disorder, or condition is an autoimmunity such as, but not limited to, Autoimmune disseminated encephalomyelitis, Autoimmune inner ear disease, Batten disease / Neuronal Ceroid Lipofuscinoses, Chronic inflammatory demyelinating polyneuropathy, Encephalitis lethargica, Anti-basal ganglia, Guillain-Barre syndrome, Hashimoto's Encephalopathy, Anti-TPO, Isaac's syndrome / acquired neuromyotonia, Miller Fisher syndrome Morvan's syndrome, Multiple sclerosis, Myasthenia gravis, Narcolepsy PANDAS, Rasmussen's encephalitis, Stiff-person syndrome, Vogt-Koyanagi-Harada syndrome, Addison's disease, Autoimmune hypoparathyroidism, Autoimmune hypophysitis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune polyglandular syndrome I (APECED), Autoimmune polyglandular syndrome II, Autoimmune polyglandular syndrome III, Diabetes mellitus, type 1, Graves' disease, Hashimoto's autoimmune thyroiditis, Immunodysregulation, polyendocrinopathy, enteropathy, X-linked, Autoimmune hepatitis type 1, Autoimmune hepatitis type 2, Autoimmune pancreatitis, Coeliac disease, Crohn's disease, Pernicious anemia / atrophic gastritis, Primary biliary' cirrhosis, Primary sclerosing cholangitis, Ulcerative colitis, Acquired hemophilia A, Antiphospholipid syndrome, Autoimmune hemolytic anemia, Autoimmune lymphoproliferative syndrome, Autoimmune neutropenia, Evans syndrome, Felty's syndrome, Immune thrombocytopenic purpura, Polymyositis / dermatomyositis, Relapsing polychondritis, Rheumatoid arthritis, Still's disease, Alopecia areata, Bullous pemphigoid, Cicatricial pemphigoid, Dermatitis herpetiformis, Discoid lupus erythematosus, Epidermolysis bullosa acquisita. Linear morphea, Pemphigus foliaceus, Pemphigus vulgaris, Vitiligo, Behcet disease, Churg-Strauss syndrome, Cogan's syndrome, CREST syndrome, Anti-fibrillarin, Essential mixed cryoglobulinemia, Mixed connective tissue disease, POEMS syndrome, Scleroderma, Sjogren's syndrome, Systemic lupus erythematosus, Erythema elevatum diutinum, Kawasaki disease, Microscopic polyangiitis. Polyarteritis nodosa, Rheumatic fever, Takayasu arteritis Temporal arteritis, Wegener's granulomatosis, HLA-B27-associated acute anterior uveitis, Sympathetic ophthalmia, and Goodpasture's disease.

[0032] Various embodiments of the invention herein provide a therapeutic delivery system comprising: (a) an engineered platelet presenting the chimeric platelet receptor, wherein the engineered platelet has been produced through genetic modification of a progenitor megakaryocyte to be non-thrombogenic and non-immunogenic; and (b) at least one therapeutic agent selected from the group consisting of: a cargo as defined herein, a toxin, a protein, a small molecule drug, and a nucleic acid packaged within a vesicle inside the platelet, i) wherein the therapeutic agent is the nucleic acid or the protein, loading occurs through expression in a progenitor megakaryocyte, or li) wherein the therapeutic agent is loaded by incubation of the engineered platelet with the therapeutic agent. DETAILED DESCRIPTION OF THE INVENTION I. INTRODUCTION

[0033] Genetically engineered platelets generated outside of the body may be targeted to respond to specific proteins expressed on a target tissue or cell (e.g., on cancer) and release a therapeutic agent (e.g., a small molecule drug, antibody, or a nucleic acid encoding a protein). These engineered platelets would become targeted drug deliver}'- devices. Unlike when transplanting other tissues, platelets require limited matching to a recipient’s immune system and thus, the engineered platelets could function “off the shelf,” without having to be matched to a specific patient (which is a major problem with current cell therapies).

[0034] The engineered platelets described herein may be generated outside the body from megakaryocytes. As the megakaryocyte is maintained in culture outsi de of the body, it can be extensively edited at the genome level (e.g. by CRISPR / Cas9) without fear of oncogenic transformation in the patient, which is not possible with other competing cell therapy products. The engineered platelets would have a lifespan in the body of 7-10 days, with little to no potential for continued reproduction, thus little to no chance of forming a tumour itself.

[0035] Platelets can be frozen and stored for extended period of time resulting in an extended shelflife, and with currently available technology, engineered platelets could be produced, stored, transported and administered to patients without issue due to their lack of immunogenicity.

[0036] Engineered platelets could be stripped of all thrombogenic potential by genome editing of megakaryocytes in vitro to alleviate potential thrombotic safety concerns. An engineered platelet, also called a S YNLET™ therapeutic delivery system, may act as a blank template, effectively functioning as a scaffold, having the capacity to store cargo internally in vesicles, and genetic alterations of megakary ocytes allow the engineered platelets to respond to specific antigens or signals. Platelets contain a variety of signaling pathways, therefore engineered inputs could be positive or negative, allowing the engineered platelets to integrate and compute a variety of stimuli before making the decision to activate. Interestingly, platelets also have the capacity to transfer RNA to nearby cells providing the potential to genetically manipulate target cells. For example, a CRISPR / Cas9 system may be delivered to a target cell by an engineered platelet. Additionally, signaling pathways within platelets can trigger the de novo translation of proteins, so these could be harnessed to deliver potentially toxic proteins locally to target locations.

[0037] In contrast to chimeric antigen receptor T (CAR-T) cells, the present invention provides an engineered platelet that is a universal product which does not require a match to a patient before administration. Further, platelet production in vitro from progenitors described herein, removes the need to continuously produce virus and edit cells. Due to the short life span of the engineered platelets described herein, safety concerns are limited as compared to current gene editing therapeutics. For example, gene editing and genome stability is less of a concern than with CAR-T cells because platelets are enucleate and therefore the complexity of the platelet therapy is not limited by the efficiency of editing or culture time limits. Additionally, due to their smaller size, the engineered platelets may provide better access to solid tumors than CAR-T cells.

[0038] Enucleated red blood cells, such as those commercially available from Rubius Therapeutics, Inc., have also been contemplated in the art for delivering therapeutic agents. In contrast to red blood cells, the engineered platelets described herein are highly metabolically active and include signaling systems that can be re-engineered. In fact, more targeted uses are possible with the engineered platelets compared to red blood cells. Vesscle degranulation of the platelets also allows for “hiding” of protein until the desired target is engaged, which is not possible with enucleated red blood cells because the biotherapeutic proteins are generally expressed on the surface of the cell. Accordingly, in one embodiment binding of the targeting domain of the chimeric platelet receptor to the target or antigen results in degranulation of a platelet that comprises the chimeric platelet receptor. The engineered platelets described herein are smaller than red blood cells likely resulting in better biodistribution. IL GENE NOMENCLATURE

[0039] Gene symbols are used herein, along with ENSEMBL Gene IDs, to refer to genes from humans. Unless otherwise noted, the gene name and ENSEMBL Gene (ENSG) IDs corresponding to each gene symbol are shown in Table 1. The unique identifiers for each ENSEMBL entry has been modified to remove the first five leading zeros (0) of the identifier after the ENSG label. Table 1. ENSEMBL identifiers for genes Given Symbol Given Name ENSG RAB27A RAS oncogene 069974 HP haptoglobin 257017 integrin AIIbB3 or ITGB3 glycoprotein beta III platelet subunit alpha 2 259207 GPlb-IX-V Glycoprotein lb complexed with glycoprotein IX N / A Par t or NR 112 protease activated receptor 1 144852 Par-1 or F2RL3 protease activated receptor 4 127533 P2Y1 orP2RYl purinergic receptor P2Y1 169860 P2Y12 orP2RY12 purinergic receptor P2Y12 169313 IPorPTGIR PGI2R or prostaglandin 12 receptor 160013 TP or TBXA2R TxA2R or Thromboxane A2 Receptor 006638 TLR1 toil-like receptor 1 174125 TLR2 toil-like receptor 2 137462 TLR3 toil-like receptor 3 164342 TLR4 toil-like receptor -1 136869 TLR5 toil-like receptor 5 187554 TLR6 toil-like receptor 6 174130 TLR7 toil-like receptor 7 196664 TLR8 toil-like receptor 8 101916 TLR9 toil-like receptor 9 239732 TLR10 toil-like receptor 10 174123 GPVI or GP6 glycoprotein VI 274050, 275931, 275633, 274566, 278316, 088053, 278670, 277439, 276211, 276065 a2Bl orlTGBl type 1 collagen receptor 150093 GPIIbniA orITGA2B Glycoprotein III? Platelet Subunit Alpha 005961 CLEC-2 or CLEC1B C-type lectinlike receptor 2 165682 MyD88 orMYD88 Myeloid Differentiation Primaiy Response 88 172936 Galphaq or GNAQ G-protein alpha pathway q 156052 LIMK1 orLIMKl LIMDomain Kinase 1 106683 vW or W von Willebrand 110799 PGA Fibrinogen 171560 FGB Fibrinogen 171564 FGG Fibrinogen 171557 PDGFA platelet derived growth factor A 197461 PDGFB platelet derived growth factor B 100311 PDGFC platelet derived growth factor C 145431 PDGFD platelet derived growth factor D 170962 VEGF or VEGF A vascular endothelial growth factor 112715 F5 Factor V 198734 F8 Factor VIII 185010 Fil Factor XI 088926 F13A1 Factor XIII A 124491 F13B Factor XIIIB 143278 CXCL4 orPF4 C-X-C motif chemokine ligand 4 or platelet factor 4 163737, 163737 NAP2 orPPBP Nucleosome Assembly Protein 2 163736 F2 Prothrombin 180210 PAI-1 or SERPINE1 Plasminogen activator inhibitor 1 106366 SERF IN or SERPINF1 a2-antiplasmin 282307, 132386 PLG plasminogen 122194 SEEP P-Selectin 174175 CXCL7 or PPBP C-X-C motif chemokine ligand 7 163736 FGF1 fibroblast growth factor 1 113578 FGF2 fibroblast growth factor 2 138685 FGF3 fibroblast growth factor 3 186895 FGF4 fibroblast growth factor 4 075388 FGF5 fibroblast growth factor 5 138675 FGF6 fibroblast growth factor 6 111241 FGF7 fibroblast growth factor 7 140285 FGF8 fibroblast growth factor 8 107831 FGF9 fibroblast growth factor 9 102678 FGF10 fibroblast growth factor 10 070193 FGF11 fibroblast growth factor 11 161958 FGF12 fibroblast growth factor 12 283903 FGF13 fibroblast growth factor 13 114279 FGF14 fibroblast growth factor 14 129682 FGF15 fibroblast growth factor 15 102466 FGF16 fibroblast growth factor 16 196468 FGF17 fibroblast growth factor 17 158815 FGF18 fibroblast growth factor 18 156427 FGF19 fibroblast growth factor 19 162344 FGF20 fibroblast growth factor 20 078579 FGF21 fibroblast growth factor 21 105550 FGF22 fibroblast growth factor 22 070388 FGF23 fibroblast growth factor 23 118972 EGF elongation growth factor 138798 HGF hepatocyte growth factor 019991 IGF or IGF1 insulin-like growth factor 017427 ANGPT or ANGPT1 Angiopoetin 154188 TEXAS 1 Thromboxane synthase 059377 PAF or PCLAF platelet activating factor 166803 cPLA2a or PLA2G1B Phospholipase A2 170890 TUB SI Thrombospondin 137801 CD40L or CD40LG CD40 ligand 102245 Sglll or SCG3 Secretogranin III 104112 COL18A1 Endo statin 182871 TGF-P orTGFBl transforming growth factor beta 105329 TLN1 Talinl 137076 MOG myelin oligodendrocyte glycoprotein 232641, 137345, 236561, 137345, 204655, 234623, 237834, 234096 GAD2 glutamic acid decarboxylase 2 136750, 136750 MAG myelin associated glycoprotein 105695 PMP22 peripheral myelin protein 22 109099 TPO thyroid peroxidase 277603, 115705 VGKC voltage-gated potassium channel genes N / A PLP or PLP1 proteolipid protein 123560 AC11R or CHRN Al acetylcholine receptor 138435 AChRorCHRNAlO acetyl cholinereceptor 129749 AChR or CHRNA2 acely 1 choli nereceptor 120903 AChR or CHRNA3 acetyl cholinereceptor 080644 AChR or CHRNA4 acely 1 cholinereceptor 101204 AChR or CHRNA5 acely 1 cholinereceptor 169684 AChR or CHRNA6 acely 1 cholinereceptor 147434 AChR or CHRNA7 acetylcholinereceptor 175344 AChR or CHRNA9 acetylcholinereceptor 174343 AChRorCHRNBl acetylcholinereceptor 170175 AChRorCHRNBl acetylcholinereceptor 283946 AChR or CHRNB2 acetylcholinereceptor 160716 AChR or CHRNB3 acetylcholinereceptor 147432 AChR or CHRNB4 acetylcholinereceptor 117971 AChR or CHRND acetylcholinereceptor 135902 AChR or CHRNE acety Icho linereceptor 108556 AChR or CHRNG acety Icho linereceptor 196811 TR1B2 tribbles pseudokinase 2 071575 GluR or GRIA1 N-methyl-D-aspartate (NMDA)-type glutamate receptor 155511 GluR or GRIA2 N-methyl-D-aspartate (NMDA)-type glutamate receptor 120251 GluR or GRIA3 N-methyl-D-aspartate (NMDA)-type glutamate receptor 125675 GluR or GRIA4 N-methyl-D-aspartate (NMDA)-type glutamate receptor 152578 GluR or GR1K3 N-methyl-D-aspartate (NMDA)-type glutamate receptor 163873 GAD2 glutamate decarboxylase 2 136750, 136750 ARMC9 Armadillo repeat containing 9 135931 CYP21A2 Cytochrome P450 Family 21 Subfamily A Member 2 231852, 235134, 198457, 232414, 233151, 206338 CASR calcium sensing receptor 036828 NASP nuclear autoanti genic sperm protein 132780 INS insulin 254647 TSHR thyroid stimulating hormone receptor 165409 TPO thyroperoxidase 277603, 115705 ASGR1 asioglycoprotein receptor 1 141505 ASGR2 asioglycoprotein receptor 2 161944 CYP2D6 Cytochrome P450 Family 2 Subfamily D Member 6 272532, 275211, 100197, 280905,282966,283284 LF or LIE lactoferrin 012223 TTG or TGM1 tissue trans-glutaminase 1 285348, 092295 TTG or TGM2 tissue trans-glutaminase 2 198959 TTG or TGM3 tissue trans-glutaminase 3 125780 H / K ATP-ase gastric hydrogen potassium ATPase F8 Factor XIII 185010 Beta2-GPI or APOH beta2 -glycoprotein I 091583 ITGB2 B2 integrin 160255 G-CSF or CSF3 granulocyte-colony stimulating factor 108342 GP Ilb / IIa glycoprotein N / A COL 11 or COL2A1 collagen II 1392 '19 MPO myeloperoxidase 005381 CYO orMYH7 cardiac myosin 092054 PRTN3 proteinase 3 277804, 196415 TCHH trichohyalin 159450 GP1orGTPBP1 glycoprotein 1 100226 LM332 laminin-332 N / A COL VII COL7A1 type VII collagen 114270 COIL P80 Coilin 121058 DSG1 Desmoglein I 134760 DSG3 Desmoglein III 134757 SOX 10 SRY-Box 10 100146 70SNRNP70 orRNUl-1 small nuclear ribonucleoprotein U1 subunit 206652 SAG S-antigen 130561, 281857 a3(IVNCI collagen) or COL4A3 Collagen a!pha-3(IV chain) 169031 ANO6 / TMEM16F Anoctamin 6 / Transmembrane Protein 16F 177119

[0040] Symbols and names are used herein, along with ENSEMBL protein IDs, to refer to proteins from humans. Unless otherwise noted, the protein name (if used to refer to the protein herein) and symbol and ENSEMBL protein (ENSP) IDs corresponding to each symbol are shown in Table 2. The unique identifiers for each ENSEMBL entry has been modified to remove the first five leading zeros (0) of the identifier after the ENSP label. Table 2. ENSEMBL identifiers for antibody targets Symbol ENSP(s) ACVR2B or ACVR2B 340361 ACVRL1 455848, 373574, 446724, 447884, 392492, 457394 AFP 379138, 226359 ANGPT2 or Ang-2 314897, 486858, 343517, 428023 ANGPTL3 360170 AOC3 or AOC3 312326, 464787, 465913, 468632, 468043, 477686, 484312 APCS 255040 APPorN / a 284981, 346129, 345463, 350578, 387483, 398879, 351796, 396923, 406539, 352760 AXL or AXL 301178, 351995,471497 B4GALNT1 n / a BSGorCD147 473664, 344707, 333769, 458665, 343809, 495088, 484849, 478958, 484624, 473393, 473528 CIS orCls 385035, 328173, 354057, 384171, 399892, 406643, 384464, 397921, 442298, 484657 C5 or C5 223642 CA9 367608, 482050 CALCA 417833, 420618, 331746, 379657, 354286 CASP2 312664, 376656, 340030, 481929 CCLllor CCL11 (eotaxin-1) 302234 CCL2 orMCP-1 462156, 225831 CCR2 or CCR2 399285, 396736, 383681,292301 CCR4 or CCR4 332659 CCR5 or CCR5 292303, 404881 CD 19 or CD 19 313419, 456201,437940 CD2 or CD2 358490, 358489 CD200 or CD200 476114, 475860, 418576, 420298, 312766, 373179, 419816 CD22 or CD22 469980, 470681, 469503, 472664, 472762, 471972, 471399, 469523, 470193, 442279, 085219, 441237, 403822, 469984, 470724, 482823, 473221, 339349 CD27 or CD27 266557 CD274 or PD-L1 370989, 370985 CD276 or CD276 455366, 320084, 441087, 453907, 452649, 452736, 454258, 453330, 452905, 453336, 456657, 452669, 454940, 453014, 453842, 320058 CD276 orB7-H3 n / a CD28 or CD28 393648, 324890, 363605 CD3 or CD3 n / a CD33 or CD33 403331, 410126, 375673, 262262 CD37 or CD37 375732, 470394, 413151, 471902, 325708, 441037, 471078, 470260, 470683 CD38 orCD38 427277, 226279, 423047 CD3E or CD3 epsilon 354566, 433975 CD4 or CD4 011653, 445167, 440720 CD40 or CD40 361359, 361350, 434825, 484074 CD40LGorCD154 (CD40L) 359663, 359662 CD44 or CD44 v6 263398, 398632, 435377, 389830, 432704, 395953, 392331, 432405, 278386, 404447, 309732, 398099, 434465, 279452, 434530, 432718, 433189, 436549, 436623, 436980, 278385, 435321, 436451,434418, 431860, 434920, 492449 CD52 or CD52 363330 CD6 or CD6 323280, 443748, 340334, 440055, 410638, 390676, 340628, 443747 CD70 or CD70 395294, 245903, 470805 CD74 or CD74 367026, 230685, 430614, 429024, 009530, 430654, 429641, 429478 CD79B or CD79B 376544, 006750, 245862 CD80 or CD80 264246, 418364, 373165 CD97 or CD97B n / a CEACAM5 or CEA 381600, 221992, 385072, 468997, 473252, 482303, 482157, 480800 CFAP221 orPCDPl 295220, 470662, 391760, 409912, 470784, 393222, 472563, 470283, 472069, 471092, 413299, 471998, 399793 CFD or CFD 478745, 488580, 332139, 468253 CLDN18 orCLDN18.2 340939, 183605,419732 CLEC6A 371505 CLTA4 or CD 152 n / a CSFlorCSFl 434527, 431547, 349854, 327513, 433837, 358817, 407317, 358816 CSF1R or CSF1R 422212, 286301, 427545, 421174, 445282 CSF2 or CSF2 296871 CSF2RA 370940, 370935, 410667, 416437, 370920, 476684, 348058, 436825, 347606, 370911, 440491, 394227 CTGF or CTGF 356954 CTLA4 or CTLA-4 497102, 303939, 295854, 497319, 417779 CXCL10 305651 CXCR4 or CXCR4 (CD 184) 386884, 241393 DLL3 or DLL3 348810, 471688,205143 DLL4 or DLL4 497860,249749 DPP4 or DPP4 353731, 402259, 401359, 410264, 486421 EGFL7 orEGFL7 360764, 385639, 473338, 360763, 307843 EGFR or EGFR 415559, 342376, 345973, 413843, 275493, 413354, 492462, 395243 ENG 362299, 341917, 479015 EPCAM or EpCAM 385476, 410675, 263735, 389028 EPHA3 337451, 399926,419190 ERBB2 or HER2 462438, 462808, 404047, 463714, 462024, 463427, 269571, 463719, 464420, 464252, 463002, 385185, 446466 ERBB3 orERBB3 (HER3) 495453, 448636, 449138, 267101, 415753, 448671, 448483, 447510, 449713, 408340, 482073, 448946, 449129, 448729 F3 V<-4i45. 359226 F9, F10 n / a FAP or FAP 441940, 417028, 188790, 411391, 400137, 407404, 485844 FCER2 or CD23 264072, 471974, 472067, 353178 FCGRT or FCGRT 221466, 472350, 472794, 469968, 410798, 469933, 471300, 471118, 472604, 472256, 471232 FGB or 306099, 398719, 426757 FGF23 orFGF23 237837 FGFR2orFGFR2 351276, 474011, 491912, 348559, 358056, 474109, 358055, 404219, 263451, 410294, 353262, 358052, 358054, 337665, 352309, 481464, 484892, 490905, 350166, 484154, 358057, 309878 FLT1 or VEGFR-1 282397, 437631, 484039, 491097, 442630, 484385, 443311, 484832, 437841 FN1 394423, 323534, 338200, 350534, 346839, 410422, 415018, 399538, 348285, 416139, 392565, 398907, 352696 FOLH1 256999, 349129, 434928, 344131, 431463, 436569, 431577, 431263 FOLRI 308137, 377286, 377284, 377281 FOLR2 405638, 298223, 414094, 443307, 441547, 438568, 444794, 321957, 440337, 480592 FUT4 or CD 15 351602 FZD1 287934 GCGR or GCGR 383558, 460976, 458930 GPC3 359854, 486325, 385307, 377836 GPNMB or GPNMB 258733, 371420, 386476, 497362 GUCY2C or GUCY2C 261170 HGF orHGF 494899, 222390, 391238, 389854, 408270, 413829, 494355, 346164, 496217, 396307, 388592 HLA-DRA orHLA- DR 372746, 372745, 404533, 392789, 410443, 411610, 479287, 405295, 398838, 378786, 364121, 372608, 403385, 402951, 412562 HSP90AA1, HSP90AA2, HSP90AB1, HSOP90B1, TRAP I or Hsp90 216281, 335153, 451400, 450712, 452241, 489370 ICAM1 orlCAM-1 264832,413124, 465680 ICOS or CD278, aka ICOS 319476, 415951 ICOSLG or ICOSL 494882, 339477, 384432, 383230, 383228 IFNA1 orlFN-a 276927 IFNAR1, IFNAR2 270139, 400161 IFNG 229135 IGF1R orCD221 497069, 496919, 268035, 453007, 453630, 454115, 456950 IGHE or IGHE 492979, 374983,481089 IL12A or IL-12 303231,420184,419046 IL 13 orlL-13 304915, 479835 IL17A or IL 17 A n / a IL17F or IL17F 337432 ILIA or ILIA 263339 IL IB orIL-ip 263341, 407219, 409680, 400854 IL2 or IL2 226730 IL20 or IL 20 356065, 356063, 375796 IL22 or IL-22 442424, 329384 IL23A or IL23 228534 IL2RA or CD25 369293, 369287, 256876, 402024 IL31RA 380048, 380046, 415900, 351935, 427533, 347047, 297015, 479432 IL3RA or IL 3 receptor 327890, 414867, 370878 IL4 or 11.4 231449, 325190, 480581 IL5 or IL-5 231454,409825 IL5RA or CD 125 412209, 390753, 256452, 373358, 309196, 400400, 392059, 398117, 391274, 388858 IL6 or IL6 385675, 405150, 385718, 385043, 384928, 385227, 258743 IL6R or IL-6R 357470, 340589, 423184, 423668, 423036, 477739 IL9 or IL9 274520 ITGA2orITGA2 (CD49b) 296585, 426489, 422095, 424397, 424642, 422145 ITGA2B or CD41 498119, 467269,262407 ITGA5 293379, 450267, 405865, 447347 ITGAL orLFA-1 (CD Ha) 349252, 456521, 350886, 457785, 454908, 454342, 456888, 409377, 461006, 458739 ITGAVorCD51 261023, 364042, 404291, 389442 ITGB2 orITGB2 (CD 18) 380950, 380955, 380952, 347279, 380948, 427732, 317697, 428503, 428979, 428413, 428125, 428434, 430901, 428870, 380944, 429683, 303242 ITGB3 452786, 461626, 465586 ITGB7 267082, 456446, 408741, 455374, 437375, 450366, 456305, 446703 KDR or VEGFR2 495159,263923 KIR2DL1, KIR2DL2 orKIR2D 480247, 484701, 477690, 479363, 484700, 482506, 478633, 484559, 481123, 478054, 478567, 480989, 479574, 482449, 336769, 291633, 478202, 484361, 479644, 483525, 478232, 481722, 478604, 484871, 478895, 482501, 478263, 482120, 479941, 484582, 482456, 481187, 492250, 492549, 492477, 491211, 491668, 492815, 491499, 492598, 492436, 492695, 491930, 491721, 491975, 492286, 491348, 492859 KLRC1 orNKG2A 441432, 352064, 385304, 256965, 442545, 438038 LAG3 or LAG3 413825,203629 LINGO! or LINGO-1 347451,453853, 453780, 455605, 454465, 454687, 454051, 454245, 454577, 456516, 457101 LOXL2 orLOXL2 373783, 473322, 427907, 427826, 427883, 429778, 430519, 428497, 428933 LRRC15 orLRRC15 306276, 413707 LT A or LT A 403495, 413450, 372791, 372793, 383131, 372991, 395976, 416509, 395895, 407133, 416337, 387924, 412555, 402413 LYPD3 orLYPD3 244333 MADCAM1 475575, 304247, 215637, 372130, 480908, 484317, 480104, 483663, 484153 MAG 470772, 376048, 355234, 473125, 473245, 440695 MAPT 487613, 488245, 482244, 488081, 487819, 488373, 488046, 487837, 488101, 484491, 484321, 478602, 483396, 480217, 486039, 487570, 485913, 477703, 481769, 487403, 483784, 485831, 479142, 460048, 334886, 408975, 413056, 410838, 458742, 460965, 389250, 262410, 303214, 340820, 443028, 340438 MASP2 orMASP-2 383690, 383691 MCAMorMCAM 264036 MET 413857, 380860, 317272, 398776, 398140, 410980 XHF orMIF 482779, 215754 MMP9 361405 MS4A1 or CD20 433179, 432219, 433519, 433277, 432270, 437002, 314620, 374589 MSLN 456008, 442965, 456702, 372313, 456132, 458003, 454295, 457847 MST1R orMSTIR (aka RON) 296474, 407926, 341325, 393294, 414792, 482642, 481084, 482827 MSTN or GDF-8 260950 MUC1 481231, 479471, 478068, 357377, 389098, 482688, 357378, 357374, 357381, 339690, 342814, 483128, 484006, 484730, 357383, 357375, 338983, 483482, 343482, 483473, 484824, 483581, 388172, 482988, 480335, 480333 MUC16 or CA-125 381008, 472883, 470885, 472781 MUC5AC or 5 AC 485659, 490794 MYH7 347507 NCAM1 or CD56 480132, 384055, 481083, 479353, 318472, 482852, 484943, 482205, 480774, 484481, 479687, 475074, 486406, 480269, 478072, 486241, 477835, 480797, 477808, 479241 NECTIN4 356991 NGF orHNGF 358525 NOTCH 1 or Notch 1 277541 NRP1 orNRPl 364009, 265371, 390447, 416147, 476896, 393071, 363954, 363955, 363956, 408911, 390567, 379317, 364001, 363949 NTSE 358660, 257770, 414674, 387630, 358665 PCDHAC1 orPCDCl 386356, 253807 PCSK9 orPCSK9 303208 PDCDJ orPD-1 480684, 486779, 487175, 335062, 390296, 340808 PDGFRA orPDGF-R a 257290, 425648, 425626, 424218, 425902, 426472, 425232 PDGFRB 261799, 430026, 429218, 430715 PTDSS1 430548, 337331, 430928 PTK7 orPTK7 418386, 420186, 418462, 419096, 418545, 420765, 420165, 418754, 230418, 325992, 326029, 325462, 419037, 420322, 230419, 417607 PTPRC or CD45 356349, 494132, 306782, 411355, 433536, 494327, 356337, 356334, 405494, 469141, 393360, 458846, 461347, 458322, 458662, 461074, 458191, 458418, 482203, 461712, 483380 RGMA orRGMA 330005, 440025, 451505, 452126, 452170, 456290, 451709, 452350, 404442, 442498 RHDorRHD 331871, 498055, 413849, 396420, 350150, 456966, 339577, 399640, 478087 RHD, RHCE 294413, 345084, 311185, 431741, 344485, 334570, 435401, 415417, 331871, 498055, 413849, 396420, 350150, 456966, 339577, 399640, 478087 ROR1 or ROR1 360121, 360120, 441637 RSPO3 349131, 357300 RTN4 or RTN4 378107, 384471, 349944, 337838, 322147, 350365, 378109, 385650, 489133, 397808, 411628, 384825 S1PR1 498194, 305416, 497175, 498038, 497478 SAA1, SAA2 or 348918, 436866, 497498, 384906 SDC1 or SDC1 254351, 384613, 400773, 390201, 370542 SELL or CD62L 236147 SELP 356769, 356762, 399368, 356760, 263686, 391694 SLAMF7 or CDS 19 357022, 357021, 352281, 473590, 403294, 416592, 409965, 405605, 483774 SLC39A6 or LIV-1 269187, 465915, 401139, 467724 SLITRK6 or SLITRK6 495507, 383143,496428 SNCA or NACP 338345, 343683, 378437, 378442, 426955, 422238, 421485, 479604, 426034, 423445, 396241, 484044, 378440 SOST or SOST 301691 ST8SIA1 379353, 261197, 441707, 444999, 440292, 384467, 370832 STEAP1or STEAP1 297205, 394402 TACSTD2 orTROP-2 360269 TFP1or TFPI 376172, 233156, 409177, 386344, 342306, 388159, 408170, 394185, 400179, 402954 TGFB1 orTGF-p 472767, 221930 TGFB2 or TGF beta 2 355897, 355896 TIGITorTIGIT 418917, 420552, 419085, 419706, 373167 TNC 265131, 339553, 411406, 443478, 442242, 445380, 489385, 443469, 438152 TNF or TNF-a 398698, 365290, 389492, 389490, 392858, 389265, 372988, 410668 TNFRSF10A or TRAIL-RI 221132, 428884, 480778 TNFRSF10B or TRA1L-R2 276431, 317859, 427999 TNFRSF12A 458898, 326737, 343894, 458305, 460610, 461756 TNFRSF13C orBAFF- R 291232 TNFRSF17 orBCMA 053243, 379753,454314 TNFRSF4 or OX-40 368538 TNFRSF8 or CD30 (TNFRSF8) 263932, 421938, 398337, 390650 TNFRSF9 or4-lBB (CD 137) 366729, 465272, 464978, 478699 TNFSF11 or RANKE 351347, 381775, 384042, 444913, 239849 TNFSF13B orBAFF 365048, 389540, 445334 TPBG or 5T4 358765, 440049, 441219, 489447, 489143, 489140 TRAP or TRAP n / a TSLP or TSLP 399099. 339804, 427827 TYRP1 orTYRPl 419006, 373570, 370528 VEGFA or VEGF-A 361137, 317598, 388663, 389864, 361125, 421561, 388465, 361134, 361148, 430594, 428321,430479, 429643, 409911, 430829, 429008, 430002, 230480, 429592, 478570, 483241, 484284, 492199, 478034, 492413, 492800 vim: 446007, 489830, 490509, 224237, 435613, 431702 VSIR or VSIR 378409 VWF or VWF 261405, 461331, 459134 TAG-72 n / a

[0041] CD3 or CD3 is also known as Cluster of differentiation 2 (multiple subunits). FCER2 or CD23 is also known as (IgE receptor. NT5E is also known as 5'-nucleotidase. F9, F10 is also known as activated F9, F10. ACVRL1 is also known as activin receptor-like kinase 1. AFP is also known as alpha-fetoprotein. ANGPTL3 is also known as angiopoietin 3. BSG or CD147 is also known as basigin. APP or N / 'a is also known as beta-amyloid. CAECA is also known as calcitonin gene-related peptide. CA9 is also known as carbonic anhydrase 9 (CA-IX). MYH7 is also known as cardiac myosin. MET is also known as c-Met. F3 is also known as coagulation factor III. CLEC6A is also known as dendritic cell-associated lectin 2. EGFR or EGFR is also known as elongating growth factor receptor. ENG is also known as endoglin. EPHA3 is also known as ephrin receptor A3. FGB or is also known as fibrin II, beta chain. FN1 is also known as fibronectin extra domain-B. FOLH1 is also known as folate hydrolase. FOLR2 is also known as folate receptor 2. FOLRI is also known as folate receptor alpha. FZD1 is also known as Frizzled receptor. B4GALNT1 is also known as GD2 ganglioside. ST8SIA1 is also known as GD3 ganglioside. MMP9 is also known as gelatinase B. TYRP1 or TYRP1 is also known as glycoprotein 75. GPC3 is also known as glypican 3. CSF2RA is also known as GMCSF receptor a~chain. IGFIRor CD221 is also known as IGF-1 receptor. IL31RA is also known as IL31RA. ITGA2B or CD41 is also known as integrin alpha-IIb. ITGA5 is also known as integrin a5. ITGB3 is also known as integrin ollbp3. ITGB7 is also known as integrin P7. IFNG is also known as interferon gamma. IFNAR1, IFNAR2 is also known as interferon a / p receptor. CXCLIO is also known as interferon gamma-induced protein. IL12A or IL-12 is also known as interleukin 12. IL13 or IL-13 is also known as interleukin 13. IL17A or IL17A is also known as interleukin 17 alpha. IL17F or IL17F is also known as interleukin 17 F. IL2 or IL2 is also known as interleukin 2. IL22 or IL-22 is also known as interleukin 22. IL23A or IL23 is also known, as interleukin 23. IL6 or IL6 is also known as interleukin 6. SELL or CD62L is also known as L-selectin. MSLN is also known as mesothelin. MUC1 is also known as mucin CanAg. MADCAM1 is also known as mucosal addressin cell adhesion molecule. MAG is also known as myelin-associated glycoprotein. NECTIN4 is also known as nectin-4. CASP2 is also known as neural apoptosis-regulated proteinase 2. PTDSS1 is also known as phosphatidylserine. PDGFRB is also known as platelet-derived growth factor receptor beta. RHD, RHCE is also known as Rhesus factor. RSPO3 is also known as root plate-specific spondin 3. SELP is also known as selectin P. SAA1 or SAA2 is also known as serum amyloid A protein. APCS is also known as serum amyloid P component. S1PR1 is also known as sphingosine-1-phosphate. MAPT is also known as tau protein. TNC is also known as tenascin C. TNFRSF12A is also known as TWEAK receptor. VIM is also known as vimentin. VWF is also known as von Willebrand factor. IL2RA or CD25 is also known as a chain of IL-2receptor. III. COMPOSITIONS OF THE INVENTION

[0042] Various embodiments of the inventions described herein provide engineered megakaryocyte progenitors to encoding a chimeric platelet receptor (CPR). The receptor may bind a specific antigen or target present on a tumor or specific location in the body, for example the antigen to which the CPR binds may be an endogenous antigen. In some embodiments the target is not collagen. Alternatively, platelet receptors may be deleted to prevent cargo or toxin release in response to normal platelet activation signals. The multiple edits required to generate these progenitor cells are possible because the progenitor cells never enter the patient’s body where there are concerns of continuous culture or genome instability. Only enucleated platelets are injected into the patient. A. Engineering megakaryocytes

[0043] In some embodiments, the engineered platelets described herein originate from genetically modified megakary ocytes. The genome of these megakary ocytes may include a knock-out of at least one, two, three, four, five, six, seven, eight, nine, or at least ten genes encoding an endogenous receptor, mediator protein, and / or signaling transduction protein. It will be clear that in some instances it may not be necessary to knock out or delete the entire gene. For example GPlb knockout results in abnormal platelets, however one can delete only the extracellular domain of the receptor (removing its ability to function) while retaining the intracellular domain, resulting in typical platelets that lack the ability to bind to von Willebrand factor the GPlb target). Accordingly in some embodiments, the disruptions, deletions or knockouts described herein are full disruptions, deletions or knockouts of the entire gene. In other embodiments, the disruptions, deletions and knockouts are disruptions deletions and functional knockouts i.e. disruption of the function of the protein, and in some embodiments the deletion is a deletion of the extracellular domain of the proteins. Examples of genes that may be deleted from the megakaryocyte genome are shown in Table 3. Table 3. Potential genes for deletion Gene Mediator or receptor? Gene Mediator or receptor? Rab27a Mediator Factor XIII mediator HPS genes Mediator PF4 mediator integrin AIIbB3 receptor NAP2 (Nucleosome Assembly Protein 2) mediator GPlb-lX-V receptor Prothrombin mediator Pari receptor High Molecular Weight Kininogens mediator Pari receptor Plasminogen activator inhibitor 1 mediator P2Y1 receptor a2-antiplasmin mediator P2Y12 receptor plasminogen mediator IP receptor P-Selectin mediator / receptor TP receptor CXCL4 mediator TLR (many) receptor CXCL7 mediator GPV1 receptor FGF mediator a2B 1 (type 1 collagen receptor) receptor EGF mediator GPIIblllA HGF CLEC-2 receptor IGF MyD88 (Myeloid Differentiation Primary Response 88) signal transduction Angipoetin Galphaq signal transduction Thromboxane synthase mediator LIMK1 mediator PAF Mediator vWF mediator cPLA2a mediator Fibrinogen mediator Thromospondin PDGF mediator CD40L VEGF mediator SgTII (Secretogranin III) Factor V mediator Endostatin Factor MU i mediator TGF~P (transforming growth factor beta) Factor XI mediator Talinl signal transduction ANO6 / TMEM16F mediator Kindlins signed transduction The skilled person will appreciate that there are several pathways which should be disrupted to allow' the production of a platelet with reduced thrombogenic potential. In some embodiments any one or more of the following three pathways are disrupted: recognition of primary stimuli of thrombus formation; recognition of secondary stimuli of thrombus formation; and release of secondary mediators of thrombus formation. Recognition of primary stimuli of thrombus involves the platelets recognizing factors associated with exposed tissue that becomes exposed upon wounding, for example, recognizing the subendothelium. In typically circumstances, platelets are not exposed to subendothelium. Exposure of the subendothel ium allows platelets to recognize ligands such as collagen, von Willebrand factor, fibronectin, thrombospondin via receptors on the platelet surface, such as GPIb / V / IX and GPVI (GP6), ITGA2B, integrins s aiibp3, «261. aspi and aepi. Accordingly, in some embodiments the genes encoding a protein involved in recognition of primary stimuli of thrombus formation include GPIb / V / IX and GPVI (GP6), ITGA2B, CLEC2, integrins s aiibp3, a2Pi, asPi and cwPi. Once platelets have made contact with the exposed endothelium, for example via the interactions discussed above, the platelets release secondary messengers such as ADP, thrombin and TxAj which are detected by other platelets and which cause platelet aggregation at the wound site. In some embodiments, it is preferred if the ability of the platelets to recognize the secondary messengers is disrupted. It is not desirable if a platelet of the invention is targeted to wound site for example, rather than the intended target. Accordingly, in preferred embodiments the ability of the platelets to recognize the secondary messengers is disrupted. Receptors that are involved in this function include Pari, Par4, P2Y12, GPIb / V / IX, the Thromboxane receptor (TBXA2R), P2Y1, P2X1 and integrin aiibPs. As mentioned above, once platelets have recognized the exposed tissue, they release secondary messengers to recruit other platelets to the site. Once a platelet of the invention has bound to a target, for example to a tumour antigen, it is not desirable for the platelet of the invention to then recruit other platelets to a target site and form a thrombus, for example a thrombus at a tumour site. Accordingly, in preferred embodiments, the pathway by which the activated platelet releases the secondary messengers is disrupted. The pathway can include those proteins that are involved in the production and / or storage and / or release of the secondary mediators. Genes involved in this pathway include Coxl, HI’S and thromboxane-A synthase (TEXAS 1). The skilled person will appreciate that a single gene can be involved in two or three of the above functions. In some embodiments it is preferred if the megakaryocyte or progenitor thereof comprises a disruption or deletion of (e.g. a knockout of) at least one, two, three, four, five, six, seven, eight, nine, or at least ten genes encoding a protein involved in recognition of primary stimuli of thrombus formation; a protein involved in recognition of secondary' mediators of thrombus formation; and / or a protein in volved in the release of secondary mediators of thrombus formation. It will be clear to the skilled person that by a protein involved in recognition of primary stimuli of thrombus we include the meaning of any protein that is involved in this process, for example includes the protein that is directly involved in contact with or recognition of primary stimuli of thrombus, and also genes that for example lead to the expression of those proteins that are directly involved in contact with or recognition of the primary stimuli of thrombus. The skilled person will understand which proteins are considered to be involved in recognition of primary stimuli. The key feature is that disruption of the proteins are that their disruption leads to a defect in the recognition of primary stimuli of thrombus. However, in some embodiments a protein involved in recognition of primary stimuli of thrombus includes only those proteins that directly make contact with the primary stimuli of thrombus. By a protein involved in recognition of secondary mediators of thrombus formation we include those proteins that are directly involved in the contact with or recognition of secondar mediators of thrombus formation, as well as proteins that are indirectly involved in those processes, for example those proteins that are involved in the production of the proteins that are directly involved in the contact with or recognition of secondar mediators of thrombus formation. The skilled person will understand what is mean by proteins involved in recognition of secondary mediators of thrombus formation. The key feature of the proteins are that their disruption leads to a defect in the recognition of secondary mediators of thrombus formation. However, in some embodiments a protein involved in recognition of secondary mediators of thrombus formation includes only those proteins that make direct contact with the secondary mediators of thrombus formation. By a protein involved in the release of secondary mediators of thrombus formation we include those proteins that are involved in the production and / or storage and / or release of the secondary’ mediators. The key feature of the proteins are that their disruption leads to a defect in the ultimate release of the secondary? mediators. The defect may? be in the production of the secondary mediators, the storage of the secondary’ mediators, and / or the actual release process. In some embodiments the megakaryocyte or progenitor thereof comprises a disruption or deletion of at least: one gene that encodes a protein involved in recognition of primary? stimuli of thrombus formation; one gene that encodes a protein involved in recognition of secondary’ mediators of thrombus formation; and one gene that encodes a protein involved in the release of secondary' mediators of thrombus formation; In some embodiments the megakaryocyte or progenitor thereof comprises a disruption or deletion of at least: two genes that encode a protein involved in recognition of primary stimuli of thrombus formation; two genes that encode a protein involved in recognition of secondary? mediators of thrombus formation; and two genes that encode a protein involved in the release of secondary? mediators of thrombus formation; In some embodiments the megakaryocyte or progenitor thereof comprises a disruption or deletion of at least: three genes that encode a protein involved in recognition of primary stimuli of thrombus formation; three genes that encode a protein involved in recognition of secondary mediators of thrombus formation; and three genes that encode a protein involved in the release of secondary mediators of thrombus formation. Genes that are considered to encode a protein involved in recognition of primary stimuli of thrombus formation include GPIb / V / IX and GPVI (GP6), ITGA2B, CLEC2, integrins s a.iibp3, acpi, aspi and aepi, or optionally include GPVI and ITGA2B. Genes that are considered to encode a protein involved in recognition of secondary stimuli of thrombus formation include Pari, Par4, P2YI2, GPIb / V / IX, the Thromboxane receptor (TBXA2R), P2Y1, P2X1 and integrin aiibp3 or optionally include Pari, Par4 and P2Y12. Genes that are considered to a protein involved in release of secondary mediators of thrombus formation include Coxl, HPS and thromboxane-A synthase (TBXAS1), or optionally include Coxl and HPS. In some embodiments the at least one, two or three genes that encode a protein involved in recognition of primary stimuli of thrombus formation are selected from the group consisting of: GPIb / V / IX and GPVI (GP6), ITGA2B, CLEC2, integrins s ociibPy azPl, asPi and aePi„ or from the group consisting of GPVI and ITGA2B; the at least one, two or three that encode a protein involved in recognition of secondary mediators of thrombus formation are selected from the group consisting of Pari, Par4, P2Y12, GPIb / V / IX, the Thromboxane receptor (TBXA2R), P2Y1, P2X1 and integrin cuibP3 or from the group consisting of Pari, Par4 and P2Y12; and / or the at least one, two or three genes that encode a protein involved in the release of secondary mediators of thrombus formation are selected from the group consisting of Coxl, HPS and thromboxane-A synthase (TBXAS1) or from the group consisting of Coxl and HPS. In a preferred embodiment, the genetically modified megakaryocyte or progenitor thereof has a disruption or deletion in each of the following genes: GPVI, ITGA2B, Pari, Par4, P2Y12, Coxl and HPS. For example the genetically modified megakaryocyte or progenitor thereof may comprise a knockout of each of GPVI, ITGA2B, Pari, Par4, P2Y12, Coxl and HPS.

[0044] In some embodiments, expression of the genes in Table 3 may be altered or “knocked-out” using a CRISPR / Cas system, zinc finger nucleases, transcription activator-1 ike effector nucleases (TALENs), a RNA interference construct (RNAi) (e.g., small interfering RNA (siRNA) or microRNA (miRNA)), or a short hairpin RNA (shRNA).

[0045] The effects of knock-out of a gene in a megakaryocyte on the resulting engineered platelet may be varied. For example, RAB27a (RAS oncogene) and HPS (haptoglobin) genes function in dense granule loading and formation, respectively. Knock-out or deletion of Rab27a may result in engineered platelets with no dense granule mediators but with otherwise normal platelet biology. Knock-out or deletion of HPS genes may result in engineered platelets containing no dense granules. Knock-out or deletion of AIIbB3 or GPlb-IX-V may result in failure of the platelets to aggregate with each other by decreasing interaction between the platelet and von Willebrand factors (vWF) after activation. Further, AIIbB3 is also involved in inside-out signaling to increase the affinity of the integrin for fibrinogen (See, Durrant, Blood. 2017 Oct 5; 130(14): 1607-1619). Knock-out or deletion of IP (PGI2R or prostaglandin 12 receptor) may result in negative regulation of prostaglandin. Knock-out or deletion of TP (TxA2R or Thromboxane A2 Receptor) may result in reduction of recruitment of additional platelets on activation to stimulate clotting.

[0046] GPVI (ITAM receptor) has been observed to still be stimulated in G-protein alpha-q (Galphaq) knockout mice. Conversely, IT AM agonists, such as collagen, induce release of G-protem-coupled receptors (GPCR agonists), such as ADP and thromboxane A2 receptor (TXA2), thus indirectly activating phospholipase C (PLC) through the Gq pathway. Further, Galphaq is active for proper function for thrombin, ADP, 5-hydroxytryptamine (5HT), PAF, and thromboxane A (TXA).

[0047] Knock-out or deletion of P-selectin, thromboxane synthase, and platelet activating factor (PAF) may result in failure of platelet aggregation once activated. Knock-out or deletion of LIM Domain Kinase 1 (LIMK1) will likely reduce TxA2 synthesis. CXCL4 (C-X-C motif chemokine ligand 4) and CXCL7 (C-X-C motif chemokine ligand 7) are chemokines; therefore, knock-out or deletion of the gene would likely interfere in at least one signaling pathway. Talinl and kindlins function in signal transduction to allow integrins to enter a sensitive state.

[0048] Knock-out or deletion of ANO6 / TMEM16F disrupts the platelets ability to expose phosphatidylserine on platelet activation. Phosphatidlyserine is a membrane lipid which is usually kept on the cytoplasmic face of the platelet. On platelet activation, calcium influx triggers phosphatidylserine exposure on the outside of the platelet via ANO6 / TMEM16F, where it acts to catalyse the production of active thrombin in combination with clotting factors. Thus, knockout of TMEM16F prevents phosphatidylserine exposure and thus would decrease platelet thrombogenicity. This is exemplified by Scott’s syndrome patients, who feature ANO6 mutations and clinically have increased risk of bleeding. B. Chimeric platelet receptors (CPU)

[0049] In some embodiments, the engineered platelets described herein may include alterations to the endogenous platelet receptors. Alterations include, but are not limited to, deletions or additions or entire receptors or domains of these receptors, or combinations with domains from non-endogenous receptors to result in differences in the behavior of an engineered platelet compared to a platelet without the alteration. To stimulate activation of platelets, domains from an immunoreceptor tyrosine-based activation motif (ITAM) receptor may be used in a chimeric platelet receptor. To inhibit activation of platelets immunoreceptor tyrosine-based inhibition motif (ITIM). It will be clear to the skilled person that domains from an ITAM receptor that is not typically expressed in platelets will still function in the invention, since the ITAM domains are still capable of activating the same downstream signaling components as ITAM receptors are endogenously found in platelets. 1. Endogenous platelet receptors

[0050] In some embodiments, platelets may be redirected to degranulate by an antigen, rather than collagen. ITIM containing receptors inhibit platelet activation to directly counteract ITAM receptor activation. CEACAM-1, PECAM-1, and G6b-B are ITIM containing receptors. G6b-B clustering by antibody inhibits platelet activation through GPVI and CLEG- 2 as shown in Mori et al. “G6b-B inhibits constitutive and agonist-induced signaling by glycoprotein VI and CLEC-2”. JBC, 2008, which is hereby incorporated by reference in its entirety. Adding a chimeric “off’ receptor may be used to improve specificity of the synthetic platelets described herein. An engineered chimeric immunoreceptor tyrosine-based inhibition motif (ITIM) receptor would allow logic gate construction.

[0051] Alternatively, ITAM receptors mediate platelet activation and stimulate an immune response. Glycoprotein VI (GPVI) binds to collagen and is a central mediator of platelet activation. It features extracellular IgG like domains, and the internal tyrosine kinase signaling pathway is triggered by receptor clustering through the Fc receptor (FcR) gamma chain. In certain embodiments, the intracellular domain is retained and the extracellular domain is swapped to target an antigen. For example, in some embodiments, the chimeric platelet receptor comprises an intracellular domain that stimulates platelets, but does not comprise the corresponding extracellular domain. For example in some embodiments the extracellular targeting domain of the receptor is heterologous to the intracellular domain of the receptor. By heterologous extracellular targeting domain we mean that the extracellular domain is not the usual extracellular domain associated with the intracellular domain. For instance, in embodiments where the intracellular domain comprises the intracellular domain of Glycoprotein VI (GPVI), the extra cellular domain is not the extracellular domain of Glycoprotein VI (GPVI), the domains are heterologous to one another. Alternatively, C-type lectinlike receptor 2 (CLEC-2) or Fc Fragment of IgG Receptor Ila (FCgR2A) may be altered in a similar way. In other embodiments, where the intracellular domain comprises the intracellular domain of C-type lectinlike receptor 2 (CLEC-2), the extracellular targeting domain is not the extracellular domain of CLEC-2; and in some embodiments where the intracellular domain comprises Fc Fragment of IgG Receptor Ila (FCgR2A), the extracellular targeting domain does not comprise the extracellular domain of FCgR2A. It is clear that the extracellular targeting domain may be a domain that is native to the subject, but is not native to the intracellular domain. It will be clear then that in some embodiments the CPR is not a naturally occurring protein.

[0052] CLEC-2 binds to podoplanin (associated with tumors) and triggers platelet activation in response to snake venom rhodocytin and elicits aggregation of platelets through activation of Src and Syk non-receptor tyrosine kinases in the internal tyrosine kinase signaling pathway triggered by receptor clustering through signaling proteins lymphocyte cytosolic protein 2 or SH2 domain containing leukocyte protein of 76kDa (SLP-76) and l-phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma-2 (PLCy2) (See, Fu et al. Blood, 127(13):1629-30, 2016, which is hereby incorporated by reference in its entirety).

[0053] FCgr2A binds to Fc region of antibodies and triggers platelet activation in response to opsonized bacteria through signaling protein Syk non-receptor tyrosine kinase. The internal tyrosine kinase signaling pathway is triggered by receptor clustering.

[0054] In some embodiments, additional If AM receptors may be inserted into the genome of a megakaryocyte to enhance T cell signaling and stimulate an immune response. T cell receptors (TCRs) recognize antigens bound in the major histocompatibility complex (MHC) (See, James et al. Sci. Signal. 11, eaan!088 (2018), which is hereby incorporated by reference in its entirety). ITAMs on the TCRs convert the action of binding and recognition into an intracellular signal (Ibid). Inserting additional ITAMs into chimeric TCRs was observed to scale linearly with the number of ITAM receptors and decreasing or knocking-out the number of ITAM receptors was observed to inhibit T cell development by impairing thymocyte lineage commitment (Ibid).

[0055] In some embodiments, a CPR may include one or more domains or portions thereof from one or more immunoreceptor tyrosine-based activation motif (ITAM) receptors. Non-limiting examples of ITAM receptors include glycoprotein VI platelet (GPVIA), high affinity immunoglobulin epsilon receptor subunit gamma (FCERG), C-Type lectin domain family 1 (CLECl), and Fc fragment of IgG receptor II (FCGR2).

[0056] In one embodiment, domains of ITAM receptors FCERG (SEQ ID NO: 1), CLECl (SEQ ID NO: 6), FCGR2 (SEQ ID NO: 10), and / or GPVIA (SEQ ID NO: 15) shown in Table 4 may be combined for expression in a megakaryocyte resulting in a CPR in the engineered platelet.

[0057] In one embodiment, domains of ITAM receptors may be combined with T cell receptor domains to form chimeric ITAM receptors which are also referred to as chimeric platelet receptors. These chimeric receptors may be combined for expression in a megakaryocyte resulting in a CPR in the engineered platelet. Non-limiting examples of chimeric ITAM receptors for FCERG (SEQ ID NO: 20), CLECl (SEQ ID NO: 21), FCGR2 (SEQ ID NO: 22) and GPVIA (SEQ ID NO: 23) are shown in Table 4. Table 4. IT AM receptors and ITAM chimeric receptors Symbol Regions Sequence Identifier FCERG Signal Peptide (SEQ ID NO: 2); EC Domain (SEQ ID NO: 3); TM Domain (SEQ ID NO: 4); CytoDomain (SEQ ID NO: 5); stop 1 CLEC1 CytoDomain (SEQ ID NO: 7); TM Domain (SEQ ID NO: 8); EC Domain (SEQ ID NO: 9); stop 6 FCGR2 Signal Peptide (SEQ ID NO: 11); EC Domain (SEQ ID NO: 12); TM Domain (SEQ ID NO: 13); CytoDomain (SEQ ID NO: 14); stop 10 GPVIA Signal Peptide (SEQ ID NO: 16); EC Domain (SEQ ID NO: 17); TM Domain (SEQ ID NO; 18); CytoDomain (SEQ ID NO; 19); stop 15 FCERG (chimeric) Signal Peptide (SEQ ID NO: 2); FvlHChain domain (SEQ ID NO: 50); Whitlow_Linker (SEQ ID NO: 49); Fvl_Lchain (SEQ ID NO: 48); Modified Hinge IGg4 (SEQ ID NO; 51); EC Domain (SEQ ID NO: 3); TM Domain (SEQ ID NO: 4); CytoDomain (SEQ ID NO: 5); stop 20 CLEC1 (chimeric) CytoDomain (SEQ ID NO: 7); TM Domain (SEQ ID NO: 8); EC Domain (SEQ ID NO: 53); Modified Hing IGg4 (SEQ ID NO: 51); Fv IHChain (SEQ ID NO: 50); Whitlow_Linker (SEQ ID NO: 49); Fvl Lchain (SEQ ID NO: 48); stop 21 FCGR2 (chimeric) Signal Peptide (SEQ ID NO: 11); FvlHChain (SEQ ID NO: 50); Whitlow J..inker (SEQ ID NO: 49); FvlJLchain (SEQ ID NO: 48); Modified hinge IGg4 (SEQ ID NO: 51); EC Domain (SEQ ID NO: 54); TM Domain (SEQ ID NO: 13); CytoDomain (SEQ ID NO: 14); stop 22 GPVIA (chimeric) Signal Peptide (SEQ ID NO: 16); Fv IHChain (SEQ ID NO; 50); Whitlow Jinker (SEQ ID NO: 49); Fvl_Lchain (SEQ ID NO: 48); Modified hinge IGg4 (SEQ ID NO: 51); EC Domain (SEQ ID NO: 55); TM Domain (SEQ ID NO: 18); CytoDomain (SEQ ID NO: 19); stop 23

[0058] SEQ ID NO: 1 is an embodiment of a complete FCERG receptor. SEQ ID NO: 2 is an embodiment of the signal peptide of FCERG. SEQ ID NO: 3 is an embodiment of the extracellular domain of FCERG. SEQ ID NO: 4 is an embodiment of the transmembrane domain of FCERG. SEQ ID NO: 5 is an embodiment of the cytoplasmic domain of FCERG. SEQ ID NO: 6 is an embodiment of the ITAM receptor of CLEC1. SEQ ID NO: 7 is an embodiment of the cytoplasmic domain of CLEC1. SEQ ID NO: 8 is an embodiment of the transmembrane domain of CLEC1. SEQ ID NO: 9 is an embodiment of the extracellular domain of CLEC1. SEQ ID NO: 10 is an embodiment of the ITAM receptor of FCGR2. SEQ ID NO: 11 is an embodiment of the signal peptide of FCGR2. SEQ ID NO: 12 is an embodiment of the extracellular domain of FCGR2. SEQ ID NO: 13 is an embodiment of the transmembrane domain of FCGR2. SEQ ID NO: 14 is an embodiment of the cytoplasmic domain of FCGR2. SEQ ID NO: 15 is an embodiment of the ITANI receptor of GPVIA. SEQ ID NO: 16 is an embodiment of the signal peptide of GPVIA. SEQ ID NO: 17 is an embodiment of the extracellular domain of GPVIA. SEQ ID NO: 18 is an embodiment of the transmembrane domain of GPVIA. SEQ ID NO: 19 is an embodiment of the cytoplasmic domain of GPVIA.

[0059] SEQ ID NO: 20 is an embodiment of a chimeric ITANI receptor based on FCERG SEQ ID NO: 21 is an embodiment of a chimeric ITAM receptor based on CLECT. SEQ ID NO: 22 is an embodiment of a chimeric ITAM receptor based on FCGR2. SEQ ID NO: 23 is an embodiment of a chimeric ITAM receptor based on GPVIA.

[0060] In some embodiments, a CPR may include one or more domains or portions thereof from one or more immunoreceptor tyrosine-based inhibition motif (ITIM) receptors. Non-limiting examples of ITIM receptors include platelet and endothelial cell adhesion molecule 1 (PEC AMI), triggering receptor expressed on myeloid cells like 1 (TLT1), leukocyte immunoglobulin like receptor B2 (LILRB2), carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1), megakaryocyte and platelet inhibitory receptor G6b (G6b-B).

[0061] In one embodiment, domains of ITIM receptors LILRB2 (SEQ ID NO: 34), PEC AMI (SEQ ID NO: 38), TLT1 (SEQ ID NO: 43), and CEACAM1 (SEQ ID NO: 24) shown in Table 5 may be combined for expression in a megakaryocyte resulting in a CPR in the engineered platelet.

[0062] In one embodiment, domains of ITIM receptors may be combined with T cell receptor domains to form chimeric ITIM receptors which are also referred to as chimeric platelet receptors. These chimeric receptors may be combined for expression in a megakaryocyte resulting in a CPR in the engineered platelet. Table 5. ITIM receptors Symbol Regions Sequence Identifier LILRB2 Signal Peptide (SEQ ID NO: 35); EC Domain (SEQ ID NO: 36); TM Domain (SEQ ID NO: 37); CytoDomain (SEQ ID NO: 52); stop 34 PECAM1 Signal Peptide (SEQ ID NO: 39); EC Domain (SEQ ID NO: 40); TM Domain (SEQ ID NO: 41); CytoDomain (SEQ ID NO: 42); stop 38 TLT1 Signal Peptide (SEQ ID NO: 44); EC Domain (SEQ ID NO: 45); TM Domain (SEQ ID NO: 46); CytoDomain (SEQ ID NO: 47); stop 43 CEACA Ml Signal Peptide (SEQ ID NO: 25); EC Domain (SEQ ID NO: 26); TM Domain (SEQ ID NO: 27); CytoDomain (SEQ ID NO: 28); stop 24

[0063] SEQ ID NO: 24 is an embodiment of the ITIM receptor of CEACAM1. SEQ ID NO: 25 is an embodiment of the signal peptide of CEACAM1. SEQ ID NO: 26 is an embodiment of the extracellular domain of CEACAM1. SEQ ID NO: 27 is an embodiment of the transmembrane domain of CEACAM1. SEQ ID NO: 28 is an embodiment of the cytoplasmic domain of CEACAM1. SEQ ID NO: 29 is an embodiment of the ITIM receptor of G6b-B. SEQ ID NO: 30 is an embodiment of the signal peptide of G6b-B. SEQ ID NO: 31 is an embodiment of the extracellular domain of G6b-B. SEQ ID NO: 32 is an embodiment of the transmembrane domain of G6b-B. SEQ ID NO: 33 is an embodiment of the cytoplasmic domain of G6b-B. SEQ ID NO: 34 is an embodiment of the ITIM receptor of LILRB2. SEQ ID NO: 35 is an embodiment of the signal peptide of LILRB2. SEQ ID NO: 36 is an embodiment of the extra domain of LILRB2. SEQ ID NO: 37 is an embodiment of the transmembrane domain of LILRB2. SEQ ID NO: 38 is an embodiment of the ITIM receptor of PECAM1. SEQ ID NO: 39 is an embodiment of the signal peptide of PECAM1. SEQ ID NO: 40 is an embodiment of the extracellular domain of PECAM1. SEQ ID NO: 41 is an embodiment of the transmembrane domain of PEC AMI. SEQ ID NO: 42 is an embodiment of the cytoplasmic domain of PEC AMI. SEQ ID NO: 43 is an embodiment of the ITIM receptor of TLT1. SEQ ID NO: 44 is an embodiment of the signal peptide of TLT1. SEQ ID NO: 45 is an embodiment of the extracellular domain of TLT1. SEQ ID NO: 46 is an embodiment of the transmembrane domain of TLT1. SEQ ID NO: 47 is an embodiment of the cytoplasmic domain of TLT1. a. Domains

[0064] A CPR may comprise any combination of a signal peptide, an extracellular domain, a transmembrane domain, a cytoplasmic domain, or linker or targeting domain.

[0065] In one embodiment, a CPR may comprise a signal peptide selected from Table 6. Table 6. Signal peptides Sequence Identifier Description 2 FCERG Signal Peptide 11 FCGR2 Signal Peptide 16 GPVIA Signal Peptide 2^ CEACAM1 Signal Peptide 30 G6b-B Signal Peptide 35 LILRB2 Signal Peptide 39 PEC AMI Signal Peptide 44 TLT1 Signal Peptide

[0066] In one embodiment, a CPR comprises at least one FCERG signal peptide. As a nonlimiting example, the FCERG signal peptide is SEQ ID NO: 2.

[0067] In one embodiment, a CPR comprises at least one FCGR2 signal peptide. .As a nonlimiting example, the FCGR2 signal peptide is SEQ ID NO: 11.

[0068] In one embodiment, a CPR comprises at least one GPVIA signal peptide. As a nonlimiting example, the GPVIA signal peptide is SEQ ID NO: 16.

[0069] In one embodiment, a CPR comprises at least one CEACAM1 signal peptide. As a nonlimiting example, the CEACAM1 signal peptide is SEQ ID NO: 25.

[0070] In one embodiment, a CPR comprises at least one G6b-B signal peptide. As a non-limiting example, the G6b-B signal peptide is SEQ ID NO: 30.

[0071] In one embodiment, a CPR comprises at least one LILRB2 signal peptide. As a nonlimiting example, the LILRB2 signal peptide is SEQ ID NO: 35.

[0072] In one embodiment, a CPR comprises at least one PECAM1 signal peptide. As a nonlimiting example, the PECAM1 signal peptide is SEQ ID NO: 39.

[0073] In one embodiment, a CPR comprises at least one TLT1 signal peptide. As a non-limiting example, the TLT1 signal peptide is SEQ ID NO: 44.

[0074] The CPR may include a portion of the signal peptide in Table 6 or a signal peptide known in the art. The portion may be 10-30, 10-15, 10-20, 10-25, 15-20, 15-25, 15-30, 20-25, or 20-30, nucleotides of any of the sequences in Table 6 such as, but not limited to, SEQ ID NO: 2, 11, 16, 25, 30, 35, 39, and 44. The portion may be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides of any of the sequences in Table 7 such as, but not limited to, SEQ ID NO: 2, 11, 16, 25, 30, 35, 39, and 44.

[0075] A CPR may comprise an extracellular (EC) domain or portion thereof selected from Table 7. Table 7. Extracellular domain Sequence Identifier Description 3 FCERG EC Domain 9 CLECl EC Domain 53 CLECl EC Domain 12 FCGR2 EC Domain 54 FCGR2 EC Domain 17 GPVIA EC Domain 55 GPVIA EC Domain 26 CEACAM1 EC Domain 31 G6b-B EC Domain 36 LILRB2 EC Domain 40 PECAM1 EC Domain 45 TLT1 EC Domain 10076]   In one embodiment, a CPR comprises at least one FCERG EC domain. As a non-limiting example, the FCERG EC domain is SEQ ID NO: 3. 10077]   In one embodiment, a CPR comprises at least one CLECl EC domain. As a non-limiting example, the CLECl EC domain is SEQ ID NO: 9. 10078]   In one embodiment, a CPR comprises at least one CLECl EC domain. As a non-limiting example, the CLEC1 EC domain is SEQ ID NO: 53.

[0079] In one embodiment, a CPR comprises at least one FCGR2 EC domain. As a non-limiting example, the FCGR2 EC domain is SEQ ID NO: 12.

[0080] In one embodiment, a CPR comprises at least one FCGR2 EC domain. As a non-limiting example, the FCGR2 EC domain is SEQ ID NO: 54.

[0081] In one embodiment, a CPR comprises at least one GPVIA EC domain. As a non-limiting example, the GPVIA EC domain is SEQ ID NO: 17.

[0082] In one embodiment, a CPR comprises at least one GPVIA EC domain. As a non-limiting example, the GPVIA EC domain is SEQ ID NO: 55.

[0083] In one embodiment, a CPR comprises at least one CEACAM1 EC domain. As a nonlimiting example, the CEACAM1 EC domain is SEQ ID NO: 26.

[0084] In one embodiment, a CPR comprises at least one G6b-B EC domain. As a non-limiting example, the G6b-B EC domain is SEQ ID NO: 31.

[0085] In one embodiment, a CPR comprises at least one LILRB2 EC domain. As a non-limiting example, the LILRB2 EC domain is SEQ ID NO: 36.

[0086] In one embodiment, a CPR comprises at least one PECAM1 EC domain. As a nonlimiting example, the PECAM1 EC domain is SEQ ID NO: 40.

[0087] In one embodiment, a CPR comprises at least one TLT1 EC domain. As a non-limiting example, the TLT1 EC domain is SEQ ID NO: 45.

[0088] The CPR may include a portion of the EC domain in Table 7 or a EC domain known in the art. The portion may be 10-30, 10-15, 10-20, 10-25, 15-20, 15-25, 15-30, 20-25, or 20-30, nucleotides of any of the sequences in Table 7 such as, but not limited to, SEQ ID NO: 3, 9, 12, 17, 26, 31, 36, 40, and 45. The portion may be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides of any of the sequences in Table 7 such as, but not limited to, SEQ ID NO: 3, 9, 12, 17, 26, 31, 36, 40, and 45.

[0089] In one embodiment, CPR may include a portion of the FCERG EC domain in Table 7. The portion may be 10-30, 10-15, 10-20, 10-25, 15-20, 15-25, 15-30, 20-25, or 20-30, nucleotides of SEQ ID NO: 3. The portion may be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides of SEQ ID NO: 3.

[0090] In one embodiment, CPR may include a portion of the CLEC1 EC domain in Table 7. The portion may be 10-30, 10-15, 10-20, 10-25, 15-20, 15-25, 15-30, 20-25, or 20-30, nucleotides of SEQ ID NO: 9. The portion may be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21,22,23,24, 25, 26, 27, 28, 29, or 30 nucleotides of SEQ ID NO: 9.

[0091] In one embodiment, CPR may include a portion of the FCERG EC domain in Table 7 that is 10-15 nucleotides in length. The portion may be 10, 11, 12, 13, 14, or 15 nucleotides of SEQ ID NO: 3.

[0092] In one embodiment, CPR may include a portion of the CLEC1 EC domain in Table 7 that is 10-15 nucleotides in length. The portion may be 10, 11, 12, 13, 14, or 15 nucleotides of SEQ ID NO: 9 or 53. As a non-limiting example, a portion of SEQ ID NO: 9 may be SEQ ID NO: 53.

[0093] In one embodiment, CPR may include a portion of the CLEC1 EC Domain in Table 7. The portion may be 10-30, 10-15, 10-20, 10-25, 15-20, 15-25, 15-30, 20-25, or 20-30, nucleotides of SEQ ID NO: 53. The portion may be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides of SEQ ID NO: 53.

[0094] In one embodiment, CPR may include a portion of the FCGR2 EC Domain in Table 7. The portion may be 10-30, 10-15, 10-20, 10-25, 15-20, 15-25, 15-30, 20-25, or 20-30, nucleotides of SEQ ID NO: 12. The portion may be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides of SEQ ID NO: 12.

[0095] In one embodiment, CPR may include a portion of the FCGR2 EC Domain in Table 7. The portion may be 10-30, 10-15, 10-20, 10-25, 15-20, 15-25, 15-30, 20-25, or 20-30, nucleotides of SEQ ID NO: 54. The portion may be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides of SEQ ID NO: 54.

[0096] In one embodiment, CPR may include a portion of the GPVIA EC Domain in Table 7. The portion may be 10-30, 10-15, 10-20, 10-25, 15-20, 15-25, 15-30, 20-25, or 20-30, nucleotides of SEQ ID NO: 17. The portion may be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides of SEQ ID NO: 17.

[0097] In one embodiment, CPR may include a portion of the GPVIA EC Domain in Table 7. The portion may be 10-30, 10-15, 10-20, 10-25, 15-20, 15-25, 15-30, 20-25, or 20-30, nucleotides of SEQ ID NO: 55. The portion may be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides of SEQ ID NO: 55.

[0098] In one embodiment, CPR may include a portion of the CEA CAM! EC Domain in Table 7. The portion may be 10-30, 10-15, 10-20, 10-25, 15-20, 15-25, 15-30, 20-25, or 20-30, nucleotides of SEQ ID NO: 26. The portion may be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides of SEQ ID NO: 26.

[0099] In one embodiment, CPR may include a portion of the G6b-B EC Domain in Table 7. The portion may be 10-30, 10-15, 10-20, 10-25, 15-20, 15-25, 15-30, 20-25, or 20-30, nucleotides of SEQ ID NO: 31. The portion may be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides of SEQ ID NO: 31.

[0100] In one embodiment, CPR may include a portion of the L1LRB2 EC Domain in Table 7. The portion may be 10-30, 10-15, 10-20, 10-25, 15-20, 15-25, 15-30, 20-25, or 20-30, nucleotides of SEQ ID NO: 36. The portion may be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides of SEQ ID NO: 36.

[0101] In one embodiment, CPR may include a portion of the PECAM1 EC Domain in Table 7 The portion may be 10-30, 10-15, 10-20, 10-25, 15-20, 15-25, 15-30, 20-25, or 20-30, nucleotides of SEQ ID NO: 40. The portion may be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides of SEQ ID NO: 40.

[0102] In one embodiment, CPR may include a portion of the TLT1 EC Domain in Table 7. The portion may be 10-30, 10-15, 10-20, 10-25, 15-20, 15-25, 15-30, 20-25, or 20-30, nucleotides of SEQ ID NO: 45. The portion may be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides of SEQ ID NO: 45.

[0103] A CPR may comprise a transmembrane (TM) domain selected from Table 8. Table 8. Transmembrane domain Sequence Identifier Description 4 FCERG TM Domain 8 CLECl TM Domain 13 FCGR2 TM Domain 18 GPVIA TM Domain 27 CEACAM1 TM Domain 32 G6b-B TM Domain 37 L1LRB2 TM Domain 41 PECAM1 TM Domain 46 TLT1 TM Domain

[0104] In one embodiment, a CPR comprises at least one FCERG TM Domain. As a non-limiting example, the FCERG IM Domain is SEQ ID NO: 4.

[0105] In one embodiment, a CPR comprises at least one CLEC1 TM Domain. As a non-limiting example, the CLEC1 IM Domain is SEQ ID NO: 8.

[0106] In one embodiment, a CPR comprises at least one FCGR2 TM Domain. As a non-limiting example, the FCGR2 TM Domain is SEQ ID NO: 13.

[0107] In one embodiment, a CPR comprises at least one GPVIA TM Domain. As a non-limiting example, the GPVIA TM Domain is SEQ ID NO: 18.

[0108] In one embodiment, a CPR comprises at least one CEACAM1 TM Domain. As a nonlimiting example, the CEACAM1 TM Domain is SEQ ID NO: 27.

[0109] In one embodiment, a CPR comprises at least one G6b-B TM Domain. As a non-limiting example, the G6b-B TM Domain is SEQ ID NO: 32.

[0110] In one embodiment, a CPR comprises at least one LILRB2 TM Domain. As a nonlimiting example, the LILRB2 TM Domain is SEQ ID NO: 37.

[0111] In one embodiment, a CPR comprises at least one PEC AMI TM' Domain. As a non limiting example, the PEC AMI TM Domain is SEQ ID NO: 41.

[0112] In one embodiment, a CPR comprises at least one TLT1 TM Domain. As a non-limiting example, the TLT1 TM Domain is SEQ ID NO: 46.

[0113] A CPR may comprise a cytoplasm (cyto) domain selected from Table 9. Table 9. Cytoplasm domain Sequence Identifier Description 5 FCERG CytoDomain 7 CLEC1 CytoDomain 14 FCGR2 CytoDomain 19 GPVIA CytoDomain 28 CEACAM1 CytoDomain 33 G6b-B CytoDomain 52 LILRB2 CytoDomain 42 PECAM1 CytoDomain 47 TLT1 CytoDomain

[0114] In one embodiment, a CPR comprises at least one FCERG CytoDomain. As a nonlimiting example, the FCERG CytoDomain is SEQ ID NO: 5.

[0115] In one embodiment, a CPR comprises at least one CLEC1 CytoDomain. As a non-limiting example, the CLEC1 CytoDomain is SEQ ID NO: 7.

[0116] In one embodiment, a CPR comprises at least one FCGR2 CytoDomain. As a non-limiting example, the FCGR2 CytoDomain is SEQ ID NO: 14.

[0117] In one embodiment, a CPR comprises at least one GPVIA CytoDomain. As a non-limiting example, the GPVIA CytoDomain is SEQ ID NO: 19.

[0118] In one embodiment, a CPR comprises at least one CEACAM1 CytoDomain. As a nonlimiting example, the CEACAM1 CytoDomain is SEQ ID NO: 28.

[0119] In one embodiment, a CPR comprises at least one G6b-B CytoDomain. As a non-limiting example, the G6b-B CytoDomain is SEQ ID NO: 33.

[0120] In one embodiment, a CPR comprises at least one LILRB2 CytoDomain. As a nonlimiting example, the LILRB2 CytoDomain is SEQ ID NO: 52.

[0121] In one embodiment, a CPR comprises at least one PECAM1 CytoDomain. As a nonlimiting example, the PECAM1 CytoDomain is SEQ ID NO: 42.

[0122] In one embodiment, a CPR comprises at least one TLTI CytoDomain. .As a non-limiting example, the TLTI CytoDomain is SEQ ID NO: 47.

[0123] Genes encoding fusion peptides, targeting domain, or linking protein may be added to the genome of the megakaryocyte as shown in Table 10, such as the L chain of variable fragment 1 (Fvl Lchain) with a nucleic acid sequence of SEQ ID NO: 48 or an improved linker from a singlechain variable fragment with reduced aggregation and enhanced proteolytic stability (Whitlow linker) with a nucleic acid sequence of SEQ ID NO: 49. Alternatively, at least a portion of an antibody may be added to the genome of the megakaryocyte for expression in a resulting platelet, such as a kappa light chain of an anti-human B cell CD19 antibody (FlHChain__CD19FMC63) with a nucleic acid sequence of SEQ ID NO: 50 and a modified IGg4 hinge region with a nucleic acid sequence of SEQ ID NO: 51 also shown in Table 10.

[0124] In some embodiments, a CPR comprises at least one domain selected from Tables 4-9 and a linker and / or targeting domains selected from Table 10. Table 10. Linkers and Targeting Domains Sequence Identifier Description 48 Fvl Lchain (Light Chain) 49 Whitlow linker (Linker) 50 FvlHChain CD19FMC63 (Heavy Chain) 51 Modified hinge !Gg4 (Hinge)

[0125] In one embodiment, the CPR has a domain, having at least 95% identity to any of the sequences of Tables 4-10, including, SEQ ID NO: 1-55. In one embodiment, the CPR has a domain having 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity' to one or more of the sequences of Tables 4-10, including, SEQ ID NO: 1-55.

[0126] In one embodiment, the CPR has at least one signal peptide, having at least 95% identity to any of the sequences of Table 6, including, SEQ ID NO: 2, 11, 16, 25, 30, 35, 39, and 44. In one embodiment, the CPR has at least one signal peptide domain having 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to one or more of the sequences of Table 6, including, SEQ ID NO: 2, 11, 16, 25, 30, 35, 39, and 44.

[0127] In one embodiment, the CPR has at least one extracellular domain, having at least 95% identity to any of the sequences of Table 7, including, SEQ ID NO: 3, 9, 53, 12, 54, 17, 55, 26, 31, 36, 40, or 45. In one embodiment, the CPR has at least one extracellular domain having 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to one or more of the sequences of Table 7, including, SEQ ID NO: 3, 9, 53, 12, 54, 17, 55, 26, 31, 36, 40, or 45.

[0128] In one embodiment, the CPR has at least one transmembrane domain, having at least 95% identity to any of the sequences of Table 8, including, SEQ ID NO: 4, 8, 13, 18, 27, 32, 37, 41, or 46. In one embodiment, the CPR has at least one transmembrane domain having 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to one or more of the sequences of Table 8, including, SEQ ID NO: 4, 8, 13, 18, 27, 32, 37, 41, or 46.

[0129] In one embodiment, the CPR has at least one cytoplasmic domain, having at least 95% identity to any of the sequences of Table 9, including, SEQ ID NO: 5, 7, 14, 19, 28, 33, 52, 42, or 47. In one embodiment, the CPR has at least one cytoplasmic domain having 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to one or more of the sequences of Table 9, including, SEQ ID NO: 5, 7, 14, 19, 28, 33, 52, 42, or 47.

[0130] In one embodiment, the CPR has at least one linker or targeting domain, having at least 95% identity to any of the sequences of Table 10, including, SEQ ID NO: 48, 49, 50, or 51. In one embodiment, the CPR has at least one linker or targeting domain having 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to one or more of the sequences of Table 10, including, SEQ ID NO: 48, 49, 50, or 51. 10131] In one embodiment, the CPR comprises a signal peptide, extracellular domain, a transmembrane domain and a cytoplasm domain.

[0132] In one embodiment, the CPR comprises an extracellular domain, a transmembrane domain and a cytoplasm domain. b. Domain swapping

[0133] In one embodiment, any of the domains in the ITAM and / or ITIM receptors in Tables 4 and 5, respectfully, may be replaced with domains from other ITAM and / or HIM receptors.

[0134] In one embodiment, the EC domain in the ITAM receptors in Table 4 may be replaced with domains from other ITAM and / or ITIM receptors. For example, the EC domain in the FCERG ITAM receptor may be replaced by a CLEC1 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the FCERG ITAM receptor may be replaced by a FCGR2 EC domain or a portion thereof in order to create a CPR For example, the EC domain in the FCERG ITAM receptor may be replaced by a GPVIA EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the FCERG ITAM receptor may be replaced by a LILRB2 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the FCERG ITAM receptor may be replaced by a PEC AMI EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the FCERG ITAM receptor may be replaced by a TLT1 EC domain or a portion thereof in order to create a CPR, For example, the EC domain in the FCERG ITAM receptor may be replaced by a CEACAM1 EC domain or a portion thereof in order to create a CPR.

[0135] For example, the TM domain in the FCERG ITAM receptor may be replaced by a CLEC1 IM domain or a portion thereof in order to create a CPR. For example, the TM domain in the FCERG ITAM receptor may be replaced by a FCGR2 TM' domain or a portion thereof in order to create a CPR. For example, the TM domain in the FCERG ITAM receptor may be replaced by a GPVIA TM' domain or a portion thereof in order to create a CPR. For example, the TM' domain in the FCERG ITAM receptor may be replaced by a LILRB2 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the FCERG ITAM receptor may be replaced by a PEC AMI TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the FCERG ITAM receptor may be replaced by a TLT1 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the FCERG IT AM receptor may be replaced by a CEACAM1 TM domain or a portion thereof in order to create a CPR. 10136] For example, the signal peptide in the FCERG ITAM receptor may be replaced by a CLEC1 signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the FCERG ITAM receptor may be replaced by a FCGR2 signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the FCERG ITAM receptor may be replaced by a GPVIA signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the FCERG ITAM receptor may be replaced by a LILRB2 signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the FCERG ITAM receptor may be replaced by a PEC AMI signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the FCERG ITAM receptor may be replaced by a TLT1 signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the FCERG ITAM receptor may be replaced by a CEACAM1 signal peptide or a portion thereof in order to create a CPR.

[0137] For example, the cytodomain in the FCERG ITAM receptor may be replaced by a CLEC1 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the FCERG ITAM receptor may be replaced by a FCGR2 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the FCERG ITAM receptor may be replaced by a GPVIA cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the FCERG ITAM receptor may be replaced by a LILRB2 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the FCERG ITAM receptor may be replaced by a PECAM1 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the FCERG ITAM receptor may be replaced by a TLT1 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the FCERG ITAM receptor may be replaced by a CEACAM1 cytodomain or a portion thereof in order to create a CPR.

[0138] For example, the EC domain in the CLECl ITAM receptor may be replaced by a FCGR2 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the CLECl ITAM receptor may be replaced by a GPVIA EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the CLECl ITAM receptor may be replaced by a L1LRB2 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the CLECl ITAM receptor may be replaced by a PECAM1 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the CLECl ITAM receptor may be replaced by a TLT1 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the CLECl ITAM receptor may be replaced by a CEACAM1 EC domain or a portion thereof in order to create a CPR.

[0139] For example, the TM domain in the CLEC1 ITAM receptor may be replaced by a FCERG TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the CLEC1 TEAM receptor may be replaced by a FCGR2 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the CLEC1 ITAM receptor may be replaced by a GPVIA TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the CLEC1 ITAM receptor may be replaced by a LILRB2 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the CLEC1 ITAM receptor may be replaced by a PEC AM I TAI domain or a portion thereof in order to create a CPR. For example, the TM domain in the CLECl ITAM receptor may be replaced by a TLT1 TM domain or a portion thereof in order to create a CPR. For example, the TAI domain in the CLEC1ITAAI receptor may be replaced by a CEACAM1 TAI domain or a portion thereof in order to create a CPR,

[0140] For example, the signal peptide in the CLEC1 ITAAI receptor may be replaced by a FCERG signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the CLECl ITAAI receptor may be replaced by a FCGR2 signal peptide or a portion thereof in order to create a CPR, For example, the signal peptide in the CLECl ITAAI receptor may be replaced by a GPVIA signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the CLEC1 ITAM receptor may be replaced by a LILRB2 signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the CLEC1 ITAAI receptor may be replaced by a PECAM1 signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the CLEC1 ITAM receptor may be replaced by a TLT1 signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the CLECl ITAAI receptor may be replaced by a CEACAM1 signal peptide or a portion thereof in order to create a CPR.

[0141] For example, the cytodomain in the CLECl ITAM receptor may be replaced by a FCERG cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the CLECl ITAAI receptor may be replaced by a FCGR2 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the CLECl ITAAI receptor may be replaced by a GPVIA cytodomain or a portion thereof in order to create a CPR. For exampie, the cytodomain in the CLEC1ITAM receptor may be replaced by a LILRB2 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the CLEC1 ITAM receptor may be replaced by a PEC AMI cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the CLEC1 ITAM receptor may be replaced by a TLT1 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the CLEC1 ITAM receptor may be replaced by a CEACAM1 cytodomain or a portion thereof in order to create a CPR.

[0142] For example, the EC domain in the FCGR2 ITAM receptor may be replaced by a CLEC1 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the FCGR2 ITAM receptor may be replaced by a GPVIA EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the FCGR2 ITAM receptor may be replaced by a LILRB2 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the FCGR2 ITAM receptor may be replaced by a PEC AMI EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the FCGR2 ITAM receptor may be replaced by a TLT1 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the FCGR2 ITAM receptor may be replaced by a CEACAM1 EC domain or a portion thereof in order to create a CPR.

[0143] For example, the TM domain in the FCGR2 ITAM receptor may be replaced by a FCER.G TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the FCGR2 ITAM receptor may be replaced by a CLEC1 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the FCGR2 ITAM receptor may be replaced by a GPVIA TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the FCGR2 ITAM receptor may be replaced by a LILRB2 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the FCGR2 ITAM receptor may be replaced by a PECAM1 IM domain or a portion thereof in order to create a CPR. For example, the TM domain in the FCGR2 ITAM receptor may be replaced by a TLT1 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the FCGR2 ITAM receptor may be replaced by a CEACAM1 TM' domain or a portion thereof in order to create a CPR.

[0144] For example, the signal peptide in the FCGR2 ITAM receptor may be replaced by a FCERG signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the FCGR2 TEAM receptor may be replaced by a CLEC1 signal peptide or a portion thereof in order to create a CPR. For exampie, the signal peptide in the FCGR2 IT AM receptor may be replaced by a GPVIA signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the FCGR2 ITAM receptor may be replaced by a LILRB2 signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the FCGR2ITAM receptor may be replaced by a PEC AMI signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the FCGR2 ITAM receptor may be replaced by a TLT1 signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the FCGR2 ITAM receptor may be replaced by a CEACAM1 signal peptide or a portion thereof in order to create a CPR.

[0145] For example, the cytodomain in the FCGR2 ITAM receptor may be replaced by a FCERG cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the FCGR2 ITAM receptor may be replaced by a CLEC1 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the FCGR2 ITAM receptor may be replaced by a GPVIA cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the FCGR2 ITAM receptor may be replaced by a LILRB2 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the FCGR2 ITAM receptor may be replaced by a PECAM1 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the FCGR2 ITAM receptor may be replaced by a TLT1 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the FCGR2 ITAM receptor may be replaced by a CEACAM1 cytodomain or a portion thereof in order to create a CPR.

[0146] For example, the EC domain in the GPVIA ITAM receptor may be replaced by a CLEC1 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the GPVIA ITAM receptor may be replaced by a FCGR2 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the GPVIA ITAM receptor may be replaced by a LILRB2 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the GPVIA ITAM receptor may be replaced by a PEC AMI EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the GPVIA ITAM receptor may be replaced by a TLT1 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the GPVIA ITAM receptor may be replaced by a CEACAM1 EC domain or a portion thereof in order to create a CPR.

[0147] For example, the TM domain in the GPVIAITAM receptor may be replaced by a FCERG TM domain or a portion thereof in order to create a CPR For example, the TM domain in the GPVIA ITAM receptor may be replaced by a CLEC1 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the GPVIA ITAM receptor may be replaced by a FCGR2 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the GPVIA ITAM receptor may be replaced by a LILRB2 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the GPVIA ITAM receptor may be replaced by a PECAM1 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the GPVIA ITAM receptor may be replaced by a TLT1 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the GPVIA ITAM receptor may be replaced by a CEACAM1 TM domain or a portion thereof in order to create a CPR.

[0148] For example, the signal peptide in the GPVIA ITAM receptor may be replaced by a FCERG signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the GPVIA ITAM receptor may be replaced by a CLEC1 signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the GPVIA ITAM receptor may be replaced by a FCGR2 signal peptide or a portion thereof m order to create a CPR. For example, the signal peptide in the GPVIA ITAM receptor may be replaced by a LILRB2 signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the GPVIA ITAM receptor may be replaced by a PEC AMI signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the GPVIA ITAM receptor may be replaced by a TLT1 signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the GPVIA ITAM receptor may be replaced by a CEACAM1 signal peptide or a portion thereof in order to create a CPR.

[0149] For example, the cytodomain in the GPVIA ITAM receptor may be replaced by a FCERG cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the GPVIA ITAM receptor may be replaced by a CLEC1 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the GPVIA ITAM receptor may be replaced by a FCGR2 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the GPVIA ITAM receptor may be replaced by a LILRB2 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the GPVIA ITAM receptor may be replaced by a PEC AMI cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the GPVIA IT AM receptor may be replaced by a TLT1 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the GPVIA IT AM receptor may be replaced by a CEACAM1 cytodomain or a portion thereof in order to create a CPR.

[0150] In one embodiment, the EC domain in the HIM receptors in Table 5 may be replaced with domains from other ITAM and / or ITIM receptors.

[0151] For example, the EC domain in the LILRB2 ITIM receptor may be replaced by a CLEC1 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the LILRB2 HIM receptor may be replaced by a GPVIA EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the LILRB2 HIM receptor may be replaced by a FCGR2 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the LILRB2 HIM receptor may be replaced by a PEC AMI EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the LILRB2 ITIM receptor may be replaced by a TLT1 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the LILRB2 HIM receptor may be replaced by a CEACAM1 EC domain or a portion thereof in order to create a CPR.

[0152] For example, the TM domain in the LILRB2 ITIM receptor may be replaced by a FCERG TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the LILRB2 HIM receptor may be replaced by a CLECl TAI domain or a portion thereof in order to create a CPR. For example, the TM domain in the LILRB2 ITIM receptor may be replaced by a GPVIA TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the LILRB2 ITIM receptor may be replaced by a FCGR2 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the LILRB2 ITIM receptor may be replaced by a PECAM1 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the LILRB2 ITIM receptor may be replaced by a TLT1 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the LILRB2 HIM' receptor may be replaced by a CEACAM1 TM' domain or a portion thereof in order to create a CPR.

[0153] For example, the signal peptide in the LILRB2 HIM receptor may be replaced by a FCERG signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the LILRB2 ITIM receptor may be replaced by a CLECl signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the LILRB2 ITIM receptor may be replaced by a GPVIA signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the LILRB2ITIM receptor may be replaced by a FCGR2 signal peptide or a portion thereof in order to create a CPR For example, the signal peptide in the LILRB2 ITIM receptor may be replaced by a PEC AMI signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the LILRB2 ITIM receptor may be replaced by a TLT1 signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the LILRB2 ITIM receptor may be replaced by a CEACAM1 signal peptide or a portion thereof in order to create a CPR.

[0154] For example, the cytodomain in the LILRB2 ITIM receptor may be replaced by a FCERG cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the LILRB2 ITIM receptor may be replaced by a CLECl cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the LILRB2 ITIM receptor may be replaced by a GPVIA cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the LILRB2 ITIM receptor may be replaced by a FCGR2 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the LILRB2 ITIM receptor may be replaced by a PECAM1 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the LILRB2 ITIM receptor may be replaced by a TLT1 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the LILRB2 ITIM receptor may be replaced by a CEACAM1 cytodomain or a portion thereof in order to create a CPR.For example, the EC domain in the PECAM1 ITIM receptor may be replaced by a CLECl EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the PEC AMI ITIM receptor may be replaced by a GPVIA EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the PEC AMI ITIM receptor may be replaced by a FCGR2 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the PECAM1 ITIM receptor may be replaced by a LILRB2 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the PECAM1 ITIM receptor may be replaced by a TLT1 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the PECAM1 ITIM receptor may be replaced by a CEACAM1 EC domain or a portion thereof in order to create a CPR.

[0155] For example, the TM domain in the PECAM1 ITIM receptor may be replaced by a FCERG TM' domain or a portion thereof in order to create a CPR. For example, the TM domain in the PEC AMI ITEM receptor may be replaced by a CLECl TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the PECAM1 ITIM receptor may be replaced by a GPVIA TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the PECAM1 ITEM receptor may be replaced by a FCGR2 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the PEC AMI ITIM receptor may be replaced by a LILRB2 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the PECAM1 ITIM receptor may be replaced by a TLT1 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the PEC AMI ITIM receptor may be replaced by a CEACAM1 TM domain or a portion thereof in order to create a CPR.

[0156] For example, the signal peptide in the PECAM1 ITIM receptor may be replaced by a FCERG signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the PECAM1 HIM receptor may be replaced by a CLEC1 signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the PECAM1 ITIM receptor may be replaced by a GPVIA signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the PEC AMI ITIM receptor may be replaced by a FCGR2 signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the PEC AMI ITIM receptor may be replaced by a LILRB2 signal peptide or a porti on thereof in order to create a CPR. For example, the signal peptide in the PEC AMI ITIM receptor may be replaced by a TLT1 signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the PECAM1 ITIM receptor may be replaced by a CEACAM1 signal peptide or a portion thereof in order to create a CPR.

[0157] For example, the cytodomain in the PECAM1 ITEM receptor may be replaced by a FCERG cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the PEC AMI ITIM receptor may be replaced by a CLECl cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the PECAM1 ITIM receptor may be replaced by a GPVIA cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the PECAM1 ITIM receptor may be replaced by a FCGR2 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the PECAM1 HIM receptor may be replaced by a LILRB2 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the PECAM1 ITIM receptor may be replaced by a TLT1 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the CEACAM1 ITIM receptor may be replaced by a CEACAM1 cytodomain or a portion thereof in order to create a CPR.

[0158] For example, the EC domain in the CEACAMl ITIM receptor may be replaced by a CLEC1 EC domain or a portion thereof in order to create a CPR For example, the EC domain in the CEACAMl ITIM receptor may be replaced by a GPVIA EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the CEACAMl ITIM receptor may be replaced by a FCGR2 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the CEACAM1 ITIM receptor may be replaced by a LILRB2 EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the CEACAM1 ITIM receptor may be replaced by a PEC AMI EC domain or a portion thereof in order to create a CPR. For example, the EC domain in the CEACAM1 HIM receptor may be replaced by a TLT1 EC domain or a portion thereof in order to create a CPR.

[0159] For example, the TM domain in the CEACAM1 ITIM receptor may be replaced by a FCERG TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the CEACAM1 ITIM receptor may be replaced by a CLEC1 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the CEACAM1 ITIM receptor may be replaced by a GPVIA TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the CEACAM1 HIM receptor may be replaced by a FCGR2 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the CEACAMl ITIM receptor may be replaced by a LILRB2 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the CEACAM1 ITIM receptor may be replaced by a PECAM1 TM domain or a portion thereof in order to create a CPR. For example, the TM domain in the CEA CAM! ITIM receptor may be replaced by a TLT1 TM domain or a portion thereof in order to create a CPR.

[0160] For example, the signal peptide in the CEACAMl ITIM receptor may be replaced by a FCERG signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the CEACAMl ITIM receptor may be replaced by a CLEC1 signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the CEACAM1 ITIM' receptor may be replaced by a GPVIA signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the CEACAMl ITIM receptor may be replaced by a FCGR2 signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the CEACAM1 ITIM receptor may be replaced by a LILRB2 signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the CEACAMl ITIM receptor may be replaced by a PECAM1 signal peptide or a portion thereof in order to create a CPR. For example, the signal peptide in the CEACAM1ITIM receptor may be replaced by a TLT1 signal peptide or a portion thereof in order to create a CPR. 10161] For example, the cytodomain in the CEACAM1 ITIM receptor may be replaced by a FCERG cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the CEACAM1 HIM receptor may be replaced by a CLEC1 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the CEACAM1 HIM receptor may be replaced by a GPVIA cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the CEACAM1 HIM receptor may be replaced by a FCGR2 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the CEACAM1 ITIM receptor may be replaced by a LILRB2 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the CEACAM1 ITIM receptor may be replaced by a PECAM1 cytodomain or a portion thereof in order to create a CPR. For example, the cytodomain in the CEACAM1 ITIM receptor may be replaced by a TLT1 cytodomain or a portion thereof in order to create a CPR.

[0162] In some embodiments, the signal peptide, EC domain, TM domain, or cytodomain of an ITIM or ITAM reception may be replaced by a portion of a domain from a different receptor. The portion may have a length within the range of 10-30, 10-15, 10-20, 10-25, 15-20, 15-25, 15-30, 2025, or 20-30 nucleotides. The portion may be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides of any of the sequences in Tables 6-10 herein, for example, but not limited to, SEQ ID NO: 1-55. In certain embodiments, an EC domain from a CLEC1 ITAM receptor is SEQ ID NO: 53. In certain embodiments, an EC domain from a FCGR2 ITAM receptor is SEQ ID NO: 54. In certain embodiments, an EC domain from a GPVIA ITAM receptor is SEQ ID NO: 55. 2. Antibodies or fragments thereof

[0163] The CPR may include a region comprising any ligand or fragment thereof or epitope that recognizes and binds to a target, for example, a neoantigen on tumor cells, with high specificity and affinity. The region of the CPR may be an antibody or variants thereof or a variant or fragment thereof that can bind to the target on tumor cells such as a tumor specific antigen (TSA), or recognition components such as a linked cytokine that leads to recognition of target cells bearing the cytokine receptor, or a natural ligand of a receptor or fragment thereof. In some embodiments, the CPR of the engineered platelets described herein may be a scFv. An antibody, variant, or fragment thereof can be generated using routine recombinant DNA technology techniques known in the art.

[0164] In some embodiments, the engineered platelets comprise a CPR with a region including an antibody or an antibody fragment to bind a target of interest. For example, the CPR may include a variable heavy chain domain of an antibody. For example, the CPR may include a variable light chain domain of an antibody. Alternatively, the CPR of the engineered platelets may include a kappa light chain or a fragment thereof targeting CD 19.

[0165] In some embodiments, the antibody or the antibody fragment thereof is chosen from Table 11. The antibodies are listed with their DrugBank identifier (DB ID). Table 11. Antibodies for use in chimeric receptors Antibody (Given Name) IGMT / mAb-BB 1» INN (International Nonproprietary Name) INN Number Abagovomab 111 abagovomab 8659 Abciximab 146 abciximab 7200 Abituzumab 489 abituzumab 9509 rkbrezekimab 804 abrezekimab 10745 Abrilumab 495 abrilumab 9921 Actoxumab 410 actoxumab 9568 Adali mumab 165 adalimumab 7860 Adecatumumab 164 adecatumumab 8449 Atidortoxumab 763 atidortoxumab 10638 Aducanumab 479 aducanumab 9838 Afasevikumab 576 afasevikumab 10178 Afelimomab 128 afelimomab 7340 Alemtuzumab 11 alemtuzumab 8005 Alirocumab 412 alirocumab 9620 Amatuximab 64 amatuximab 9343 Anatumomab mafenato x 287 anatumo mab mafenato x 7655 Andecaliximab 533 andecaliximab 10035 Anetumab ravtansine 471 anetumab ravtansine 9788 Anifrolumab 474 anifrolumab 9800 Anrukinzumab 231 anrukinzumab 8942 Apolizumab 18 apolizumab 8210 Apmtumab ixadotin 656 aprutumab ixadotin 10383 Arcitumomab 113 arcitumomab 7417 Ascrinvacumab 561 ascrinvacumab 10106 Aselizumab 272 aselizumab 8291 Atezolizumab 526 atezolizumab 9814 Atinumab 358 atinumab 9336 Atorolirnumab 308 atorolirnumab 7647 Avelumab 512 avelumab 10062 Azintuxizumab vedotin 721 azintuxizumab vedotin 10499 Bapineuzumab 252 bapineuzumab 8624 Basiliximab 148 basiliximab 7578 Bavituximab 149 bavituximab 8734 Bectumomab 306 bectumomab 7514 Begelomab 503 begelomab 9959 Belantamab mafodotin 784 belantamab mafodotin 10754 Belimumab 266 belimumab 8381 Bemarituzumab 770 bemarituzumab 10681 Benralizumab 334 benralizumab 9233 Berlimatoxumab 764 berlimatoxumab 10639 Bersanlimab 800 bersanlimab 10709 Bertilimumab 170 beriilimumab 8332 Besilesomab 258 besilesomab 8451 Bevacizumab 24 bevacizumab 8017 Bezlotoxumab 411 bezlotoxumab 9608 Biciromab 131 biciromab 6867 Bimagnimab 456 bimagnimab 9711 Bimekizumab 486 bimekizumab 9878 Birtamimab 619 birtamimab 10198 Bleselumab 563 bleselumab 10114 Blinatumomab 101 blinatumomab 9028 Blontuvetmab 593 blontuvetmab 10194 Blosozumab 375 blosozumab 9440 Bococizumab 485 bococizumab 9840 Brazikumab 664 brazikumab 10425 Brentuximab vedotin 324 brentuximab vedotin 9144 Biiakinumab 162 briakiiiumab 9153 Brodalumab 376 brodalumab 9475 Brolucizumab 536 brolucizumab 10053 Brontictuzumab 492 brontictuzumab 9982 Burosumab 647 burosumab 10301 Cabiralizumab 587 cabiralizumab 10121 Camidanlumab tesirine 775 camidanlumab tesirine 10592 Camrelizumab 659 camrelizumab 10400 Canakinumab 244 canakinumab 8836 Cantuzumab mertansine 52 cantuzumab mertansine 8223 Cantuzumab ravtansine 387 cantuzumab ravtansine 9441 Caplacizumab 401 caplacizumab 9511 Carlumab 359 carlumab 9372 Carotuximab 605 carotuximab 10244 Catumaxomab 218 catumaxomab 8406 Cedelizumab 78 cedelizumab 7567 CemipJimab 846 cemiplimab 10691 Cergutuzumab amunaleukin 555 cergutuzumab amunaleukin 10080 Certolizumab pegol 242 certolizumab pegol 8448 Cetrelimab 809 cetrelimab 10757 Cetuximab 151 cetuximab 7906 Cibisatamab 795 cibisatamab 10636 Citatuzumab bogatox 236 citatuzumab bogatox 9046 Cixutumumab 290 cixutumumab 9099 Clazakizumab 414 clazakizumab 9599 Clenoliximab 152 clenoliximab 7615 Clivatuzumab tetraxetan 560 clivatuzumab tetraxetan 10103 Codrituzumab 466 codrituzumab 9759 Cofetuzumab peiidotin 777 cofetuzumab peiidotin 10674 Coltuximab ravtansine 490 coltuximab ravtansine 9558 Conatumumab 224 conatumumab 9029 Concizumab 447 concizumab 9636 Cosfroviximab 726 cosfroviximab 10535 Crenezumab 378 crenezumab 9482 Crizanlizumab 667 crizanlizumab 10316 Crotedumab 595 crotedumab 10196 Cusatuzumab 792 cusatuzumab 10558 Dacetuzumab 232 dacetuzumab 8959 Daclizumab 36 daclizumab 7164 Dalotuzumab 333 dalotuzumab 9200 Dapirolizumab pegol 481 dapirolizumab pegol 9869 Daratumumab 301 daratumumab 9128 Dectrekumab 537 dectrekumab 10059 Demcizumab 415 demcizumab 9572 Denintuzumab mafodotin 493 denintuzumab mafodotin 9886 Denosumab 249 denosumab 8653 Depatuxizumab mafodotin 645 depatuxizumab mafodotin 10263 Detumomab 313 detumomab 7156 Dezamizumab 652 dezamizumab 10364 Dinutuximab 464 dinutuximab 9754 Diridavumab 494 diridavumab 9922 Domagrozumab 610 domagrozumab 10286 Dorlimomab aritox 207 dorlimomab aritox 6516 Dostariimab 849 dostariimab 10787 Drozitumab 348 drozitumab 9255 Duligotuzumab 416 duligotuzumab 9646 Dupilumab 449 dupilumab 9669 Dunalumab 528 durvalumab 10010 Dusigitumab 451 dusigitumab 9679 Duvortuxizumab 640 duvortuxizumab 10506 Ecromeximab 274 ecromeximab 8239 Eculizumab 37 eculizumab 8231 Edobacomab 118 edobacomab 7056 Edrecolomab 119 edrecolomab 7471 Efalizumab 38 efalizumab 8122 Efungumab 173 efungumab 8658 Eldelumab 463 eldelumab 9746 Elezanumab 650 elezanumab 10344 Elgemtumab 534 elgemtumab 10041 Elotuzumab 291 elotuzumab 9074 Elsilimomab 268 elsilimomab 8371 Emactuzumab 501 emactuzumab 9951 Emapalumab 666 emapalumab 10319 Emibetuzumab 496 emibetuzumab 9932 Emicizumab 564 emicizumab 10115 Enapotamab vedotin 814 enapotamab vedotin 10769 Enavatuzumab 360 enavatuzumab 9354 Enfortumab vedo tin 476 enfortumab vedotin 9821 Enlimomab pegol 317 enlimomab pegol 7525 Enoblituzumab 590 enoblituzumab 10165 Enokizumab 361 enokizumab 9262 Enoticumab 417 enoticumab 9575 Ensituximab 349 ensituximab 9300 Epitumomab cituxetan 269 epitumomab cituxetan 8372 Epratuzumab 40 epratuzumab 7920 Eptinezumab 648 eptinezumab 10308 Erenumab 618 erenumab 10296 Erlizumab 280 erlizumab 8076 Ertumaxomab 219 ertumaxomab 8407 Etaracizumab 240 etaracizumab 8862 Etigilimab 803 etigilimab 10742 Etrolizumab 362 etrolizumab 9290 Evinacumab 529 evinacumab 10013 Evolocumab 448 evolocumab 9643 Exbivirumab 262 exbivirumab 8536 Faralimomab 305 faralimomab 7496 Faricimab 793 faricimab 10563 Farletuzumab 292 farletuzumab 9067 Fasinumab 418 fasinumab 9589 Felvizumab 86 felvizumab 7623 Fezakinumab 323 fezakinumab 9137 Fidatuzumab 379 fidatuzumab 9465 Figitumumab 293 figitumumab 9085 Firivumab 506 firivumab 9975 Flanvotumab 403 flanvotumab 9520 Fletikumab 480 fletikumab 9876 Flotetuzumab 679 flotetuzumab 10569 Fontolizumab 43 fontolizumab 8264 Foralumab 350 foralumab 9309 Foravirumab 90 foravirumab 9053 Fremanezumab 646 fremanezumab 10299 Fresolimumab 174 fresolimumab 9158 Frovocimab 850 frovocimab 10859 Frunevetmab 717 franevetmab 10440 Fulranumab 363 fulranumab 9373 Futuximab 419 futuximab 9612 Galcanezumab 609 galcanezumab 10277 Galiximab 154 galiximab 8339 Gancotamab 865 gancotamab 10562 Ganitumab 168 ganitumab 9323 Gantenerumab 223 gantenerumab 8894 Gatipotuzumab 740 gatipotuzumab 10336 Gavilimomab 112 gavilimomab 8060 Gedivumab 719 gedivumab 10459 Gemtuzumab ozogamicin 649 gemtuzumab ozogamicin 10315 Gevokizumab 102 gevokizumab 9310 Gilvetmab 725 gilvetmab 10528 Gimsilumab 756 gimsilumab 10534 Girentuximab 328 girentuximab 9116 Glembatumumab vedotin 565 glembatumumab vedotin 10123 Golimumab 175 golimumab 8497 Gosuranemab 851 gosuranemab 10663 Guselkumab 468 guselkumab 9774 lanalumab 758 ianalumab 10580 Ibalizumab 241 ibalizumab 8818 Ibritumomab tiuxetan 122 ibritumomab tiuxetan / 8 / 3 Icrucumab 365 icrucumab 9370 Idarucizumab 462 idarucizumab 9698 Ifabotuzumab 572 ifabotuzumab 10149 Igovomab 123 igovomab 7433 Uadatuzumab vedotin 774 Uadatuzumab vedotin 10647 Imalumab 504 imalumab 9961 Imaprelimab 808 imaprelimab 10753 Imciromab 124 imciromab 6605 Imgatuzumab 420 imgatuzumab 9598 Inclacumab 402 inclacumab 9512 Indatuximab ravtansine 389 indatuximab ravtansine 9486 Indusatumab vedotin 532 indusatumab vedotin 10033 Inebilizumab 553 inebilizumab 9985 Infliximab 156 infliximab 7602 Intetumumab 321 intetumumab 9134 Inolimomab 126 inolimomab 7253 Inotuzumab ozogamicin 259 inotuzumab ozogamicin 8574 Ipilimumab 180 ipilimumab 8568 Iratumumab 250 iratumumab 8713 Isatuximab 539 isatuximab 10068 Iscalimab 799 iscalimab 10707 Istiratumab 545 istiratumab 10431 Itolizumab 351 itolizumab 9321 Ixekizumab 380 ixekizumab 9467 Keliximab 157 keliximab 7560 Labetuzumab 62 labetuzumab 8127 Lacnotuzumab 724 lacnotuzumab 10524 Ladiratuzumab vedotin 7^3 ladiratuzumab vedotin 10625 Lampalizumab 421 lampalizumab 9578 Lanadelumab 607 lanadelumab 10265 Landogrozumab 578 landogrozumab 10188 Laprituximab emtansine 600 laprituximab emtansine 10236 Larcaviximab 728 larcaviximab 10537 Lebrikizumab 325 lebrikizumab 9165 Lemalesomab 281 lemalesomab 8046 Lenvervimab 805 lenvervimab 10746 Lenzilumab 505 lenzilumab 9965 Lerdelimumab 182 lerdelimumab 7882 Leronlimab 807 leronlimab 10751 Lesofavumab 718 lesofavumab 10458 Letolizumab 715 letolizumab 10436 Lexatumumab 183 lexatumumab 8753 Libivirumab 263 libivirumab 8481 Lifastuzumab vedotin 478 lifastuzumab vedotin 9835 Ligelizumab 422 ligelizumab 9653 Loncastuximab tesirine 749 loncastuximab tesirine 10586 Losatuxizumab vedotin 712 losatuxizumab vedotin 10342 Lintuzumab 53 lintuzumab 7580 Liriiumab 423 liriiumab 9415 Lodelcizumab 461 lodelcizumab 9733 Lokivetmab 527 lokivetmab 10002 Lorv o tuzumab me rtans ine 58 lorvotuzumab mertansine 9299 Lucatumumab 176 lucatumumab 8887 Lulizumab pegol 499 lulizumab pegol 9940 Lumiliximab 158 lumiliximab 8443 Lumretuzumab 502 lumretuzumab 9952 Lupartumab amadotin 665 lupartumab amadotin 10257 Lutikizumab 651 lutikizumab 10347 Mapatumumab 184 mapatumumab 8635 Margetuximab 473 margetuximab 9799 Marstacimab 852 marstacimab 10789 Maslimomab 318 maslimomab 6614 Mavrilimumab 335 mavrilimumab 9234 Matuzumab 39 matuzumab 8103 Mepolizumab 87 mepolizumab 7876 Metelimumab 186 metelimumab 8087 Milatuzumab 135 milatuzumab 8922 Minretumomab 309 minretumomab 7821 Mirikizumab 767 mirikizumab 10657 Mirvetuximab soravtansi ne 575 mirvetuximab soravtansine 10176 Mitumomab 130 mitumomab 7934 Modotuximab 433 modotuximab 9613 Mogamulizumab 366 mogamulizumab 9374 Monalizumab 562 monalizumab 10113 Morolimumab 311 morolimumab 7646 Mo sunetuzumab 760 mo sunetuzumab 10621 Motavizumab 73 motavizumab 8693 Moxetumomab pasudotox 198 moxetumomab pasudotox 9236 Muro mo nab -CD 3 132 muromonab-CD3 6281 Nacolomab tafenatox 316 nacolomab tafenatox 7227 Namilumab 367 namilumab 9382 Naptumomab estafenatox 65 naptumomab estafenatox 8598 Naratuximab emtansine 602 naratuximab emtansine 10238 Namatumab 381 namatumab 9447 Natalizumab 75 natalizumab 7716 Navicixizumab 597 navicixizumab 10220 Navivumab 551 navivumab 9976 Nebacumab 193 nebacumab 6658 Necitumumab 294 necitumumab 9083 Nemolizumab 538 nemolizumab 10064 Nerelimomab 307 nerelimomab 7546 Nesvacumab 452 nesvacumab 9688 Netakimab 790 netakimab 10387 Nimotuzumab 76 nimotuzumab 8545 Nirsevimab 853 nirsevimab 10780 Nivolumab 424 nivolumab 9623 Obiltoxaximab 549 obiltoxaximab 9825 Obinutuzumab 238 obinutuzumab 9043 Ocaratuzumab 425 ocaratuzumab 9590 Ocrelizumab 227 ocrelizumab 8636 Odulimomab 134 odulimomab 7364 Ofatumumab 194 ofatumumab 8606 Olaratumab 352 olaratumab 9308 Oleclumab 729 oleclumab 10545 Olendalizumab 585 olendalizumab 10037 Olokizumab 353 olokizumab 9333 Omalizumab 77 omalizumab 8039 Omburtamab 855 omburtamab 10803 Onartuzumab 368 onartuzumab 9368 Ontuxizumab 491 ontuxizumab 9519 Onvatilimab 810 onvatilimab 10758 Opicinumab 557 opicinumab 10090 Oportuzumab monatox 237 oportuzumab monatox 9045 Oregovomab 136 oregovomab 8183 Orticumab 426 orticumab 9635 Otelixizumab 235 otelixizumab 8864 Otilimab 189 otilimab 10783 Otlertuzumab 488 otlertuzumab 9832 Oxelumab 354 oxelumab 9320 Ozanezumab 454 ozanezumab 9703 Ozoralizumab 382 ozoralizumab 9369 Pagibaximab 253 pagibaximab 8643 Palivizumab 79 palivizumab 7753 Panuevlumab 554 pamrevlumab 10060 Panitumumab 196 panitumumab 8499 Panobacumab 243 panobacumab 8888 Parsatuzumab 427 parsatuzumab 9647 Pascolizumab 88 pascolizumab 8227 Pasotuxizumab 498 pasotuxizumab 9937 Pateclizumab 383 pateclizumab 9428 Patritumab 407 patritumab 9549 Pembrolizumab 472 pembrolizumab 9798 Perakizumab 428 perakizumab 9648 Pertuzumab 80 pertuzumab 8380 Pexelizumab 81 pexelizumab 8153 Pidilizumab 453 pidilizumab 9689 Pinatuzumab vedotin 457 pinatuzumab vedotin 9713 Placulumab 429 placulumab 9567 Plozabzumab 566 plozalizumab 10124 Polatuzumab vedotin 458 polatuzumab vedotin 9714 Ponezumab 369 ponezumab 9322 Porgaviximab 727 porgaviximab 10536 Prasinezumab 769 prasinezumab 10680 Priliximab 160 priliximab 7263 Pritoxaximab 459 pritoxaximab 9723 Pritumumab 270 pritumumab 8132 Quilizumab 406 quilizumab 9541 Racotumomab 225 racotumomab 8998 Radretumab 370 radretumab 9340 Rafivimmab 94 rafivimmab 9052 Ralpancizumab 484 ralpancizumab 9841 Ramucirumab 295 ramucimmab 9098 Ranevetmab 663 ranevetmab 10422 Ranibizumab 84 ranibizumab 8313 Raxibacumab 260 raxibacumab 8580 Ravagalimab 806 ravagalimab 10750 Ravulizumab 674 ravulizumab 10659 Refanezumab 591 refanezumab 10174 Regavirumab 197 regavirumab 7250 Relatlimab 781 relatlimab 10735 Remtolumab 517 remtolumab 10345 Reslizumab 279 reslizumab 8106 Rilotumumab 302 rilotumumab 9123 Rinucumab 574 rinucumab 10175 Risankizumab 567 risankizumab 10128 Rituximab 161 rituximab 7609 Rivabazumab pegol 106 rivabazumab pegol 10144 Robatumumab 296 robatumumab 9092 Roledumab 355 roledumab 9335 Romilkimab 794 romilkimab 10622 Romosozumab 404 romosozumab 9533 Rontalizumab 327 rontalizumab 9114 Rosmantuzumab 660 rosmantuzumab 10415 Rovalpituzumab tesirine 569 rovalpituzumab tesirine 10141 Rovelizumab 304 rovelizumab 7869 Rozanol ixizumab 642 rozanolixizumab 10213 Ruplizumab 17 ruplizumab 8014 Sacituzumab govitecan 559 sacituzumab govitecan 10097 Samalizumab 356 samalizumab 9307 Samrotamab vedotin 815 samrotamab vedotin 10791 Sarilumab 400 sarilumab 9476 Satralizumab 586 satralizumab 10065 Secukinumab 326 secukinumab 9182 Selicrelumab 723 selicrelumab 10523 Seribantumab 455 seribantumab 9710 Setoxaximab 460 setoxaximab 9724 Setrusumab 632 setrusumab 10539 Sevirumab 83 sevinimab 6560 Sibrotuzumab 285 sibrotuzumab 7866 Sifalimumab 322 sifalimumab 9135 Siltuximab 297 siltuximab 9051 Simtuzumab 430 simtuzumab 9626 Siplizumab 71 siplizumab 8251 Sirtratumab vedotin 772 sirtratumab vedotin 10467 Sirukumab 384 sirukumab 9431 Sofituzumab vedotin 482 sofituzumab vedotin 9861 Solanezumab 298 solanezumab 9097 Solitomab 405 solitomab 9537 Sontuzumab 251 sontuzumab 8438 Spartalizumab 761 spartalizumab 10624 Stamulumab 192 stamulumab 8683 Sulesomab 139 sulesomab 7519 Suptavumab 621 suptavumab 10303 Sutimlimab 802 sutimlimab 10737 Suvizumab 330 suvizumab 9185 Suviatoxumab 716 suviatoxumab 10441 Tabalumab 385 tabalumab 9430 Tadocizumab 103 tadocizumab 8651 Talacotuzumab 754 talacotuzumab 10508 Talizumab 271 talizumab 8370 Tamtuvetmab 594 tamtuvetmab 10195 Tanezumab 230 tanezumab 8941 Taplitumomab paptox 282 taplitumomab paptox 8047 Tarextumab 467 tarextumab 9762 Tavolimab 662 tavolimab 10420 Tefibazumab 261 tefibazumab 8500 Telimomab aritox 320 telimomab aritox 6345 Telisotuzumab vedotin 653 telisotuzumab vedotin 10365 Tenatumomab 226 tenatumomab 8832 Teneliximab 276 teneliximab 8211 Teplizumab 92 teplizumab 8869 Tepoditamab 812 tepoditamab 10766 Teprotumumab 336 teprotumumab 9107 Tesidolumab 535 tesidolumab 10051 Tezepeiumab 573 tezepeiumab 10172 Tibulizumab 776 tibulizumab 10656 Tildrakizumab 450 tildrakizumab 9672 Tigatuzumab 234 tigatuzumab 8979 Timigutuzumab 739 timigutuzumab 10335 Timolumab 606 timolumab 10248 Tislelizumab tislelizumab 10553 Tisotumab vedotin 571 tisotumab vedotin 10148 Tocilizumab 96 tocilizumab 8394 Tomuzotuximab 738 tomuzotuximab 10334 Toralizumab 60 toralizumab 8232 Tosatoxumab 465 tosatoxumab 9757 Tositumomab 142 tositumomab 7827 Tovetumab 469 tovetumab 9778 Tralokinumab 171 tralokinumab 9235 Trastuzumab 97 trastuzumab 7637 Trastuzumab emtansine 357 trastuzumab emtansine 9295 Tregalizumab 371 tregalizumab 9413 Tremelimumab 248 tremelimumab 8716 Trevogrumab 556 trevogrumab 10087 Tucotuzumab celmo leukin 254 tucotuzumab celmoleukin 8652 Tuvirumab 169 tuvirumab 6559 Ublituximab 372 ublituximab 9334 Ulocuplumab 483 ulocuplumab 9854 Urelumab 373 urelumab 9365 Urtoxazumab 265 urtoxazumab 8276 Ustekinumab 172 ustekinumab 8954 Utomilumab 657 utomilumab 10385 Vadastuximab talirine 552 vadastuximab talirine 9983 Vandortuzumab vedotin 531 vandortuzumab vedotin 10018 Vantictumab 470 vantictumab 9779 Vanucizumab 500 vanucizumab 9950 Vapaliximab 277 vapaliximab 8207 Varisacumab 714 varisacumab 10427 Varlilumab 497 varlilumab 9933 Vatelizumab 386 vatelizumab 9439 Vedolizumab 300 vedolizumab 9093 Veltuzumab 21 veltuzumab 8932 Vepalimomab 310 vepalimomab 7757 Vesencumab 374 vesencumab 9380 Visilizumab 100 visilizumab 8054 Vobarilizumab 523 vobarilizumab 10210 Volociximab 256 volociximab 8600 Vonlerolizumab 608 vonlerolizumab 10272 Vopratelimab 801 vopratelimab 10730 Vo rsetuzumab mafodo tin 432 vorsetuzumab mafodotin 9610 Votumumab 199 votumumab 7165 Vunakizumab 658 vunakizumab 10399 Xentuzumab 588 xentuzumab 10129 Zalutumumab 200 zalutumumab 8605 Zanolimumab 201 zanolimumab 8298 Zenocutuzumab 771 zenocutuzumab 10687 Ziralimumab 8 ziralimumab 8061 Zolbetuximab 753 zolbetuximab 10473 Zolimomab aritox 314 zolimomab aritox 7055

[0166] In some embodiments, the antibody may target or bind an antigen associated with a disease, disorder, or condition. Further, the antibody or antibody fragment may be effective in the treatment of the disease, disorder, or condition by binding the target antigen. In some embodiments, the target of the antibody may be used to identify or describe said antibody. For example, 3F8 targets GD2 ganglioside for treatment of neuroblastoma. For example, 8H9 targets B7-H3 for treatment of neuroblastoma, sarcoma, metastatic brain cancers. For example, Abagovomab targets CA-125 (imitation) for treatment of ovarian cancer. For example, Abciximab targets CD41 (integrin alpha-nb) for treatment of platelet aggregation inhibitor. For example, Abituzumab targets CD51 for treatment of cancer. For example, Abrezekimab targets interleukin 13. For example, Abrilumab targets integrin a4p7 for treatment of inflammatory bowel disease, ulcerative colitis, Crohn's disease. For example, Actoxumab targets Clostridium difficile for treatment of Clostridium difficile colitis. For example, Adalimumab targets TNF-a for treatment of Rheumatoid arthritis, Crohn's disease, Plaque Psoriasis, Psoriatic Arthritis, Ankylosing Spondylitis, Juvenile Idiopathic Arthritis, Hemolytic disease of the newborn. For example, Adecatumumab targets EpCAM for treatment of prostate and breast cancer. For example, Atidortoxumab targets Staphylococcus aureusalpha toxin. For example, Aducanumab targets beta-amyloid for treatment of Alzheimer's disease. For example, Afasevikumab targets IL17A and IL17F for treatment of multiple sclerosis. For example, Afelimomab targets TNF-a for treatment of sepsis. For example, Alacizumab pego targets VEGFR2 for treatment of cancer. For example, Alemtuzumab targets CD52 for treatment of Multiple sclerosis. For example, Alirocumab targets PCSK9 for treatment of hypercholesterolemia. For example, Altumomab pentetate targets CEA for treatment of colorectal cancer (diagnosis). For example, Amatuximab targets mesothelin for treatment of cancer. For example, Anatumomab mafenatox targets TAG-72 for treatment of non-small cell lung carcinoma. For example, Andecaliximab targets gelatinase B for treatment of gastric cancer or gastroesophageal junction adenocarcinoma. For example, Anetumab ravtansine targets MSLN for treatment of cancer. For example, Anifrolumab targets interferon a / 'P receptor for treatment of systemic lupus erythematosus. For example, Anrukinzumab targets IL-13 for treatment of asthma. For example, Apolizumab targets HLA-DR for treatment of hematological cancers. For example, Aprutumab ixadotin targets FGFR2. For example, Arcitumomab targets CEA for treatment of gastrointestinal cancers (diagnosis). For example, Ascrinvacumab targets activin receptor-like kinase 1 for treatment of cancer. For example, Aselizumab targets L-selectin (CD62L) for treatment of severely injured patients. For example, Atezolizumab targets PD-L1 for treatment of cancer. For example, Atinumab targets RTN4. For example, Atorolimumab targets Rhesus factor for treatment of hemolytic disease of the newborn[citation needed]. For example, Avelumab targets PD-L1 for treatment of cancer. For example, Azintuxizumab vedotin targets CD319 for treatment of cancer. For example, Bapineuzumab targets beta amyloid for treatment of Alzheimer's disease. For example, Basiliximab targets CD25 (a chain of IL-2receptor) for treatment of prevention of organ transplant rejections. For example, Bavituximab targets phosphatidyl serine for treatment of cancer, viral infections. For example, BCD-100 targets PD-1 for treatment of melanoma. For example, Bectumomab targets CD22 for treatment of non-Hodgkin's lymphoma (detection). For example, Begelomab targets DPP4. For example, Belantamab mafodotin targets BCMA for treatment of cancer. For example, Belimumab targets BAFF for treatment of non-Hodgkin lymphoma. For example, Bemarituzumab targets FGFR2 for treatment of gastric cancer or gastroesophageal junction adenocarcinoma. For example, Benralizumab targets CD125 for treatment of asthma. For example, Berlimatoxumab targets Staphylococcus aureus bi-component leukocidin. For example, Bermekimab targets ILLA for treatment of colorectal cancer. For example, Bersanlimab targets ICAM-1. For example, Bertihmumab targets CCL11 (eotaxin-1) for treatment of severe allergic disorders. For example, Besilesomab targets CEA-related antigen for treatment of inflammatory lesions and metastases (detection). For example, Bevacizumab targets VEGF-A for treatment of metastatic cancer, retinopathy of prematurity. For example, Bezlotoxumab targets Clostridium difficile for treatment of Clostridium difficile colitis. For example, Biciromab targets fibrin II, beta chain for treatment of thromboembolism (diagnosis). For example, Bimagrumab targets ACVR2B for treatment of myostatin inhibitor. For example, Bimekizumab targets IL 17A and IL 17F for treatment of ankylosing spondylitis, psoriasis. For example, Birtamimab targets serum amyloid A protein for treatment of amyloidosis. For example, Bivatuzumab mertansine targets CD44 v6 for treatment of squamous cell carcinoma. For example, Bleselumab targets CD40 for treatment of organ transplant rejection. For example, Blinatumomab targets CD19 for treatment of pre~B ALL (CD19+). For example, Blontuvetmab targets CD20. For example, Blosozumab targets SOST for treatment of osteoporosis. For example, Bococizumab targets neural apoptosis-regulated proteinase 1 for treatment of dyslipidemia. For example, Brazikumab targets IL23 for treatment of Crohn's disease. For example, Brentuximab vedotin targets CD30 (TNFRSF8) for treatment of Hodgkin lymphoma, Anaplastic large-cell lymphoma. For example, Briakinumab targets IL-12, IL-23 for treatment of psoriasis, rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis. For example, Brodalumab targets IL-17 for treatment of Plaque psoriasis. For example, Brolucizumab targets VEGFA for treatment of wet age-related macular degeneration. For example, Brontictuzumab targets Notch 1 for treatment of cancer. For example, Burosumab targets FGF 23 for treatment of X-linked hypophosphatemia. For example, Cabiralizumab targets CSF1R for treatment of metastatic pancreatic cancer. For example, Camidanlumab tesirine targets CD25 for treatment of B-cell Hodgkin’s lymphoma, non-Hodgkin lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia. For example, Camrelizumab targets PD-1 for treatment of hepatocellular carcinoma. For example, Canakinumab targets IL-1 for treatment of Cryopyrin-associated periodic syndrome. For example, Cantuzumab mertansine targets mucin CanAg for treatment of colorectal cancer. For example, Cantuzumab ravtansine targets MUC1 for treatment of cancers. For example, Caplacizumab targets VWF for treatment of thrombotic thrombocytopenic purpura, thrombosis. For example, Capromab pendetide targets prostatic carcinoma cells for treatment of prostate cancer (detection). For example, Carlumab targets MCP-1 for treatment of oncology / immune indications. For example, Carotuximab targets endoglin for treatment of angiosarcoma. For example, Catumaxomab targets EpCAM, CD3 for treatment of ovarian cancer, malignant ascites, gastric cancer. For example, cBR96-doxorubicin immunoconjugate targets Lewis-Y antigen for treatment of cancer. For example, Cedelizumab targets CD4 for treatment of prevention of organ transplant rejections, treatment of autoimmune diseases. For example, Cemiplimab targets PCDC1 for treatment of cutaneous squamous cell carcinoma. For example, Cergutuzumab amunaleukin targets IL2 for treatment of cancer. For example, Certolizumab pegol targets TNF-a for treatment of Crohn's disease, Rheumatoid arthritis, axial spondyloarthritis, psoriasis arthritis. For example, Cetrelimab targets PD-1 for treatment of cancer. For example, Cetuximab targets EGFR for treatment of metastatic colorectal cancer and head and neck cancer. For example, Cibisatamab targets CEACAM5 for treatment of cancer. For example, Cirmtuzumab targets R0R1 for treatment of chronic lymphocytic leukemia. For example, Citatuzumab bogatox targets EpCAM for treatment of ovarian cancer and other solid tumors. For example, Cixutumumab targets IGF-1 receptor (CD221) for treatment of solid tumors. For example, Clazakizumab targets IL6 for treatment of rheumatoid arthritis. For example, Clenoliximab targets CD4 for treatment of rheumatoid arthritis. For example, Clivatuzumab tetraxetan targets MUC1 for treatment of pancreatic cancer. For example, Codrituzumab targets glypican 3 for treatment of cancer. For example, Cofetuzumab pelidotin targets PTK7 for treatment of cancer. For example, Coltuximab ravtansine targets CD 19 for treatment of cancer. For example, Conatumumab targets TRAIL-R2 for treatment of cancer. For example, Concizumab targets TFPI for treatment of bleeding. For example, Cosfroviximab targets ebola virus glycoprotein for treatment of Ebola virus. For example, Crenezumab targets 1-40-3-amyloid for treatment of Alzheimer's disease. For example, Crizanlizumab targets selectin P for treatment of sickle-cell disease. For example, Crotedumab targets GCGR for treatment of diabetes. For example, CR6261 targets Influenza A hemagglutinin for treatment of infectious disease / influenza A. For example, Cusatuzumab targets CD70 for treatment of cancer. For example, Dacetuzumab targets CD40 for treatment of hematologic cancers. For example, Daclizumab targets CD25 (a chain of IL-2receptor) for treatment of prevention of organ transplant rejections, multiple sclerosis. For example, Dalotuzumab targets IGF-1 receptor (CD221) for treatment of cancer. For example, Dapirolizumab pegol targets CD154 (CD40L). For example, Daratumumab targets CD38 for treatment of Multiple myeloma. For example, Dectrekumab targets IL-13. For example, Demcizumab targets DLL4 for treatment of cancer. For example, Denintuzumab mafodotin targets CD 19 for treatment of cancer. For example, Denosumab targets RANKL for treatment of osteoporosis and bone metastases. For example, Depatuxizumab mafodotin targets EGFR for treatment of glioblastoma. For example, Derlotuximab biotin targets histone complex for treatment of recurrent glioblastoma multiforme. For example, Detumomab targets B-lymphoma cell for treatment of lymphoma. For example, Dezamizumab targets serum amyloid P component. For example, Dinutuximab targets GD2 ganglioside for treatment of neuroblastoma. For example, Diridavumab targets hemagglutinin for treatment of influenza A. For example, Domagrozumab targets GDF-8 for treatment of Duchenne muscular dystrophy. For example, Dostarlimab targets PCDP1 for treatment of cancer. For example, Drozitumab targets DR5 for treatment of cancer. For example, DS-8201 targets HER2 for treatment of gastric or gastroesophageal junction adenocarcinoma. For example, Duiigotuzumab targets ERBB3 (HER3) for treatment of testicular cancer. For example, Dupilumab targets IL4 for treatment of atopic diseases. For example, Durvalumab targets PD-L1 for treatment of cancer. For example, Dusigitumab targets ILGF2 for treatment of B-cell malignancies. For example, Duvortuxizumab targets GDI 9, CD3E for treatment of cancer. For example, Ecromeximab targets GD3 ganglioside for treatment of malignant melanoma. For example, Eculizumab targets C5 for treatment of paroxysmal nocturnal hemoglobinuria, atypical HUS. For example, Edobacomab targets endotoxin for treatment of sepsis caused by Gram-negative bacteria. For example, Edrecolomab targets EpCAM for treatment of colorectal carcinoma. For example, Efalizumab targets LFA-1 (GDI la) for treatment of psoriasis (blocks T-cell migration). For example, Efungumab targets Hsp90 for treatment of invasive Candida infection. For example, Eldelumab targets interferon gamma-induced protein for treatment of Crohn's disease, ulcerative colitis. For example, Elezanumab targets RGMA for treatment of spinal cord injury and multiple sclerosis. For example, Elgemtumab targets ERBB3 (HER3) for treatment of cancer. For example, Elotuzumab targets SLAMF7 for treatment of multiple myeloma. For example, Elsilimomab targets IL-6. For example, Emactuzumab targets CSF1R for treatment of cancer. For example, Emapalumab targets interferon gamma for treatment of hemophagocytic lymphohistiocytosis. For example, Emibetuzumab targets HHGFRfor treatment of cancer. For example, Emicizumab targets activated F9, F10 for treatment of haemophilia A. For example, Enapotamab vedotin targets AXL for treatment of cancer. For example, Enavatuzumab targets TWEAK receptor for treatment of cancer etc. For example, Enfortumab vedotin targets nectin-4 for treatment of urothelial cancer. For example, Enlimomab pegol targets ICAM-1 (CD54). For example, Enoblituzumab targets CD276 for treatment of cancer. For example, Enokizumab targets IL9 for treatment of asthma. For example, Enoticumab targets DLL4. For example, Ensituximab targets 5 AC for treatment of cancer. For example, Epitumomab cituxetan targets episialin. For example, Epratuzumab targets CD22 for treatment of cancer, SEE. For example, Eptinezumab targets calcitonin gene-related peptide for treatment of migraine. For example, Erenumab targets CGRP for treatment of migraine. For example, Erlizumab targets ITGB2 (CD 18) for treatment of heart attack, stroke, traumatic shock. For example, Ertumaxomab targets HER2 / neu, CD3 for treatment of breast cancer etc. For example, Etaracizumab targets integrin avp3 for treatment of melanoma, prostate cancer, ovarian cancer etc. For example, Etigilimab targets TIGIT. For example, Etrolizumab targets integrin P" for treatment of inflammatory bowel disease. For example, Evinacumab targets angiopoietin 3 for treatment of dyslipidemia. For example, Evolocumab targets PCSK9 for treatment of hypercholesterolemia. For example, Exbivirumab targets hepatitis B surface antigen for treatment of hepatitis B. For example, Fanolesomab targets CD15 for treatment of appendicitis (diagnosis). For example, Faralimomab targets interferon receptor. For example, Faricimab targets VEGF-A and Ang-2 for treatment of angiogenesis, ocular vascular diseases. For example, Farletuzumab targets folate receptor 1 for treatment of ovarian cancer. For example, Fasinumab targets HNGF for treatment of acute sciatic pain. For example, FBTA05 targets CD20 for treatment of chronic lymphocytic leukaemia. For example, Felvizumab targets respiratory' syncytial virus for treatment of respirator}'- syncytial virus infection. For example, Fezakinumab targets IL-22 for treatment of rheumatoid arthritis, psoriasis. For example, Fibatuzumab targets ephrin receptor A3. For example, Ficlatuzumab targets HGF for treatment of cancer. For example, Figitumumab targets IGF-1 receptor (CD221) for treatment of adrenocortical carcinoma and non-small cell lung carcinoma. For example, Firivumab targets influenza A virus hemagglutinin. For example, Flanvotumab targets TYRP1 (glycoprotein 75) for treatment of melanoma. For example, Fletikumab targets IL 20 for treatment of rheumatoid arthritis. For example, Flotetuzumab targets IL 3 receptor for treatment of hematological malignancies. For example, Fontolizumab targets IFN-y for treatment of Crohn’s disease. For example, Foralumab targets CD3 epsilon. For example, Foravirumab targets rabies virus glycoprotein for treatment of rabies (prophylaxis). For example, Fremanezumab targets calcitonin gene-related peptide alpha for treatment of migraine and cluster headache. For example, Fresolimumab targets TGF-p for treatment of idiopathic pulmonary fibrosis, focal segmental glomerulosclerosis, cancer. For example, Frovocimab targets PCSK9 for treatment of hypercholesterolemia. For example, Frunevetmab targets NGF. For example, Fulranumab targets NGF for treatment of pain. For example, Futuximab targets EGFR for treatment of cancer. For example, Galcanezumab targets calcitonin for treatment of migraine. For example, Galiximab targets CD80 for treatment of B-cell lymphoma. For example, Gancotamab targets HER2 / neu for treatment of cancer. For example, Ganitumab targets IGF-1 receptor (CD221) for treatment of cancer. For example, Gantenerumab targets beta amyloid for treatment of Alzheimer's disease. For example, Gatipotuzumab targets MUC1 for treatment of cancer. For example, Gavilimomab targets GDI 47 (basigin) for treatment of graft versus host disease. For example, Gedivumab targets hemagglutinin HA. For example, Gemtuzumab ozogamicin targets CD33 for treatment of acute myelogenous leukemia. For example, Gevokizumab targets IL-ip for treatment of diabetes. For example, Gilvetmab targets PCDC1. For example, Gimsilumab targets CSF2 for treatment of rheumatoid arthritis. For example, Girentuximab targets carbonic anhydrase 9 (CA-IX) for treatment of clear cell renal cell carcinoma. For example, Glembatumumab vedotin targets GPNMB for treatment of melanoma, breast cancer. For example, Golimumab targets TNF-a for treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis. For example, Gomiliximab targets CD23 (IgE receptor) for treatment of allergic asthma. For example, Gosuranemab targets tau protein for treatment of progressive supranuclear palsy. For example, Guselkumab targets IL23 for treatment of psoriasis. For example, lanalumab targets BAFF-R for treatment of autoimmune hepatitis. For example, Ibalizumab targets CD4 for treatment of HIV infection. For example, IBI308 targets PD-1 for treatment of squamous cell non-small cell lung cancer. For example, Ibritumomab tiuxetan targets CD20 for treatment of non-Hodgkin’s lymphoma. For example, Icrucumab targets VEGFR-1 for treatment of cancer. For example, Idarucizumab targets dabigatran for treatment of reversal of anticoagulant effects of dabigatran. For example, Ifabotuzumab targets EPHA3. For example, Igovomab targets CA-125 for treatment of ovarian cancer (diagnosis). For example, Iladatuzumab vedotin targets CD97B for treatment of cancer. For example, IMAB362 targets CLDN18.2 for treatment of gastrointestinal adenocarcinomas and pancreatic tumor. For example, Imalumab targets MIF for treatment of cancer. For example, Imaprelimab targets MCAM. For example, Imciromab targets cardiac myosin for treatment of cardiac imaging. For example, Imgatuzumab targets EGFR for treatment of cancer. For example, Inclacumab targets selectin P for treatment of cardiovascular disease. For example, Indatuximab ravtansine targets SDC1 for treatment of cancer. For example, Indusatumab vedotin targets GUCY2C for treatment of cancer. For example, Inebilizumab targets CD19 for treatment of cancer, systemic sclerosis, multiple sclerosis. For example, Infliximab targets TNF-a for treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn's disease, ulcerative colitis. For example, Intetumumab targets CD51 for treatment of solid tumors (prostate cancer, melanoma). For example, Inolimomab targets CD25 (a chain of IL- 2receptor) for treatment of graft versus host disease. For exampie, Inotuzumab ozogamicin targets CD22 for treatment of ALL. For example, Ipilimumab targets CD152 for treatment of melanoma. For example, lomab-B targets CD45 for treatment of ablation of bone marrow. For example, Iratumumab targets CD30 (TNFRSF8) for treatment of Hodgkin's lymphoma. For example, Isatuximab targets CD38 for treatment of multiple myeloma. For example, Iscalimab targets CD40. For example, Istiratumab targets IGF1R, CD221 for treatment of advanced solid tumors. For example, Itolizumab targets CD6 for treatment of psoriasis. For example, Ixekizumab targets IL 17A for treatment of autoimmune diseases. For example, Keliximab targets CD4 for treatment of chronic asthma. For example, Labetuzumab targets CEA for treatment of colorectal cancer. For example, Lacnotuzumab targets CSF1, MCSF for treatment of cancer. For example, Ladiratuzumab vedotin targets LIV-1 for treatment of cancer. For example, Lampalizumab targets CFD for treatment of geographic atrophy secondary to age-related macular degeneration. For example, Lanadelumab targets kallikrein for treatment of angioedema. For example, Landogrozumab targets GDF-8 for treatment of muscle wasting disorders. For example, Laprituximab emtansine targets EGFR. For example, Larcaviximab targets ebolavirus glycoprotein for treatment of Ebola virus. For example, Lebrikizumab targets IL-13 for treatment of asthma. For example, Lemalesomab targets NCA-90 (granulocyte antigen) for treatment of diagnostic agent. For example, Lendalizumab targets C5. For example, Lenvervimab targets hepatitis B surface antigen for treatment of hepatitis B. For example, Lenzilumab targets CSF2 for treatment of chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia. For example, Lerdelimumab targets TGF beta 2 for treatment of reduction of scarring after glaucoma surgery. For example, Leronlimab targets CCR5. For example, Lesofavumab targets hemagglutinin HA. For example, Letolizumab targets TRAP for treatment of inflammatory diseases. For example, Lexatumumab targets TRAIL-R2 for treatment of cancer. For example, Libivirumab targets hepatitis B surface antigen for treatment of hepatitis B. For example, Lifastuzumab vedotin targets phosphate-sodium co-transporter for treatment of cancer. For example, Ligelizumab targets IGHE for treatment of severe asthma and chronic spontaneous urticaria. For example, Loncastuximab tesirme targets CD 19 for treatment of cancer. For example, Losatuxizumab vedotin targets EGRF, ERBB1 FIERI for treatment of cancer. For example, Lilotomab satetraxetan targets CD37 for treatment of cancer. For example, Lintuzumab targets CD33 for treatment of cancer. For example, Lirilumab targets KIR2D for treatment of solid and hematological cancers. For example, Lodelcizumab targets PCSK9 for treatment of hypercholesterolemia. For example, Lokivetmab targets Canis lupus familiaris IL3I for treatment of clinical signs of atopic dermatitis in dogs

[50] . For example, Lorvotuzumab mertansine targets CD56 for treatment of cancer. For example, Lucatumumab targets CD40 for treatment of multiple myeloma, non-Hodgkin's lymphoma, Hodgkin’s lymphoma. For example, Lulizumab pegol targets CD28 for treatment of autoimmune diseases. For example, Lumiliximab targets CD23 (IgE receptor) for treatment of chronic lymphocytic leukemia. For example, Lumretuzumab targets ERBB3 (HER3) for treatment of cancer. For example, Lupartumab amadotin targets LYPD3. For example, Lutikizumab targets interleukin 1 alpha. For example, Mapatumumab targets TRAIL-RI for treatment of cancer. For example, Margetuximab targets HER2 for treatment of breast cancer. For example, Marstacimab targets TFPI for treatment of bleeding with hemophilia. For example, Maslimomab targets T-cell receptor. For example, Mavrilimumab targets GMCSF receptor a-chain for treatment of rheumatoid arthritis. For example, Matuzumab targets EGFR for treatment of colorectal, lung and stomach cancer. For example, Mepolizumab targets IL-5 for treatment of asthma and white blood cell diseases. For example, Metelimumab targets TGF beta 1 for treatment of systemic scleroderma. For example, Milatuzumab targets CD74 for treatment of multiple myeloma and other hematological malignancies. For example, Minretumomab targets TAG-72 for tumor detection and therapy. For example, Mirikizumab targets IL23A for treatment of psoriasis. For example, Mirvetuximab soravtansine targets folate receptor alpha for treatment of ovarian cancer. For example, Mitumomab targets GD3 ganglioside for treatment of small cell lung carcinoma. For example, Modotuximab targets EGFR extracellular domain III for treatment of cancer. For example, Mogamulizumab targets CCR4 for treatment of adult T-cell leukemia / lymphoma. For example, Monalizomab targets NKG2A for treatment of rheumatoid arthritis, gynecologic malignancies, and other cancers. For example, Morolimumab targets Rhesus factor. For example, Mosunetuzumab targets CD3E, MS4A1, CD20 for treatment of cancer. For example, Motavizumab targets respiratory syncytial virus for treatment of respiratory syncytial virus (prevention). For example, Moxetumomab pasudotox targets CD22 for treatment of hairy cell leukemia. For example, Muromonab-CD3 targets CD3 for treatment of prevention of organ transplant rejections. For example, Nacolomab tafenatox targets C242 antigen for treatment of colorectal cancer. For example, Namilumab targets CSF2. For example, Naptumomab estafenatox targets 5T4 for treatment of non-small cell lung carcinoma, renal cell carcinoma. For example, Naratuximab emtansine targets CD37 for treatment of. For example, Narnatumab targets MST1R (aka RON) for treatment of cancer. For example, Natalizumab targets integrin a4 for treatment of multiple sclerosis, Crohn's disease. For example, Navicixizumab targets DLL4 and VEGFA for treatment of cancer. For example, Navivumab targets influenza A virushemagglutinin HA. For example, Naxitamab targets c-Met for treatment of high-risk neuroblastoma and refractory osteomedullary disease. For example, Nebacumab targets endotoxin for treatment of sepsis. For example, Necitumumab targets EGFR for treatment of non-small cell lung carcinoma. For example, Nemolizumab targets IL31RA for treatment of eczema

[53] , For example, NEOD001 targets amyloid for treatment of primary systemic amyloidosis. For example, Nerelimomab targets TNF-a. For example, Nesvacumab targets angiopoietin 2 for treatment of cancer. For example, Netakimab targets interleukin 17A. For example, Nimotuzumab targets EGFR for treatment of squamous cell carcinoma, head and neck cancer, nasopharyngeal cancer, glioma. For example, Nirsevimab targets RSVFR for treatment of respiratory syncytial virus. For example, Nivolumab targets PD-1 for treatment of cancer. For example, Nofetumomab merpentan treats cancer (diagnosis). For example, Obiltoxaximab targets Bacillus anthracis anthrax for treatment of Bacillus anthracis spores. For example, Obinutuzumab targets CD20 for treatment of Chronic lymphatic leukemia. For example, Ocaratuzumab targets CD20 for treatment of cancer. For example, Ocrelizumab targets CD20 for treatment of rheumatoid arthritis, lupus erythematosus. For example, Odulimomab targets LFA-1 (CD1 la) for treatment of prevention of organ transplant rejections, immunological diseases. For example, Ofatumumab targets CD20 for treatment of chronic lymphocytic leukemia. For example, Olaratumab targets PDGF-R a for treatment of cancer. For example, Oleclumab targets 5'-nucleotidase for treatment of pancreatic and colorectal cancer. For example, Olendalizumab targets complement C5a for treatment of systemic lupus erythematosus, lupus nephritis, acute graft-versus-host disease. For example, Olokizumab targets IL6 for treatment of rheumatoid arthritis. For example, Omalizumab targets IgE Fc region for treatment of allergic asthma. For example, Omburtamab targets CD276 for treatment of cancer. For example, OMS721 targets MASP-2 for treatment of atypical hemolytic uremic syndrome. For example, Onartuzumab targets human scatter factor receptor kinase for treatment of cancer. For example, Ontuxizumab targets TEM1 for treatment of cancer. For example, Onvatilimab targets VSIR. For example, Opicinumab targets LINGO-1 for treatment of multiple sclerosis. For example, Oportuzumab monatox targets EpCAM for treatment of bladder cancer. For example, Oregovomab targets CA-125 for treatment of ovarian cancer. For example, Orticumab targets oxLDL. For example, Otelixizumab targets CD3 for treatment of diabetes mellitus type 1. For example, Otilimab targets GMCSF for treatment of osteoarthritis, rheumatoid arthritis. For example, Otlertuzumab targets CD37 for treatment of cancer. For exampie, Oxelumab targets OX-40 for treatment of asthma. For example, Ozanezumab targets NOGO-A for treatment of ALS and multiple sclerosis. For example, Ozoralizumab targets TNF-a for treatment of inflammation. For example, Pagibaximab targets lipoteichoic acid for treatment of sepsis (Staphylococcus). For example, Palivizumab targets F protein of respiratory syncytial virus for treatment of respiratory syncytial virus (prevention). For example, Pamrevlumab targets CTGF for treatment of idiopathic pulmonary fibrosis (IPF), pancreatic cancer. For example, Panitumumab targets EGFR for treatment of colorectal cancer. For example, Pankomab targets tumor specific glycosylation of MUC1 for treatment of ovarian cancer. For example, Panobacumab targets Pseudomonas aeruginosa for treatment of Pseudomonas aeruginosa infection. For example, Parsatuzumab targets EGFL7 for treatment of cancer. For example, Pascolizumab targets IL-4 for treatment of asthma. For example, Pasotuxizumab targets folate hydrolase for treatment of cancer. For example, Pateclizumab targets LTA for treatment of TNF. For example, Patritumab targets ERBB3 (HER3) for treatment of cancer. For example, PDR001 targets PD-1 for treatment of melanoma. For exampl e, Pembrolizumab targets PD-1 for treatment of melanoma and other cancers. For example, Pemtumomab targets MUC1 for treatment of cancer. For example, Perakizumab targets IL 17A for treatment of arthritis. For example, Pertuzumab targets HER2 / neu for treatment of cancer. For example, Pexelizumab targets C5 for treatment of reduction of side effects of cardiac surgery. For example, Pidilizumab targets PD-1 for treatment of cancer and infectious diseases. For example, Pinatuzumab vedotin targets CD22 for treatment of cancer. For example, Pintumomab targets adenocarcinoma antigen for treatment of adenocarcinoma (imaging). For example, Placulumab targets human TNF for treatment of pain and inflammatory diseases. For example, Plozalizumab targets CCR2 for treatment of diabetic nephropathy and arteriovenous graft patency. For example, Pogalizumab targets TNFR superfamily member 4. For example, Polatuzumab vedotin targets CD79B for treatment of diffuse large B-cell lymphoma. For example, Ponezumab targets human beta-amyloid for treatment of Alzheimer's disease. For example, Porgaviximab targets Zaire ebolavirus glycoprotein for treatment of Ebola virus disease. For example, Prasinezumab targets NACP for treatment of Parkinson’s disease. For example, Prezalizumab targets ICOSL. For example, Prihximab targets CD4 for treatment of Crohn's disease, multiple sclerosis. For example, Pritoxaximab targets E. coli shiga toxin type-I. For example, Pritumumab targets vimentin for treatment of brain cancer. For example, PRO 140 targets CCR5 for treatment of HIV infection. For example, Quilizumab targets IGHE for treatment of asthma. For example, Racotumomab targets NGNA ganglioside for treatment of non-small cell lung cancer. For example, Radretumab targets fibronectin extra domain-B for treatment of cancer. For example, Rafivirumab targets rabies virus glycoprotein for treatment of rabies (prophylaxis). For example, Ralpancizumab targets neural apoptosis-regulated proteinase 1 for treatment of dyslipidemia. For example, Ramucirumab targets VEGFR2 for treatment of solid tumors. For example, Ranevetmab targets NGF for treatment of osteoarthritis in dogs. For example, Ranibizumab targets VEGF-A for treatment of macular degeneration (wet form). For example, Raxibacumab targets anthrax toxin, protective antigen for treatment of anthrax (prophylaxis and treatment). For example, Ravagalimab targets CD40 for treatment of Crohn's disease. For example, Ravulizumab targets C5 for treatment of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome. For example, Refanezumab targets myelin-associated glycoprotein for treatment of recovery of motor function after stroke. For example, Regavirumab targets cytomegalovirus glycoprotein B for treatment of cytomegalovirus infection. For example, Relatlimab targets LAG3 for treatment of melanoma. For example, Remtolumab targets interleukin 17 alpha (TNF-a). For exampl e, Reslizumab targets IL-5 for treatment of inflammations of the airways, skin and gastrointestinal tract. For example, Rilotumumab targets HGF for treatment of solid tumors. For exampl e, Rinucumab targets platelet-derived growth factor receptor beta for treatment of neovascular age-related macular degeneration. For example, Risankizumab targets IL23A for treatment of Crohn’s disease, psoriasis, psoriatic arthritis, and asthma. For example, Rituximab targets CD20 for treatment of lymphomas, leukemias, some autoimmune disorders. For example, Rivabazumab pegol targets Pseudomonas aeruginosa type III secretion system. For example, Robatumumab targets IGF-1 receptor (CD221) for treatment of cancer. For example, Rmab targets rabies virus G glycoprotein for treatment of post-exposure prophy laxis of rabies. For example, Roledumab targets RHD for treatment of Rh disease. For example, Romilkimab targets interleukin 13. For example, Romosozumab targets sclerostin for treatment of osteoporosis. For example, Rontalizumab targets IFN-a for treatment of systemic lupus erythematosus. For example, Rosmantuzumab targets root plate-specific spondin 3 for treatment of cancer. For example, Rovalpituzumab tesirine targets DLL3 for treatment of small cell lung cancer. For example, Rovelizumab targets CD11, CD18 for treatment of hemorrhagic shock. For example, Rozanolixizumab targets FCGRT. For example, Ruplizumab targets CD154 (CD40L) for treatment of rheumatic diseases. For example, SA237 targets IL-6R for treatment of neuromyelitis optica and neuromyelitis optica spectrum disorders. For example, Sacituzumab govitecan targets TROP-2 for treatment of triple-negative breast cancer. For example, Samalizumab targets CD200 for treatment of cancer. For example, Samrotamab vedotin targets LRRC15 for treatment of cancer. For example, Sarilumab targets IL6 for treatment of rheumatoid arthritis, ankylosing spondylitis. For example, Satralizumab targets IL6 receptor for treatment of neuromyelitis optica. For example, Satumomab pendetide targets TAG-72 for treatment of cancer (diagnosis). For example, Secukinumab targets IL 17A for treatment of uveitis, rheumatoid arthritis psoriasis. For example, Seiicrelumab targets CD40. For example, Seribantumab targets ERBB3 (HER3) for treatment of cancer. For example, Setoxaximab targets E. coii shiga toxin type-2. For example, Setrusumab targets SOST. For example, Sevirumab targets cytomegalovirus for treatment of cytomegalovirus infection. For example, Sibrotuzumab targets FAP for treatment of cancer. For example, SGN-CD19A targets GD I 9 for treatment of acute lymphoblastic leukemia and B-cell non-Hodgkin lymphoma. For example, SHP647 targets mucosal addressin cell adhesion molecule for treatment of Crohn’s disease. For example, Sifalimumab targets IFN-a for treatment of SEE, dermatomyositis, polymyositis. For example, Siltuximab targets IL-6 for treatment of cancer. For example, Simtuzumab targets LOXL2 for treatment of fibrosis. For example, Siplizumab targets CD2 for treatment of psoriasis, graft-versus-host disease (prevention). For example, Sirtratumab vedotin targets SLITRK6 for treatment of cancer. For example, Sirukumab targets IL-6 for treatment of rheumatoid arthritis. For example, Sofituzumab vedotin targets CA-125 for treatment of ovarian cancer. For example, Solanezumab targets beta amyloid for treatment of Alzheimer's disease. For example, Solitomab targets EpCAM for treatment of gastrointestinal, lung, and other cancers. For example, Sonepcizumab targets sphingosine-1-phosphate for treatment of choroidal and retinal neovascularization. For example, Sontuzumab targets episialin. For example, Spartalizumab targets PDCD1, CD279 for treatment of melanoma. For example, Stamulumab targets myostatin for treatment of muscular dystrophy. For example, Sulesomab targets NCA-90 (granulocyte antigen) for treatment of osteomyelitis. For example, Suptavumab targets RSVFR for treatment of medically attended lower respiratory disease. For example, Sutimlimab targets Cis for treatment of cold agglutinin disease. For example, Suvizumab targets HIV-1 for treatment of viral infections. For example, Suvratoxumab targets Staphylococcus aureusalpha toxin for treatment of nosocomial pneumonia. For example, Tabalumab targets BAFF for treatment of B-cell cancers. For example, Tacatuzumab tetraxetan targets alpha fetoprotein for treatment of cancer. For example, Tadocizumab targets integrin allbp3 for treatment of percutaneous coronary intervention. For example, Talacotuzumab targets CD123. For example, Talizumab targets IgE for treatment of allergic reaction. For example, Tamtuvetmab targets CD52 for treatment of. For example, Tanezumab targets NGF for treatment of pain. For example, Taplitumomab paptox targets CD19 for treatment of cancer. For example, Tarextumab targets Notch receptor for treatment of cancer. For example, Tavolimab targets CD134 for treatment of cancer. For example, Tefibazumab targets clumping factor A for treatment of Staphylococcus aureus infection. For example, Telisotuzumab vedotin targets HGFR for treatment of cancer. For example, Tenatumomab targets tenascin C for treatment of cancer. For example, Teneliximab targets CD40 for treatment of autoimmune diseases and prevention of organ transplant rejection. For example, Teplizumab targets CD3 for treatment of diabetes mellitus type 1. For example, Tepoditamab targets dendritic cell-associated lectin 2 for treatment of cancer. For example, Teprotumumab targets IGF-1 receptor (CD221) for treatment of thyroid eye disease. For example, Tesidolumab targets C5. For example, Tetulomab targets CD37 for treatment of cancer. For example, Tezepelumab targets TSLP for treatment of asthma, atopic dermatitis. For example, TGN1412 targets CD28 for treatment of chronic lymphocytic leukemia, rheumatoid arthritis. For example, Tibulizumab targets BAFF for treatment of autoimmune disorders. For example, Tildrakizumab targets IL23 for treatment of immunologically mediated inflammatory disorders. For example, Tigatuzumab targets TRAIL-R2 for treatment of cancer. For example, Timigutuzumab targets HER2 for treatment of cancer. For example, Timolumab targets AOC3. For example, Tiragotumab targets TIGIT for treatment of cancer. For example, Tislelizumab targets PCDC1, CD279 for treatment of non-small cell lung cancer. For example, Tisotumab vedotin targets coagulation factor III for treatment of relapsed or refractory cervical cancer for example, TNX-650 targets IL-13 for treatment of Hodgkin's lymphoma. For example, Tocilizumab targets IL-6 receptor for treatment of rheumatoid arthritis. For example, Tomuzotuximab targets EGFR, HER1 for treatment of cancer. For example, Toralizumab targets CD 154 (CD40L) for treatment of rheumatoid arthritis, lupus nephritis. For example, Tosatoxumab targets Staphylococcus aureus. For example, Tositumomab targets CD20 for treatment of follicular lymphoma. For example, Tovetumab targets PDGFRA for treatment of cancer. For example, Tralokinumab targets IL-13 for treatment of asthma, atopic dermatitis. For example, Trastuzumab targets HER2 / neu for treatment of breast cancer. For example, Trastuzumab emtansine targets HER2 / neu for treatment of breast cancer. For example, TRBS07 targets GD2 ganglioside for treatment of melanoma. For example, Tregalizumab targets CD4 for treatment of. For example, Tremelimumab targets CTLA-4 for treatment of non-small cell lung, head & neck, urothelial cancer. For example, Trevogrumab targets growth differentiation factors for treatment of muscle atrophy due to orthopedic disuse and sarcopenia. For example, Tucotuzumab celmoleukm targets EpCAM for treatment of cancer. For example, Tuvirumab targets hepatitis B virus for treatment of chronic hepatitis B. For example, Ublituximab targets MS4A1 for treatment of multiple sclerosis, chronic lymphocytic leukemia. For example, Ulocuplumab targets CXCR4 (CD 184) for treatment of hematologic malignancies. For example, Urelumab targets 4- IBB (CD 137) for treatment of cancer. For example, Urtoxazumab targets Escherichia coll for treatment of diarrhea caused by E. coli. For example, Ustekinumab targets IL-12, IL-23 for treatment of multiple sclerosis, psoriasis, psoriatic arthritis. For example, Utomilumab targets 4-1BB (CD137) for treatment of diffuse large B-cell lymphoma. For example, Vadastuximab talirine targets CD33 for treatment of Acute myeloid leukemia. For example, Vanalimab targets CD40. For example, Vandortuzumab vedotin targets STEAP1 for treatment of cancer. For example, Vantictumab targets Frizzled receptor for treatment of cancer. For example, Vanucizumab targets angiopoietin 2 for treatment of cancer. For example, Vapaliximab targets AOC3 (VAP-1). For example, Varisacumab targets VEGF-A for treatment of angiogenesis. For example, Varlilumab targets CD27 for treatment of solid tumors and hematologic malignancies. For example, Vatelizumab targets ITGA2 (CD49b). For example, Vedolizumab targets integrin a4p7 for treatment of Crohn’s disease, ulcerative colitis. For example, Veltuzumab targets CD20 for treatment of non-Hodgkin's lymphoma. For example, Vepalimomab targets AOC3 (VAP-1) for treatment of inflammation. For example, Vesencumab targets NRP1 for treatment of solid malignancies. For example, Visiltzumab targets CD3 for treatment of Crohn's disease, ulcerative colitis. For example, Vobarilizumab targets IL6R for treatment of inflammatory autoimmune diseases. For example, Volociximab targets integrin a5pi for treatment of solid tumors. For example, Vonlerolizumab targets CD 134 for treatment of cancer. For example, Vopratelimab targets CD278, aka ICOS. For example, Vorsetuzumab mafodotin targets CD70 for treatment of cancer. For example, Votumumab targets tumor antigen CTAA16.88 for treatment of colorectal tumors. For example, Vunakizumab targets interleukin 17 alpha. For example, Xentuzumab targets IGF1, IGF2. For example, XMAB-5574 targets CD19 for treatment of diffuse large B-cell lymphoma. For example, Zalutumumab targets EGFR for treatment of squamous cell carcinoma of the head and neck. For example, Zanolimumab targets CD4 for treatment of rheumatoid arthritis, psoriasis, T-cell lymphoma. For example, Zatuximab targets HER1 for treatment of cancer. For example, Zenocutuzumab targets ERBB3, FIER3 for treatment of cancer. For example, Ziralimumab targets CD 147 (basigin). For example, Zolbetuximab targets CLDN18 for treatment of cancer. For example, Zolimomab aritox targets CD 5 for treatment of systemic lupus erythematosus, graft-versus-host disease.

[0167] In some embodiments, the antibody or antibody fragment may be human. Alternatively, the antibody or the antibody fragment may be from a mouse. In some embodiments, the antibody or the antibody fragment may be humanized.

[0168] In some embodiments, the antibody or antibody fragment may bind a protein selected from Table 2. In some embodiments, the antibody or the antibody fragment may bind a protein encoded by IL2 (interleukin 2; ENSG00000109471). In some embodiments, the antibody or antibody fragment may bind a histone complex. In some embodiments, the antibody or antibody fragment may bind a protein encoded by kallikrein (KLK; ENSG00000167759). In some embodiments, the antibody or antibody fragment may bind amyloid. In some embodiments, the antibody or antibody fragment may bind a Notch receptor. In some embodiments, the antibody or antibody fragment may bind a protein encoded by oxidized low density' receptor 1(OLR1; ENSG00000173391). 3. Signaling pathways

[0169] Engineered platelets described herein may contain genetic modifications within the gene components of pathways for platelet adhesion, migration, and extravasation, or the engineered platelets may be loaded with proteins, nucleic acids, or small molecule drugs. The engineered platelets may not respond to endogenous stimuli usually resulting in clot formation, may not be recruited by other activated platelets, and on activation, may not be able to recruit and activate endogenous platelets in the patient.

[0170] Alternatively, the deletion or modification is introduced to genes that mediate platelet signal transduction, such as FIPS (biogenesis of lysosomal organelles complex 3 subunit) genes, which are vital to ADP, serotonin, and AIT release from dense granules; and mitochondrially encoded cytochrome C oxidase II (COX2), which generates inflammatory and prothrombogenic mediators and is a target of aspirin. Alternatively, the deletion or modification is introduced to genes expressing thrombotic mediators, such as prothrombin (major protein thrombotic inducer); PDGF which is a pro-angiogenic factor; EGF (elongation growth factor); and von Willebrand Factor (collagen adaptor protein). 10171] The combinatorial loss of thrombin and ADP signaling has been observed to abrogate vessel occlusion, but ITAM receptors can still be activated (See, Boulaftali et al. “Platelet ITAM signaling is critical for vascular integrity in inflammation”. JCI, 2013 and Cornelissen et al. “Roles and interactions among protease-activated receptors and P2ryl2 in hemostasis and thrombosis”, PNAS. 2010, each of which is hereby incorporated by reference in its entirety). This work demonstrates that disruption of crucial endogenous platelet signaling pathways does not abrogate a platelet’s ability to signal through ITAM receptors, indicating that the engineered CPRs described herein are likely to function on a non-thrombogenic platelet background.

[0172] For example, thrombin activates platelets through cleavage of PARs (protease activated receptors). Platelet signaling is also driven by protease activated GPCRs, namely PARI and PAR4 which are cleaved by thrombin. Signaling is potent and acts to recruit platelets and facilitate positive feedback between platelets after platelet activation. The thrombin cleavage sequence on PARI and PAR4 is well defined,

[0173] In some embodiments, the engineered platelets described herein may comprise at least one deletion or modification introduced into or replacing domains of endogenous platelet receptors, such as, but not limited to, PAR4 (protease activated receptor 4), which is a primary thrombin receptor; GPlb-lX-V (Glycoprotein lb complexed with glycoprotein IX), which is a primary anchor receptor; P2Y12 (purinergic receptor P2Y12), which is an ADP (adenosine diphosphate) receptor and target of clopidogrel inhibition; GPVI (glycoprotein deletiontein VI platelet), which is a collagen receptor; or a thromboxan receptor to prevent activation of the engineered platelet.

[0174] In some embodiments, the engineered platelets can synthesize protein in response to an activation signal. For example, in Weyrich et al., BCL-3 was specifically upregulated in activated platelets through a mechanistic target of rapamycin (mTOR) dependent signaling mechanism (See, Weyrich et al. “Signal-dependent translation of a regulator}7 protein, Bcl-3, in activated human platelets”. PNAS, 1998, which is hereby incorporated by reference in its entirety). Therefore, knockin of a gene into the BCL-3 locus or identification of the minimal 5 ’ UTR region that mediates activation dependent translation would allow synthetic gene expression regulation in platelets. Therefore, platelets described herein may have an altered signaling pathway resulting in signaling induced protein translation. For example, expressing a toxic protein once activated or triggering downstream events following target cell recognition. 4. Proteins associated with autoimmunity

[0175] In some embodiments, a CPR of the engineered platelets described herein may comprise at least a portion of a protein associated with autoimmunity. For example, the CPR may comprise at least a portion of a protein selected from the group consisting of: myelin oligodendrocyte glycoprotein (MOG), glutamic acid decarboxylase 2 (GAD65), myelin associated glycoprotein (MAG), peripheral myelin protein 22 (PMP22), thyroid peroxidase (TPO), voltage-gated potassium channel (VGKC), proteolipid protein (PLP), acetylcholine receptor (AChR), tribbles pseudokinase 2 (TRIB2), N-methyl-D-aspartate (NMDA)-type glutamate receptor (GluR), glutamate decarboxylase 2 (GAD2), Armadillo repeat containing 9 (ARMC9), Cytochrome P450 Family 21 Subfamily A Member 2 (CYP21A2), calcium sensing receptor (CASR), nuclear autoantigenic sperm protein (NASP), insulin, thyroid stimulating hormone receptor (TSHR), thyroperoxidase, asioglycoprotein receptor, Cytochrome P450 Family 2 Subfamily D Member 6 (CYP2D6), lactoferrin (LF), tissue trans-glutaminase (TTG), H / K ATP-ase, Factor XIII (F8), beta2-glycoprotein I (Beta2-GPI), erythrocyte LI, B2 integrin (ITGB2), granulocyte-colony stimulating factor (G-CSF), glycoprotein (GP) nb / IIa, collagen II (COLD), fibrinogen (FBG) pa, myeloperoxidase (MPO), cardiac myosin (CYO), proteinase 3 (PRTN3), trichohyalin (TCHH), bullous pemphigoid associated (BP), glycoprotein 1 (GP1), laminin-332 (LM332), transglutaminase (TGM), type VII collagen (COLVII), P80 Coilin (COIL), Desmoglein I (DSG1), Desmoglem III (DSG3), SRY-Box 10 (SOX10), small nuclear ribonucleoprotein UI subunit (70SNRNP70), S-antigen (SAG), and Collagen alpha-3 (TV) chain (a3(IV)NCl collagen). For example, desmoglein3-ITAM CPR may be used to target pemphigus vulgaris B cells. Alternatively, the engineered platelets described herein express an MHC class I -ITAM chimeric platelet receptor or MHC class 2-ITAM chimeric platelet receptor, such that the MHC class 1 or the MHC class 2 may be loaded with a peptide from the list above on the surface of the platelet to target autoimmune mediating T cells for destruction or for suppression through the release of anti-inflammatory cytokines, such as TGF-p. Additionally, RNA encoding transcription factors may be released, such as FOXP3 to transdifferentiate bound T cells into TRegs C. Universal platelets

[0176] In some embodiments, the engineered platelets described herein are less immunogenic than platelets produced in vivo, (e.g., platelets from a human donor). In vitro generated platelets may be made universal through deletion of the p2 microglobulin gene (See, Feng et al. “Scalable Generation of Universal Platelets from Human Induced Pluripotent Stem Cells”. Stem Cell Reports, 2014, which is hereby incorporated by reference in its entirety). Even without this deletion, platelets with ABO matching are generally used in clinical practice without adverse effects. O-type platelets from humans are not universal donors as they are contaminated with anti-A / B antibodies, but contamination would not be an issue with in vitro platelets. Therefore, in certain embodiments, the inventions described herein may use these technologies to mass produce gene-edited platelets, which are also easily stored, transported, and do not require patient matching. I). Cargo

[0177] Platelets naturally absorb drugs and antibodies in their environment through endocytosis and the open canalicular system (See, Xu et al. “Doxorubicin-loaded platelets as a smart drug delivery system: An improved therapy for lymphoma”. Scientific reports, 2017 and Verheul et al. “Platelets Take Up the Monoclonal Antibody Bevacizumab”. Human Cancer Biology, 2007, which of which is hereby incorporated by reference in its entirety). Platelets may be used to deliver passively loaded and genetically encoded therapeutic agents. For example, the engineered platelets may be passively loaded with therapeutic agents through endocytosis and absorption. In fact, platelet a-granules contain protein effectors and loading of soluble proteins is performed through a simple signal peptide. A minimal targeting sequence for directing proteins into platelet secretory a-granules has been previously defined (See, Golli et al. “Evidence for a Granule Targeting Sequence within Platelet Factor 4.”, JBC, 2004, which is hereby incorporated by reference in its entirety). In some embodiments, activation trigger drug release in the engineered platelets. Cargo may be soluble or m embrane-bound. The cargo may also be an imaging agent. In some preferred embodiments the cargo is not an agent that is naturally found within the platelet, i.e. the cargo is an exogenous cargo rather than an endogenous cargo with respect to the platelet. The skilled person will appreciate that a cargo can be exogenous to the platelet but endogenous to the subject. In some preferred embodiments the cargo is not an agent that is naturally found within the platelet a-granule. For example the cargo may be an agent that is naturally found within the platelet, but not naturally found within the a-granule. In some embodiments the cargo may be an agent that is endogenously found within the platelet but is found at a higher concentration or amount within the platelet, or within the a-granule of the platelet than in a platelet not of the invention. In some embodiments the cargo comprises an a-granule localization signal wherein the a-granule localization signal directs the cargo to uptake into a-granule vesicles of the engineered platelet. For example in some embodiments a therapeutic agent or an imaging agent comprises or is conjugated to an a-granule localization signal. 1. Toxins

[0178] In some embodiments, engineered platelets may be loaded with toxin, which would be cloaked from the immune system. The engineered platelets may also be loaded with chemokines and / or selectins to mediate transfer of an agent across the blood brain barrier (BBB). Other embodiments of the engineered platelets may have platelet secretory granul es loaded with membrane and / or soluble proteins. In certain embodiments, a toxin may be encoded with an a-granule localization signal attached to direct its uptake into secretory granules, which would be released on platelet receptor activation.

[0179] Platelet expression of programmed cell death protein (PD-1) and loading of an engineered platelet with cyclophosphamide has been observed to function as a potent anti-melanoma agent (See, Zhang et al, “Engineering PD-1-Presenting Platelets for Cancer Immunotherapy.” Nano Letters, 2018, which is hereby incorporated by reference in its entirety). Specifically, megakaryocytes were engineered to express PD-1, then the resulting engineered platelets were passively loaded with cyclophosphamide. Platelet targeting to the melanoma was driven by surgical wounding of the tumor in vivo, not a synthetic receptor, resulting in Treg depletion in the tumor and increased CDS” T cell mediated killing. Tumor volume was observed to be significantly less 20 days after the beginning treatment for animals in the group with both PD-I and cyclophosphamide compared to animals treated with platelets either expressing PD-1 or loaded with cyclophosphamide. 2. Nucleic acid and amino acid sequences

[0180] In some embodiments, the cargo of the engineered platelets of the invention may be a messenger RNA (mRNA). As used herein, the term “messenger RNA” (mRNA) refers to any polynucleotide which encodes a polypeptide of interest and which is capable of being translated to produce the encoded polypeptide of interest in vitro, in vivo, in situ or ex vivo. Such mRNA molecules may have the structural components or features of any of those taught in International Publication No. WO 2013 / 151666, which is incorporated herein by reference in its entirety. c. CRISPR / Cas systems

[0181] In some embodiments, a CRISPR / Cas gene editing system may be used to alter the genome of a megakaryocyte to produce the engineered platelets described herein. Alternatively, a CRISPR / Cas system may be packaged in a vesicle to be released on activation of the platelet by an antigen recognized by the CPR. CRISPR / Cas systems are bacterial adaptive immune systems that utilize RNA-guided endonucleases to target specific sequences and degrade target nucleic acids. They have been adapted for use in various applications in the field of genome editing and / or transcription modulation. Any of the enzymes or orthologs known in the art or disclosed herein may be utilized in the methods herein for genome editing.

[0182] In certain embodiments, the CRISPR / Cas system may be a Type II CRISPR / Cas9 system. Cas9 is an endonuclease that functions together with a trans-activating CRISPR RNA (tracrRNA) and a CRISPR RNA (crRNA) to cleave double stranded DNAs. The two RNAs can be engineered to form a single-molecule guide RN A by connecting the 3’ end of the crRNA to the 5’ end of tracrRNA with a linker loop. Jinek et al., Science, 337(6096):816-821 (2012), which is hereby incorporated by reference in its entirety, showed that the CRISPR / Cas9 system is useful for RNA-programmable genome editing, and international patent application WO 2013 / 176772 provides numerous examples and applications of the CRISPR / Cas endonuclease system for site-specific gene editing, which are incorporated herein by reference in their entirety. Exemplary CRISPR / Cas9 systems include those derived from Streptococcus pyogenes, Streptococcus thermophilus, Neisseria meningitidis, Treponema denticola, Streptococcus aureas, and Francisella tularensis.

[0183] In certain embodiments, the CRISPR / Cas system may be a Type V CRISPR / Cpfl system. Cpfl is a single RNA-guided endonuclease that, in contrast to Type II systems, lacks tracrRNA. Cpfl produces staggered DNA double-stranded break with a 4 or 5 nucleotide 5’ overhang. Zetsche et al. Cell. 2015 Oct 22; 163(3):759-71, which is hereby incorporated by reference in its entirety, provides examples of Cpfl endonuclease that can be used in genome editing applications, which is incorporated herein by reference in its entirety. Exemplary CRISPR / Cpfl systems include those derived from Francisella tularensis, Acidammococcus sp., and Lachnospiraceae bacterium.

[0184] In certain embodiments, nickase variants of the CRISPR / Cas endonucleases that have one or the other nuclease domain inactivated may be used to increase the specificity of CRISPR- mediated genome editing. Nickases have been shown to promote HDR versus NHEJ. HDR can be directed from individual Cas nickases or using pairs of nickases that flank the target area. |'O185] In certain embodiments, catalytically inactive CRISPR / Cas systems may be used to bind to target regions (e.g., gene encoding an antigen, such as a receptor) and interfere with their function. Cas nucleases such as Cas9 and Cpfl encompass two nuclease domains. Mutating critical residues at the catalytic sites creates variants that only bind to target sites but do not result in cleavage.

[0186] In certain embodiments, a CRISPR / Cas system may include additional functional domain(s) fused to the CRISPR / Cas endonuclease or enzyme. The functional domains may be involved in processes including but not limited to transcription activation, transcription repression, DNA methylation, histone modification, and / or chromatin remodeling. Such functional domains include but are not limited to a transcriptional activation domain (e.g., VP64 or KRAB, SID or SID4X), a transcriptional repressor, a recombinase, a transposase, a histone remodeler, a DNA methyltransferase, a cryptochrome, a light inducible / controllable domain or a chemically inducible / controllable domain.

[0187] In certain embodiments, a CRISPR / Cas endonuclease or enzyme may be administered to a cell or a patient as one or a combination of the following: one or more polypepti des, one or more mRNAs encoding the polypeptide, or one or more DNAs encoding the polypeptide. d, Guide nucleic acids

[0188] In certain embodiments, guide nucleic acids may be used to direct the activities of an associated CRISPR / Cas enzymes to a specific target sequence within a target nucleic acid. Guide nucleic acids provide target specificity to the guide nucleic acid and CRISPR / Cas complexes by virtue of their association with the CRISPR / Cas enzymes, and the guide nucleic acids thus can direct the activity of the CRISPR / Cas enzymes.

[0189] In one aspect, guide nucleic acids may be RNA molecules. In one aspect, guide RNAs may be single-molecule guide RNAs. In one aspect, guide RNAs may be chemically modified. In certain embodiments, more than one guide RNAs may be provided to mediate multiple CRISPR / Cas-mediated activities at different sites within the genome. 3. Small molecules drugs

[0190] In some embodiments, the cargo in the vesicles of an engineered platelets described herein is a small molecule drug such as, but not limited to, (-)-Epigallocatechin 3-gallate, (-)-phensenne, (+)-calanolide A, (R)-folitixorin, (R)-mequitazine, (S)-pantoprazole sodium, [11C]DASB, [11C]- raclopride, [18F]FDG, [18F] HX4, l-(2-chloroethyl)-3-cyclohexyl4-nitrosourea, 1,2-decanediol, 11,11-di-deutero-ethyl linoleate, 11C-PBR-28, 1231-iometopane, 124I-CLR-1404, 131I-WBG, 131-lodine, 13-cis-retinoic acid, 13C-labeled methacetin, 13N-ammonia, 1400W94, 17 beta-estradiol, 17-alpha hydroxyprogesterone caproate, 17-beta-estradiol, 17-beta-estradiol valerate, 17-hydroxysteroid dehydrogenase inhibitors, 18F-EF5, 18F-FDG, 2 L polyethylene glycol, 25-dihydroxy-vitamin D3, 25-OH vitamin D, 2-chloroprocaine, 2-deoxyglucose, 2-Hydroxypropyl-Beta-Cyclodextrin, 2MD, 2-methoxyestradiol, 4-aminopyridine, 4-aminosalicylic acid, 4-FEC, 4-hydroxytamoxifen, 5-aminolevulinic acid, 5-aminosalicylic acid, 5-aracytine, 5-fluorouracil (5-FU), 5-hydroxytryptophan, 5-methoxypsoralen, 6-mercaptopurme, 6-thioguanine, 9-aminocamptothecin, 9-aminofusin, 9-nitrocamptothecin, abacavir, abafungin, abametapir, abediterol, abexinostat, abiraterone, ABT-072, ABT-751, acadesine, acalabrutinib, acamprosate, acamprosate calcium, acarbose, acebilustat, acebutolol, aceclidine, aceciofenac, aceneuramic acid, acenocoumarol, Acetadote, acetaminophen, acetate-free bicarbonate, acetazolamide, acetic acid, acetylcholine, acetylcysteine, acetyl-L-carnitine, acetyl-L-carnitine hydrochloride, acetyl-L-leucine, acetylsalicylic acid, acetyl-salicylic acid, Acetylsalicylic acid (ASA), acetylsalicylic acid lysinate, aciclovir, acipimox, acitretin, aclarubicin, aclidinium, aclidinium bromide, acolbifene, acorafloxacin, acotiamide hydrochloride, ACP-104, acrivastine, ACT-01, ACT-280778, actinomycin D, acumapimod, acyline, adapalene, ADC-3680, Adderall XR, adefovir dipivoxil, ademetionine, adenosine, adinazolam, adipiplon, adomeglivant, adozelesin, adramycin, adrenalin, adrenaline, adriamycin, Advair, Advil, AE-941, afacifenacin fumarate, afatinib, afegostat, afeletecan, afimoxifene, aflibercept, aftobetin, afuresertib, aganepag isopropyl, agatolimod, agave inulin, agomelatine, Aiphagan, ajmaline, aladorian, alagebrium chloride, alanyl-glutamine dipeptide, albaconazole, albendazole, albiglutide, albitiazolium bromide, albumin, albuterol, albuterol sulphate, albuterpenoids, alcaftadine, alcipotriol / betamethasone, aldesleukin, aldoxorubicin, alectinib, aleglitazar, alemtuzumab, alendronate, alendronate sodium, alendronic acid, Alequel, Aleve, alphacalcidol, alfentanil, alfuzosin, algeldrate / magnesium oxide, Alimta, alisertib, aliskiren, alisporivir, alitretinoin, alizapride, allantoin, allisartan isoproxil, allopregnanolone, allopurinol, alltrans retinoic acid, almorexant, almotriptan, Alodan, alogliptin benzoate, alosetron, alovudine, alpelisib, alpha lipoic acid, alpha tocopherol, alpha-1 antitrypsin, alpha-cyclodextrm, alphaglucosidase inhibitor, alpha-interferon, alpha-lipoic acid, alpha-tocopherol, alpha-tocopherol acetate, alpha-trichosanthin, alprazolam, alprostadil, alprostadil alphadex, ALS-08, altinicline, Altropane, aluminium MgS, aluminum hydroxide, alvespimycin hydrochloride, alvimopan, alvocidib, amantadine, amantadine hydrochloride, ambrisentan, ambroxol, ambroxol hydrochloride, AMD-070, amdoxovir, amelubant, amenamevir, Ametop, amfetamme, amibegron, amifampridine phosphate, amifostine, amikacin, amiloride, amiloride hydrochloride, amino acid, Aminocaproic Acid, aminoglutethimide, aminoguanidine, aminolevulinic acid, aminolevulinic acid hydrochloride, aminophylline, aminopterin, amiodarone, amiprilose, amiselimod, amisulpride, amitifadine hydrochloride, amitriptyline, Amitriptyline hydrochloride, amlexanox, amlodipine, amlodipine besilate, amlodipine besylate, amlodipine camsylate, amlodipine maleate, ammonium lactate, amnion, amodiaquine, amonafide dihydrochloride, amonafide L- malate, amorolfme, amoxapine, amoxicillin, amoxicillin clavulanate, amoxicillin AIR, amoxicillin / clavulanate, amoxicillin-clavulanic acid, amoxycillin, amphetamine, amphetamine aspartate, amphetamine sulphate, amphotericin, amphotericin B, ampicillin, ampicillin sodium, ampicillin / flucloxacillin, amprenavir, amrubicin, amsacrine, amsilarotene, AN-2898, AN-9, anacetrapib, anagliptin, anagrelide, anamorelin, anastrozole, anatibant, ancriviroc, ancrod, androgen, Androxy, anecortave, angiotensin converting enzyme inhibitor, angiotensin I, angiotensin II, Angiozyme, anidulafungin, aniracetam, annamycin, antazoline, anthocyanin, anthracycline, anti-emetic, antihistamine, antilymphocyte globulin, antineoplaston A-10, antineoplaston A10-1, antineoplaston AS2-1, Antioxidant Vitamins, antipsychotic, antiretroviral drugs, antithymocyte globulin, anti-thymocyte globulin, apabet, apadenoson, apaziquone, apelin, apheresis, apilimod, apimostinel, apitolisib, apixaban, aplaviroc, aplindore, apomorphine, Apovir, apratastat, apremilast, aprepitant, apricitabine, apricoxib, aprotinin, AR-623, Ara-C, arachidonic acid, aracytine, Aralast, aramchol, arasertaconazole, arbaclofen, arbaclofen placarbil, arbekacin sulphate, arbutin, ARC-100, arformoterol, argatoroban, argatroban, arginine, arginine vasopressin, ARH-1, arhalofenate, arimoclomol, aripiprazole, armodafmil, arogliptin, arsenic trioxide, artefenomel mesylate, artemether, artemether-lumefantrine combination, artemisinin, artemisone, artemotil, artenimol, arterolane, arterolane maleate, artesunate, artesunate+mefloquine, artesunate-amodiaqume, articaine, articaine hydrochloride, arundic acid, arzoxifene, asapiprant, ASCJ-9, ascorbate, ascorbic acid, asenapine, asimadoline, ASM-024, asoprisnil, aspirin, astaxanthin, astodrimer, asunaprevir, AT-101, ataciguat, atagabalin, ataluren, atamestane, atazanavir, atazanavir sulphate, atazanavir / ritonavir, atecegatran fexenetil, Atelvia, Atenativ, atenolol, atevirdine, ATHX-105, atiprimod, atiratecan, Ativan, atomoxetine, atopaxar, atorvastatm, atovaquone, atracurium, atracurium besylate, atrasentan, atreleuton, Atripia, atropine, auranofm, auriclosene, A VAC, avacopan, avagacestat, avanafil, avasimibe, avatrombopag, AVE-0657, AVE-2268, avibactam sodium, Avd, avobenzone, avoralstat, avosentan, AWD-12-281, axelopran, Axiron, axitinib, axomadol, azacitidine, azathioprine, AZD-1775, AZD-4547, AZD-9668, Azedra, azelaic acid, azelastine, azelastine hydrochloride, azeliragon, azelnidipine, azidothimidine, azilsartan, azilsartan medoxomil potassium, azimilide, azithromycin, azithromycin dihydrate, azosemide, aztreonam, aztreonam lysine, bacitracin, baclofen, bafetinib, baicalin, balaglitazone, balicatib, balsalazide, bambuterol, banoxantrone, barasertib, bardoxolone methyl, baricitinib, barnidipine, basiliximab, basimglurant, basmisanil, batabulin, batefenterol succinate, bavisant, bazedoxifene, BCG vaccine, BCNU, becatecarin, beclabuvir, beclometasone, beciometasone dipropionate, beclomethasone, beciomethasone dipropionate, becocalcidiol, Beconase, bedaquiline, bedoradrine, bedrocon, belinostat, belladonna, belnacasan, beloranib, belotecan, bempedoic acid, benazepril, bendamustine, bendroflumethiazide, beneh, benfotiamine, benidipine, benserazide, bentamapimod, benzalkonium, benzalkonium chloride, benzathine penicillin, benzbromarone, benznidazole, benzocaine, benzodiazepine, benzophenone-3, benzoyl peroxide, benztropine, benzydamine hydrochloride, benzylic alcohol, benzylpenicillin, benzyl piperazine, Bepantol, bepotastine, beractant, beraprost sodium, berberine, berubicin, besifloxacin, besifovir, beta erythropoietin, beta-1,3 / 1,6-glucan, beta-blocker, beta-blockers, beta-carotene, beta-cryptoxanthin, betadine, Betafectin, betahistine, betaine, Betaine anhydrous, beta-lactamase inhibitor, Betamarc, betamethasone, betamethasone dipropionate, betamethasone mousse, betamethasone valerate, betamethasone dipropionate, beta-tricalcium phosphate bone substitute, betaxolol, betaxolol hydrochloride, bethanechol, bethanechol chloride, betrixaban, betulinic acid, bevacizumab, bevenopran, bevirimat, bexagliflozin, bexarotene, bezafibrate, BF-derml, BGP-15, BI-54903, biapenem, bicalutamide, bicifadine, bifeprunox, bifidobacterium, Bifidobacterium bifidum, Bifidobacterium infantis 35624, bifonazole, biguanide, BHB-G21. bilastine, BILR-355-BS, bimatoprost, bimoclomol, bimosiamose, bindarit, binimetinib, binodenoson, Bio-25, biotin, biperiden, biphentin, birabresib dihydrate, biricodar, birinapant, bisacodyl, biskalcitrate potassium, bismuth, bismuth citrate, bismuth potassium citrate, bismuth sodium tartrate, bismuth subcitrate, bismuth subsalicylate, bisoprolol, bisoprolol fumarate, bisphosphate, bitopertin, bixalomer, bleomycin, bleomycin sulphate, blonanserin, BMP-7, BNC-105P, boceprevir, boric acid, boron-anticancers, bortezomib, bosentan, bosutinib, bradanicline, bradykinin, Bramitob, branched chain amino acid, brecanavir, brexpiprazole, Bricanyl, Bricasol, brimonidine, brimonidine tartrate, Brinavess, brinzolamide, brivanib alaninate, brivaracetam, brivudine, brolucizumab, bromfenac, bromfenac sodium, bromhexine, bromocriptine, brompheniramine, bronopol, brostallicin, brotizolam, bryostatin-1, BTI-320, BTL-TML-HSV, BTS-67582, bucindolol, budesonide, budesonide / formoterol, budesonine, budiodarone, bumetanide, bunazosin, bupariisib, bupivacaine, bupivacaine hydrochloride, bupivacaine with fentanyl, bupivacaine-clonidine, buprenorphine, buprenorphine hemiadipate hydrochloride, buprenorphine hydrochloride, buprenorphine / naloxone, bupropion, bupropion hydrochloride, bupropion SR, burapitant, burixafor, buserelin, buserelin acetate, buspirone, buspirone hydrochloride, busulfan, Busulfex, butalbital, butenafine, butoconazole, butoconazole nitrate, butorphanol, butorphanol tartrate, C5a, Cabaseril, cabazitaxel, cabergoline, cabotegravir, cabozantinib S-malate, CacitD3, cadazolid, CAF regimen, caffeic acid, caffeine, caffeine citrate, caffeinol, CalcichewD3 Forte, calcipotriol, calcipotriol / betamethasone, calcitriol, calcium, calcium acetate, calcium ascorbate, calcium carbonate, Calcium chloride, calcium chloride dihydrate, calcium citrate, calcium dobesilate, calcium fluoride, calcium folinate, calcium glucarate, calcium gluconate, calcium hydrogenphosphate, calcium L-aspartate, calcium levofolinate, calcium phosphate, calcium polycarbophil, Calcium sodium phosphosilicate. Calcium supplements, calcium and vitamin D, calcium leucovorin, caldaret, calphactant, camicinal, camobucol, camptothecin, canagliflozin, candesartan, candesartan cilexetil, canertinib, canfosfamide, cangrelor, cannabidiol, Cannabidiol (CBD), cannabidivarin, cantharidin, capadenoson, capecitabine, capmatinib, Capolac, capravirine, Capros, capsaicin, captopril, carbamazepine, carbenoxolone, carbetimer, carbetocin, carbidopa, carbocisteme, carbocysteine, Carbogen, carbon [14C] oxaliplatin, carbon dioxide, carbon monoxide, carbondioxide, carboplatin, Carboxymethylcellulose sodium, cardidopa, cardonutrient, carfilzomib, carglumic acid, cariporide, cariprazine, carisbamate, carisoprodol, carmegliptin, carmoterol, carmustme, carnitine, carotegrast methyl, carteolol, carteolol hydrochloride, carvedilol, carvedilol phosphate, CASAD, casein, casopitant, caspofungin, catechin, CBT-1, CCPI, cebranopadol, cediranib, cefaclor, cefadroxil, cefalexin, cefazolin, cefazolin sodium, cefdinir, cefditoren pivoxil, cefepime, cefilavancin, cefixime, cefmetazole, cefoperazone, cefotaxime, cefotetan, cefoxitin, cefozopran, cefpirome, cefpodoxime, cefprozil, ceftaroline, ceftaroline fosamil, ceftazidime, ceftibuten, ceftobiprole medocaril, ceftolozane sulphate, ceftriaxone, cefuroxime, celecoxib, Celestone, celgosivir, celiprolol, celivarone, Cenestin, cenicriviroc, cenobamate, censavudine, centanafadine, Centrum forte, Centrum Silver, cephalexin, cephalosporin, ceralifimod, ceramide, ceritinib, cerium nitrate, cerivastatin, cerlapirdme, certoparin, cetaphil, cethromycm, cetilistat, cetirizine, cetylpyridinium chloride, cevimeline, chenodeoxycholic acid, CHF-1535, CHF-5992, chitosan, chitosan-thiomer, chlorambucil, chloramphenicol, chlordiazepoxide, chlorhexidin, chlorhexidine, chlorhexidine digluconate, chlorhexidine gluconate, chlorhexidme-alcohol, chlorhydrate, chlormadmone acetate, chloroprocaine, chloroquine, chloroquine diphosphate, chloroquine phosphate, chlorpheniramine, chlorpheniramine maleate, chlorproguanil, chlorpromazine, chlortalidone, chlorthalidone, chlorzoxazone, cholecalciferol, cholecystokinin-8, cholesterol absorption inhibitors, cholestyramine, cholic acid, choline, choline alfoscerate, choline diepalrestat, choline fenofibrate, choline magnesium trisalicylate, chondroitin, chondroitin sulphate, CHP-HER2, Chromium cobalt, Chromium Picolinate, CHS-131, CHVP-interferon, ciclesonide, cicletanine, ciclopirox, ciclopirox olamine, ciclosporin, ciclosporine A, cidofovir, cihmsetrom cilastatin, cilazapril, cilnidipine, cilomilast, cilostazol, ciluprevir, cimetidine, cimicoxib, cinacalcet, cinaciguat, cindunistat hydrochloride maleate, cinhyaluronate sodium, cinitapride, cinitapride tartrate, cinnamaldehyde, cinnarizine, cipargamin, ciprofibrate, ciprofloxacin, ciprofloxacin hydrochloride, ciraparantag, Cisapride, cisatracurium, cisatracurium besilate, cisplatin, cisplatin liposomal, cisplatinum, citalopram, citalopram hydrobromide, Citanest, citicoline, citrate, citrate fentanyl, citric acid, citric acid monohydrate, citrulline, CK-2017357, cladribine, Clarinex, clarithromycin, clavulanate, clavulanate potassium, clavulamc acid, clazosentan, clebopride, clemastine, clemastine fumarate, clenbuterol, clevidipine, clevudine, clindamicin, clindamycin, clindamycin phosphate, clindamycin / benzoyl peroxide, Clinisol, clioquinol, clobazam, clobetasol, clobetasol propionate, Clobex, clodronic acid, clofarabine, clofazimine, clomethiazole edisylate, clomifen, clomifene, clomifene citrate, clomiphene, clomiphene citrate, clomipramine, clonazepam, clonidine, clonidine hydrochloride, clopidogrel, clopidogrel hydrogen sulphate, clopidogrel napadisilate, Cloratadd-D, clorazepate, Clostridium butyricum MIYAIRI 588, clotrimazole, cioxacillin, clozapine, coamoxiclav, cobalamin, cobamamide, cobicistat, cobimetinib, cobiprostone, cocaine, codeine, codeine phosphate, coenzyme Q10, Coeruleus, cogentin, Cogentus, colchicine, col cine, colecalciferol, colecalciferol D3, coleneuramide, colesevelam, colestilan, colestipol, colfosceril palmitate, colistimethate, colistimethate sodium, colistin, colistin sulphate, colistineb, colloidal bismuth, colloidal bismuth tartrate, coloxyl, coluracetam, combretastatin, Comp-01, Comp-02, Comp-03, Comp-04, conivaptan, conivaptan hydrochloride, conjugated estrogen, conjugated estrogens, controlled-reiease carvedilol, copanlisib, copper, copper histidine, coQlO,, cortexolone 17alpha-propionate, corticosteroid, cortisol, cortivazol, cositecan, CosmoFer, cotrifazid, cotrimoxazol, cotrimoxazole, co-trimoxazole, COX-inhibitor, CPI-613, CRAd 3 / 5-delta, creatine, creatine ethyl ester, creatine monohydrate, crenolanib, crisaborole, crizotinib, CRM-197, crobenetme, crofelemer, cromoglicate, cromoglicic acid, cromolyn sodium, Crsytalloids, C-Tb, CTO, CUDC-305, Curcuma aeruginosa, curcumin, curcuminoids, curdlan sulphate, cutamesine dihydrochloride, CX-516, cyanocobalamin, cyclizine, cyclizine lactate, cyclobenzaprine, cyclobenzaprine hydrochloride, cyclodextrin, cyclodextrin-combined diclofenac, Cyclogest, cyclopentolate, cyclophophamide, cyclophosphamide, cyclophosphamide monohydrate, cyclophosphan, cycloserine, cyclosporin, cyclosporine, cyclosporine A, cyclosporine microemulsion, cyclphosphamide, cyproheptadine, cyproterane acetate, cyproteron, cyproterone, cyproterone acetate, cysteamine, Cysteamine hydrochloride, cysteine, cysteine hydrochloride monohydrate, cytarabine, cytarabine arabinoside, cytarabine-asparagine conjugate, cytophosphan, Cytosin-Arabinosid, cytosine arabinoside, cytoxan, Cytozar, D3 vitamine, DA-9601, dabigatran etexilate, dabrafenib, dacarbazine, daclatasvir, daclizumab, dacomitinib, dactinomycin, dactolisib, daglutril, daidzein, dalbavancm, dalcetrapib, dalfopristin, dalteparin sodium, D-amphetamine, danazol, danirixin, danoprevir, dantrolene, dantrolene sodium, danusertib, dapaconazole, dapagliflozin, dapagliflozin propanediol, dapansutrile, dapivirine, daporinad, dapoxetine, dapsone, dapsone gel, darapladib, darifenacin, darinaparsin, darolutamide, darotropium bromide, darunavir, darunavir / ritonavir, darusentan, dasabuvir, dasatinib, dasotraline, daunorubicin, daunorubicin hydrochloride, daunorubicine, D-cycloserine, dDAVP, DDP, DE-104, DE-110, DE-112, Deanxit, Debio-1450, Debio-1452, decadron, decarbazine, decernotinib, decitabine, decoglurant, Decuprate, defactinib, deferasirox, deferiprone, defentazole, deferoxamine, deferoxamine mesylate, deflazacort, dehydroepiandrosterone, delafloxacin, delamanid, delanzomib, delapri 1, delapril hydrochloride, delavirdine, Delazine, deleobuvir, deligoparin sodium, delorazepam, delta-8-THC, delta-9-tetrahy drocannabmol, denagliptin, denufosol tetrasodium, Depacon, Depade, depo-medroxyprogesterone, depomedroxyprogesterone acetate, depomethylprednisolone, depotestosterone, DER-45-EV, derenofylline, dersalazine sodium, desferrioxamine, desflurane, desipramine, desloratadine, desmopressin, desmopressin acetate, desogestrel, desonide, desote fumarate, desoximetasone, desvenlafaxine, Detox-B adjuvant, deutetrabenazine, dexamethasone, dexamethasone acetate, dexamethasone cipecilate, dexamethasone diphosphate, dexamethasone phosphate, dexamethasone sodium phosphate, dexamfetamine, dexanabinol, dexchlorpheniramine, dexedrine, dexelvucitabine, dexfenfluramine, dexibuprofen, Dexid, dexisometheptene mucate, dexketoprofen, dexketoprofen trometamol, dexlansoprazole, dexlipotam, dexloxiglumide, dexmecamylamine, dexmedetomidine, dexmethylphenidate, dexniguldipine, dexpanthenol, dexpramipexole, dexrazoxane, dexrazoxane hydrochloride, dextofisopam, dextran, dextroamphetamine, dextroamphetamine saccharate, dextroamphetamine sulphate, dextromethorphan, dextromethorphan hydrobromide, dextropropoxyphene, dextropropoxyphene hydrochloride, dextrose, dexverapamil, dezocine, DHEA, diacerein, diacetylmorphine, Dialysate calcium, Diamel, diammmdichloridoplatin, diamorphine, diamorphine hydrochloride, dianhydrogalactitol, dianicline, Diao Xin Xue Kang, diazemuls, diazepam, diazepam auto injector, diazoxide, diazoxide choline, dibasic dihydrate sodium phosphate, dibasic sodium phosphate, dibekacin, dichlorphenamide, Diclazuril, diclofenac, diclofenac diethylamine, diclofenac potassium, diclofenac sodium, dicloxacillin, didanosine, dienogest, diethylcarbamazine, diethylnorspermine, diethylpropion, diethylstilbestrol, diflomotecan, diflunisal, difluprednate, digitoxin, digoxin, dihematoporphyrin, dihomo gamma-linolenic acid, dihydralazine, dihydroartemisinin, dihydroartemisinin-piperaquine, dihydrocodeine, dihydroergotamine, dihydroergotamine mesylate, dihydroxy vitamin D3, diiodothyropropionic acid and its analogs, diiphenhydramine, dilaudid, dilmapimod, diltiazem, diltiazem hydrochloride, dimenhidrinate, dimenhydrinate, dimesna, dimethindene, dimethindene maleate, dimethyl fumarate, dimethylfumarate, dimiracetam, dinoprostone, diosmin, diphencyprone, diphenhydramine, diphenylcyclopropenone, dipirone, dipraglurant-IR, dipyradimole, dipyridamole, dipyrone, diquafosol sodium, diquafosol tetrasodium, disopyramide, Dispasell, disufenton sodium, disulfiram, dithranol, ditiocarb sodium, DLBS-1033, DLBS-1425, D-methadone, DNE3, dobutamine, docetaxel, dociparstat, doconexent, doconexent ethyl ester, docosahexaenoic acid [DHA], docosahexaenoic acid monoglycerides, docosanol, docusate, docusate sodium, dofetilide, dolasetron, dolastatm-10, dologesic, dolutegravir, domperidone, donepezil, donepezil hydrochloride, donu, dopamine, dopexamine, doramapimod, doravirine, doripenem, dorzolamide, dorzolamide hydrochloride, dorzolamide hydrochloride+timolol maleate, dothiepin, dovitinib, doxapram, doxazosin, doxazosin mesylate, doxepin, doxepm hydrochloride, doxercalciferol, doxifluridine, Doxil, doxophylline, doxorubicin, doxorubicin etarfolatide, doxorubicin HC1 liposome, doxorubicin hydrochloride, doxorubicin hydrochloride liposome, doxycycline, doxycycline hyclate, doxylamine, doxylamine succinate, D-penicillamine, DPP-IV inhibitors, DPS-102, draflazine, drinabant, dronabinol, dronedarone, droperidol, dropropizine, drospirenone, drotaverine, droxidopa, D-tagatose, D-TRANS fentanyl, Duac, dual-release hydrocortisone, dulaglutide, Dulcolax, duloxetine, Duracam, duramorph, Durolane, dutasteride, dutogliptin, duvelisib, duvoglustat, D-xylose, dydrogesterone, dyhydroprogesterone, DZ-1, E coli Nissle, E-7016, E-7820, ebastine, ebselen, EC-17, ecabet, ecabet sodium, Echinacea, econazole nitrate, ecopipam, ecosprin, ecraprost, Ecural, edaglitazone, edaravone, edetate calcium disodium, edivoxetine, edonerpic maleate, edotecarin, edoxaban, EES0000645 / A, efaproxiral, efatutazone, efavirenz, efinaconazole, eflornithine, efonidipine hydrochloride, EGb-761, EGCG, eicosapentaenoic acid, eicosapentanoeic acid, elacestrant, elacridar, elacytarabine, elafibranor, elagolix, elamipretide, elbasvir, elbion, eldecalcitol, eleclazine, elesclomol sodium, eletriptan, eliglustat tartrate, elinogrel, eliprodil, ELND-005, elobixibat, elocalcitol, Elomet, Elosalic, elsamitrucin, eltoprazine, eltrombopag, elubrixin, eluxadoline dihydrochloride, elvitegravir, elvorin, elvucitabine, elzasonan, Emdogain, emedastine, emepepimut-S, emicerfont, emivirine, emixustat, empagliflozin, emricasan, emtricitabine, enalapril, enalapril maleate, enalaprilat, enasidenib, encaleret sulphate, enclomifene citrate, enclomiphene, encorafenib, endocannabinoid palmitoylethanolamide, endonase, endotoxin, endoxan, enecadin, enflurane, enfuvirtide, eniluracil, ENMD-2076, enobosarm, enocitabine, enoxaparin sodium, enoximone, entacapone, entecavir, entecavir maleate, enteric-coated mycophenolate sodium, enteric-coated tegafur-uracil, Enteroaggregative E coli, entinostat, entonox, enzalutamide, enzastaurin, epacadostat, Epadel, epalrestat, eperisone, eperisone hydrochloride, epetirimod, epetraborole, ephedrine, Epiceram, epidoxirubicin, epidoxorubicin, epidural / paravertebral analgesia, epigallocatechin gallate, epigallocatechm-3-gahate, epigaUocatechin-gallate, Epiggallocatechin, epinastine, epinastine hydrochloride, epinephrine, epirubicin, epirubicin hydrochloride, Episalvan, eplerenone, epli vanserin, epoprostenol, Eppikajutsutou, eprodisate, eprosartan, eprotirome, epsilon-aminocaproic acid, eptastigmine, eptifibatide, Equine antithymocyte immunoglobulin, Equisetum arvense, eravacycline, erdosteine, Eremostachys laciniata, ergocalciferol, ergotamine, eribaxaban, eribulin mesylate, Eritex, eritoran, erlotinib, ertapenem, erteberel, ertugliflozin, erythromycin, erythromycin lactobionate, erythropoetin, erythropoietin beta, ESAT-6CFP10, esaxerenone, Escherichia coli endotoxin, escitalopram, esflurbiprofen, Eskalith, esketamine, esketamine hydrochloride, eslicarbazepine acetate, Esmeron, esmirtazapine, esmolol, esmolol hydrochloride, esomeprazole, esoxybutynin, esreboxetine, estazolam, estetrol, estradiol, estradiol acetate, estradiol cypionate, estradiol valerate, estradiol / norethmdrone acetate, estramustine, estramustine phosphate, estramustine phosphate sodium, Estratest, estriol, estriol E3, estrodiol, estrogen, estrogens, eszopiclone, etacrynic acid, etalocib, Etalpha, etanercept biosimilar, etazolate, Ethacrynic acid, ethambutol, ethambutol hydrochloride, ethanol, ethinyl estradiol, ethinyl estradiollevonorgestrel, ethinylestradiol, ethiodized oil, ethosuximide, ethyl chloride, ethyl eicosapentaenoate, ethyl hydrogen fumarate calcium, ethyl hydrogen fumarate magnesium, ethyl hydrogen fumarate zinc, ethylenediaminetetraacetate, ethylhexyl triazone, ethynylcytidme, etidronic acid, etilefrine, etodolac, etomidate, etomidate Lipuro, etomoxir, etonogestrel, etonox, etoposide, etoposide phosphate, etoricoxib, etravirine, EV-06, evacetrapib, evatanepag, everolimus, eviprostat, evofosfamide, evogliptin, exatecan, exemestane, exenatide, exeporfinium chloride, exisulind, ezatiostat, ezetiimbe, ezetimibe / atorvastatin, F-0434, F0-M0, F0-M1700, F160-M0, F160-M1000, F160-M1700, F80-M1000, F80-M1700, FA, facinicline hydrochloride, faldaprevir, famciclovir, famitinib L-malate, famotidine, fampridine, Fangji, farampator, farglitazar, faropenem, faropenem medoxomil, fasiglifam hemihydrate, fasitibant chloride, fasudil, favipiravir, FBG-18, FBP peptides, FE

[50] C, FE

[75] C, Fe-58, febuxostat, fedovapagon, fedratinib, felbamate, felbmac, felodipine, fenatnyl, fenobam, fenofibrate, fenoldopam, fenoterol, fenoterol prednisone, fenretinide, fentanyl, fentanyl citrate, fermagate, ferric carboxymaltose, ferric citrate, ferric maltol, ferric pyrophosphate, Ferripel-3, ferroquine, ferrous fumarate, ferrous sulphate, ferumoxtran-10, ferumoxytol, FeSO4, fesoterodine fumarate, fevipiprant, fexinidazole, fexofenadine, fiboflapon, fibrinogen, fidaxomicin, filanesib, filgotinib, filgrastim, filibuvir, filorexant, fimaporfin, fimasartan, finafloxacin, finafloxacin hydrochloride, finasteride, finerenone, fingohmod, Fioricet, ftpamezole, fish oil (eicosapentaenoic acid [EPA] plus docosahexaenoic acid [DHA]), Fisiogel, fispemifene, Flagyl, Flavan-3-ol, flavanone, flavoxate, flecainide, flibanserin, flomoxef, flomoxef sodium, flopristin, florbenazine, florbetapir, flortaucipir F 18, flourinic acid, flovagatran, floxuridine, fluci cl atide F 18, flucl oxacillin, fluconazole, flucytosine, fludarabine, fludeoxyglucose, fludeoxyglucose F 18, fludrocortisone, flumazenil, flunarizine, flunisolide, fluocinolone acetonide, fluocinonide, fluorescein, fluoromethoIone, fluoromethoIone acetate, fluoropyrimidine, fluoroquinolones, fluorouracil, fluoxetine, fluoxetine hydrochloride, flupenthixol, flupentixol, fluphenazine, flupirtme, flurbiprofen, flurbiprofen axetil, flurbiprofen sodium, flutamide, fluticasone, fluticasone furoate, fluticasone propionate, flutrimazole, fluvastatin, fluvoxamme, FM-VP4, folacin, folate, folate / iron, FOLFIRI, FOLFOX4, FOLFOXIRI, folic acid, folinate, folinic acid, folitixonn calcium, folhtropin beta, fonadelpar, fondaparinux sodium, Foradil, foretinib, formoterol, formoterol fumarate, forod esine, foropafant, fosalvudine tidoxil, fosamprenavir, fosamprenavir calcium, fosaprepitant, fosbretabulin, fosbretabulin disodium, foscarnet, foscarnet sodium, fosdagrocorat, fosdevirine, fosfluridine tidoxil, fosfomycin, fosfomycin trometamol, fosfructose, fosinopril, fosmidomycin, fosphenytoin, fospropofol, fostamatinib, fostemsavir tromethamine, Fostimone, Fostrap, fotemustine, fozivudine tidoxil, freselestat, Fresubin, frovatriptan, fructose, fructose-1,6-diphosphate, fruquintinib, frusemide, fucoidan, fulvestrant, fumarate, funapide, furaprevir, furazolidone, furosemide, fusidate sodium, fusidic acid, Fuzheng Huayu, gabapentin, gabapentin enacarbil, gaboxadol, gadobenic acid, gadobutrol, gadofosveset, gadolinium, gadopentetate dimeglumine, gadoterate meglumine, gadoversetamide, gadoxetate disodium, Galactooligosaccharide, Galacto-oligosaccharides, galantamine, galantamine CR, galeterone, gallium maltolate, gallium nitrate, gallopamil, gambogic acid, Gamma-Linolenic Acid, gamma-tocopherol, ganaxolone, ganciclovir, ganciclovir phosphonate, ganetespib, ganirelix acetate, ganstigmine, garenoxacin, garlic, gatifloxacin, GCS-100, G-CSF, gedatolisib, gefitmib, gelatin, Gelofusine, Gelpart, gemcabene, gemcitabine, gemcitabine elaidate, gemcitabine prodrug, gemfibrozil, gemifloxacin, gemigliptin, gemigliptin tartaric acid, Gemzar, Genaera, gemstein, genistein+ decitabine, gentamicin, gentamicin sulphate, gentamycin, gepirone, gepotidacin, gestodene, gestodone, gestrinone, gilteritinib, gimatecan, gimeracil, Ginkgo biloba, ginkgolides meglumine, ginsenoside Rg3, ginsenoside-Rd, giripladib, gisadenafil, givinostat, GKT-831, glatiramer acetate, glecaprevir, glesatinib glycolate, glibenclamide, gliclazide, glimepiride, glinide, glipizide, glitazone, GLP-1 analog, glucagon-like peptide-1, glucocorticoids, glucocorticosteroid, glucosamine, glucosamine hydrochloride, glucose, glufosfamide, glutamic acid, glutamine, glutathione, glycerin, glycerol, glycerol phenylbutyrate, glycoprotein Hb IHa inhibitor, glycopyrolate, glycopyrrolate, glycopyrronium bromide, glycopyrronium tosylate, glycopyrroniumbromide, glycyrrhizin, glyminox, GM1, GM-CT-01, GnRH antagonist, gold sodium thiosulphate, golotimod, golvatinib tartrate, gonadotopin, gonadotropin, gonadotropins, GoodBelly probiotic, goserelin acetate, goshajinkigan, gosogliptin, gplOO, GPO-Vir Z30, granisetron, granotapide, grazoprevir, grepafloxacm, griseofulvin, GR-MD-02, GSK-2269557, GSK-2330672, GSK-2339345, guaifenesin, guanethidine, guanfacine, Guizhi fulings, gusperimus trihydrochloride, GWP-42004, gycerol, Gynostemma pentapyllum, H2 blockers, haldol, halofuginone, haloperidol, haloperidol decanoate, halothane, Hangeshashin-to, HBW, HE-3286, Healon, Helico DR, heliox, heme arginate, hemin, hemoximer, heparin, heparin sodium, Her-2 / neu, heroin, hexachlorophene, hexaminolevulinate hydrochloride, Hextend, HF-0220, Hibiscus sabdariffa, hidrotalcid, himantane, histamine dihydrochloride, homatropine, honey, hpFSH, HPP-404, HQK-1004, huachansu, Huai Qi Huang, human chorionic gonadotrophin, huperzine A, Hyabest J, hyaluronan, hyaluronate sodium, hyaluronic acid, hyaluronic acid hydrogel, hydralazine, hydrochloric acid, hydrochlorothiazide, hydrochlorothiazide tablet, hydrochlorthiazide, hydrocodone, hydrocodone bitartrate, hydrocodone / acetaminophen, hydrocortisone, hydrocortisone sodium succinate, hydrocortisone-17-butyrate, hydrocortone, hydrogel, hydrogen peroxide, hydromorphine, hydromorphone, hydromorphone hydrochloride, hydroquinidine, hydroquinone, hydroxocobalamin, hydroxy carbamide, hydroxychloroquine, hydroxydaunorubicin, hydroxyethyl starch, hydroxy ethylstarch solution, Hydroxyl-propyl-methyl cellulose powder, hydroxymethylbutyrate, hydroxynortriptyline, hydroxyprogesterone caproate, hydroxypropyl cellulose, hydroxytryptophan, hydroxyurea, hydroxyzine, hylastan, Hylenex recombinant, hyoscine butylbromide, hyoscine hydrobromide, hyoscine N-butylbromide, hyoscyamine sulphate, hyperbaric bupivacaine, hypericin, Hypericum perforatum, hyperosmolar dextrose, hypertonic saline, hypromellose, ibandronate, ibandronic acid, iberogast, iberogast N, IBH-B, ibipinabant, ibodutant, ibopamine, ibrutinib, ibudilast, ibuprofen, ibutamoren mesylate, ibuterol, ibutilide, icaritin, icodextrin, icofungipen, icosabutate, icosapent, icosapent ethyl, icosapent ethyl ester, icotinib hydrochloride, idalopirdine, idarubicin, idazoxan, IdB-1016, idebenone, idelalisib, idoxuridine, idrabiotaparinux sodium, idraparinux sodium, idronoxil, iferanserin, ifetroban, ifetroban sodium, IFN-alpha2b, ifosfamide, iguratimod, IHBG-10, IL-2, ilaprazole, ilepatril, iloperidone, iloprost, iloprost betadex clathrate, imagabalin, imatinib, ImCOOH, imeglimin, imexon, imidafenacin, imidapril, imiglitazar, imipenem, imipramine, imiquimod, imisopasem manganese, IMO-2125, implitapide, incyclinide, indacaterol, indacaterol acetate, indacaterol maleate, indacaterol xinafoate, indantadol, indapamide, indapamide SR, indeglitazar, indinavir, Indinol Forto, indiplon, indisetron, indisulam, Indium In 111 anti-CD66 monoclonal antibody BW250 / 183, indocyanine green, indometacin, indomethacin, indoramin, industrial nitric oxide, inecalcitol, INF-alpha, infigratinib, infliximab, Ingavirin, ingenol mebutate, inhaled sodium nitrite, iniparib, injectable progestin, inosine, inosine pranobex, inositol, INS-1, insulin, insulin glargine, insulin NPH, intepirdine, interferon, interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta-la, interferon betalb, Interleukin, interleukin-2, interleukin-6, intetumumab, Intracel, intranasal ketamine, intravenous immunoglobulin, intravenous minocycline, iobenguane 1-131, iodine, iodine I 131 ethiodized oil, iodine! 131 monoclonal antibody BC8, iodine tincture, iodixanol, iohexol, lopamidol, iopromide, ipragliflozin, ipratropium, ipratropium bromide, IPX-159, IPX-231, irbesartan, irinotecan, irinotecan hydrochloride, irinotecan sucrosofate, irofulven, iron, iron folic acid, iron hydroxide polymaltose, iron oxide, iron proteinsuccinylate, iron solution, iron sucrose, iron supplements, irosustat, irsogladine maleate, IRX-5183, ISA-51, isavuconazonium chloride / sulphate, Iscar, iseganan, Isobide, isocaloric diet, isocarboxazid, isoflavone, isoflavones, isoflurane, Isolyte-S, isoniazid, isoniazide, isoprinosine, isopropyl alcohol, isopropyl unoprostone, isoproterenol, isoquercetin, isosorbide dinitrate, isosorbide mononitrate, isosorbide-5-mononitrate, isosulfan blue, isotretinoin, isovaleramide, ispinesib, ispronicline, isradipine, israpafant, istaroxime, itacitinib, itasetron, itopride hydrochloride, itraconazole, itriglumide, ivabradme, ivabradine hydrochloride, ivacaftor, ivermectin, ixabepilone, ixazomib citrate, Jin Fu Kang, JNJ-56914845, Jobelyn, josamycin, Juglans regia extract, Juvidex, Kamikihi-to, kanamycin, kava, KD-018, Keflin, Kenaiog, Kenaiog-10, ketamine, ketamine hydrochloride, ketanserin, ketoconazole, ketoprofen, ketorolac, ketorolac tromethamine, ketotifen, KLH, Krestin, KRX-0402, KT6-971, KW-2450, KW-2478, KWA-0711, KX2-391, L9NC, labetalol, labradimil, lacidipine, Lacidofil Strong, lacosamide, lactated ringer's solution, lactic acid, LACTIN-V, lactitol, lactobacillus, Lactobacillus acidophilus, Lactobacillus acidophilus KS400, Lactobacillus casei rhamnosus, Lactobacillus delbrueckii, Lactobacillus paracasei F19, Lactobacillus paracasei LP-33, lactobacillus plantarum 299v, Lactobacillus reuteri, Lactobacillus rhamnosus, Lactobacillus Sporogens, lactose, lactose monohydrate, lactulose, ladarixin, ladostigil, lafutidine, L-alanosine, lamivudine, lamotrigine, landiolol, lanicemine, laninamivir octanoate, laniquidar, lanoconazole, lanopepden, lanperisone, lansoprazole, lanthanum carbonate, lapaquistat, lapatinib, laquinimod, L-arginine, laromustine, laropiprant, larotaxel, L-ascorbic acid, lasmiditan, lasofoxifene, L-asparaginase, latanoprost, latanoprost, latanoprostene bunod, latrepirdine, lauric acid, lazabemide, LC-150444, L-carnitine, L-citrulline, LCL-161, Lcr-35, L-dopa, lecovorin, lecozotan, lecozotan SR, lederfolin, ledipasvir, lefamuhn, leflunomide, lemborexant, lemuteporfin, lenalidomide, lenograstim, lentinan, lentinan viral, lenvatinib mesylate, LEO-80122, L-epinephrine, lercamdipine, lersivirine, lesinurad, lesogaberan, lestaurtinib, letaxaban, leteprinim, letermovir, letrozole, leucine, leucoverin, leucovorin, leucovorin calcium, leukapheresis, leukotriene B4 (LTB4), leuprorelide, leuprorelin acetate, levalbuterol, levalbuterol hydrochloride, levamfetamine, levamisole, levamlodipine, levamlodipine besylate, levetiracetam, levobetaxolol, levobupivacaine, levocabastine hydrochloride, levocarnitine, levocetirizine, levocetirizme dihydrochloride, levodopa, levofloxacin, levofolinate, levogestrel, levoketoconazole, levoleucovorin, levo-leucovorin, levomequitazme, levomilnacipran, levonorgestrel, levo-phencynonate hydrochloride, levorphanol, levosalbutamol, levosimendan, levosulpiride, levothyroxine, levothyroxine sodium, levotofisopam, lexibulin, lexipafant, L-folinic acid, L-glutamine, LH-RH agonist, liafensine, liarozole, Libifem, licarbazepine, licochalcone A, licofelone, lidocaine, lidocaine chlorhydrate, lidocame-prilocaine, lifibrol, lifitegrast, lignocaine, LIK-066, limaprost, Limtop, linagliptm, linaprazan, lincomycin, linezolid, linifanib, linoleic acid, linopristin, linsitinib, liothyronine, liothyronine sodium, lipid, lipiodol, Lipiodol-ethanol mixture, Lipocine, LipoCol, lipoic acid, lipopolysaccharide, liposomal amphotericin B, liposomal cisplatin, liposomal doxorubicin, liposomal paclitaxel, liposomal prostaglandin E-l, liposomal vincristine, Liproca Depot, lisavanbulin hydrochloride, lisdexamfetamme, lisinopril, lisofyllme, lisuride, lithium, lithium carbonate, Lithium citrate, lithium salt, litronesib, lixivaptan, L-leucovorin, L-leucyl-L-leucine methyl ester, L-NMMA, lobaplatin, lobeglitazone, lobeline, lobeline sulphate, lobucavir, lodenafil carbonate, lodenosine, lofepramine, lofexidine, lomibuvir, lomitapide, lomustine, Lomustine (CCNU), lonafarnib, lonaprisan, Long chain fatty acids, long-chain polyunsaturated fatty acids, 1 onidamine, loperamide, loperamide hydrochloride, loperamide oxide, lopinavir, lopinavir / ritonavir, loratadine, lorazepam, lorcaserin, loredipion, lormetazepam, L-omithine L-aspartate, lornoxicam, losartan, losartan potassium, losigamone, losmapimod, loteprednol etabonate, lovastatin, loxapme, loxoprofen, lubiprostone, lucanthone, lucitamb hydrochloride, luliconazole, lumacaftor, lumateperone toluenesulfonate, lumefantrine, lumicitabine, luminespib, lumiracoxib, lunacalcipol, hirasidone, lurbinectedin, Lurotin, lurtotecan, hiseogliflozin hydrate, lusutrombopag, lutein, LY-2090314, LY-2623091, Lybrido, lycopene, lymecycline, lynestrenol, Lysomucil, macimorelin, macitentan, Macrolids, mafenide, mafosfamide, MAGE-A1, MAG-EPA oil, magnesium, magnesium aluminum hydroxide, magnesium carbonate, magnesium chloride, magnesium chloride hexahydrate, magnesium citrate, magnesium gluconate, magnesium hydroxide, magnesium isoglycyrrhizmate, magnesium oxide, magnesium sulphate, magnesium valproate, malathion, managlinat dialanetil, mangafodipir, manganese, manidipine, manidipine dihydrochloride, manitimus, mannitol, mapracorat, maprotiline, maralixibat chloride, maraviroc, maribavir, Marijuana, marimastat, marvelone, masilukast, masitinib, masoprocol, mavoglurant, maxacalcitol, mazindol, MCC-135, MDR1, MDT-10013, mebendazole, mebeverine, mebeverine hydrochloride, mecamylamine, mechlorethamme, meclinertant, meclizine, mecobalamin, mecobalamin monohydrate, Medium chain fatty acids, medroxyprogesterone, medroxyprogesterone acetate, mefenamic acid, mefloquine, megestrol, megestrol acetate, meglumine antimoniate, melagatran, Melan-A, melarsoprol, melatonin, meldonium, melfalan, meloxicam, melperone, melphalan, melphalan hydrochloride, memantine hydrochloride, menaquinone, menaquinone-7, menatetrenone, Meniace, menotropin, menotropins, menstrogol, mepacrine, meperidine, mephalan, mepivacaine, mepivacaine chlorhydrate, mepivacaine hydrochloride, mepridine, MER-104, merbarone, mercaptamine, mercaptamine bitartrate, mercaptopurine, mericitabine, merimepodib, meropenem, mesalamine, mesalazine, mesna, metadoxine, Metafolin, Metaglip, metamizole, metamizole sodium, metaraminol, Meteospasmyl, metformin, metformin glycinate, metformin HC1, metformin hydrochloride, metformin SR, methacholine, methadone, methadone hydrochloride, methamphetamine, methazolamide, methimazole, methionine, methocarbamol, methohexital, methotrexate, methotrimeprazine, methoxsalen, methoxyflurane, methoxypsoralen, methyl aminolevulinate hydrochloride, methyl prednisolone, methyl prednisolone acetate, methylcobalamin, methyldibromoglutaronitrile, methyldopa, methylene blue, methylnaltrexone bromide, methylphenidate, methylphenidate hydrochloride, methylprednisolone, methylprednisolone aceponate, methylprednisolone acetate, methylprednisolone sodium succinate, methylprednisone, methylsamidorphan, methylsulfonylmethane, methyltetrahydrofolate, methylthioninium chloride, metirosine, Metobes-compound, metocloperamide, metoclopramide, metolazone, metoprolol, metoprolol succinate, metoprolol tartrate, metoprolol XL, metranidazole, MetroGel, metronidazole, metronomic cyclophosphamide, metyrapone, mexiletine, mexiletine hydrochloride, Mexoryl SX, Mexoryl XI +titanium dioxide, mianserin, mibampator, MIBG, miconazole, miconazole nitrate, microalgal oil, micronized progesterone, micronutrient mixture, midazolam, midazolam hydrochloride, middle-chain and polyunsaturated fatty acids, midodrine, midostaurin, mifepristone, miflonide, migalastat, miglitol, miglustat, milataxel, milnacipran, milrinone, miltefosine, milveterol, mimopezil, minocycline, minocycline hydrochloride, minodronic acid, minoxidil, mirabegron, miriplatin hydrate, mirodenafil, mirtazapine, misoprostol, mitemcinal, mitiglinide, mitoguazone, mitolactol, mitomycin, Mitomycin C, mitoquinone / mitoquinol redox mixture, mitotane, mitoxantrone, mivacurium, mivacurium chloride, mivobulin, mixed salt amphetamine, mizolastine, mizoribine, MK-0782, MK-0893, MK-2206, MK-7622, MK-8457, MMF, mocetinostat dihydrobromide, moclobemide, modafinil, moexipril, molidustat, molindone, molsidomine, molybdenum, momelotinib, mometasone, mometasone furoate, monolaurin, monosodium glutamate, montanide ISA-51, montelukast, montelukast sodium, moracizine, morphine, morphine chloride, morphine glucuronide, morphine hydrochloride, morphine sulphate, mosapride, motesanib diphosphate, motexafm gadolinium, motexafin lutetium, motolimod, moxidectin, moxifloxacin, moxifloxacin hydrochloride, moxonidine, MP-435, MSC-apceth-111, MT-102, Mucaine, Mucopolysaccharide, Mucuna pruriens, multivitamins, muparfostat sodium, mupirocin, muraglitazar, mustine, Mycobacterium w, mycophenolate acid, mycophenolate mofetil, mycophenolate sodium, mycophenolic acid, mycostatin, Mydriasert, Myfenax, Myrtus Communis L, mytomycin, N2O-O2, nabilone, nabiximols, nabumetone, N-acetyl cysteine, N-acetylcisteine, N-acetylcysteine, N-acetyl-L-cysteine, N-acetyl-p-ammophenol, NaCl, nadifloxacin, nadolol, nadroparin calcium, nafamostat, nafamostat mesilate, nafarelin, NaFeEDTA, naftifine, naftifine hydrochloride, naftopidil, nalbuphine, nalbuphine sebacate, naldemedine, nalfurafine, nalmefene, naloxegol, naloxone, naltrexone, naltrexone hydrochloride, naltrexone-poly(DL-lactide), naluzotan, Namodenoson, nandrolone, Naoxintong, napabucasin, naphthoqume, naproxcinod, naproxen, naproxen etemesil, naproxen sodium, naratriptan, naronapride, narrowband UVB, nasapaque, nastorazepide calcium, natamycin, nateglinide, navamepent, navarixin, naveglitazar, navitoclax, N-chlorotaurine, nebentan, nebicapone, nebivolol, nebulized amikacin, nebulized budesonide, Nebusal, nedaplatin, nefazodone, nefiracetam, neflamapimod, nefopam, neladenoson bialanate, nelarabine, nelfinavir, nelivaptan, nelociguat, nelonicline, nelotanserin, nemonoxacin, nemorubicin, neomycin, neomycin sulphate, neostigmine, nepadutant, nepafenac, nepicastat, neramexane, neratinib, neridronic acid, nerispirdine, netarsudil, netilmicin, netivudine, netupitant, Neu-120, neurotropin, nevirapine, niacin, niacinamide, Niacor, NIC5-15, nicardipine, nicergoline, Niclosamide, niconinamide, nicorandil, nicotinamide, nicotine, nicotine polacrilex, nicotinic acid, nifedipine, nifurtimox, Nigella sativa, nikkomycinZ, nilotinib, nilutamide, nilvadipine, nimesulide, nimodipine, nimorazole, nimotuzumab, nimustine hydrochloride, nintedanib, nipradilol, niraparib, nirogacestat, nitazoxanide, nitisinone, nitrazepam, nitrendipine, nitric oxide, nitroflurbiprofen, nitrofurantoin, nitrogen gas, nitroglycerin, nitroglycerine, nitroprusside, nitrous oxide, Nitrousoxide, nivocasan, nizatidine, N-Lite, N-monomethyl-L-arginine, Nobactine, nolatrexed, nolpitantium besilate, nomegestrol acetate, non-amlodipine calcium channel blockers, nonoxynol-9, non-preserved latanoprost, norelgestromin, norepinephrine, norethandrolone, norethmdrone, norethindrone acetate, norethisterone, norethisterone acetate, norethisterone enantate, norethrindone acetate, norfloxacin, norgestimate, nortriptylatme, nortriptyline, norursodeoxycholic acid, noscapine, novabupivacaine, Novasoy, Novotaks, NPC-18, NRTI, NS-2, NS-8, NTC-510A, NucleomaxX, nucleoside antiretroviral drugs, NYB, nystatin, Nystatin LF, Nyxol, 02, obatoclax, obeticholic acid, obicetrapib, obinepitide, OBT, ocaperidone, ocinaplon, octinoxate, octocrylene, octocrylene +tinosorb, octreotide acetate, odalasvir, odanacatib, odiparcil, Odyliresin, oestrogen, ofloxacin, oglemilast, oglufanide disodium, olanzapine, olanzapine / fluoxetine, olaparib, olcegepant, oleic acid, olepra, olesoxime, oliceridine, OiigoG CF-5 / 20, olmesartan, olmesartan cilexetil, olmesartan medoxomil, olodaterol, olodaterol hydrochloride, olopatadine, olopatadine hydrochloride, olprmone, olsalazine, oltipraz, omacetaxine mepesuccinate, omadacycline, omapatriiat, omarigliptin, omaveloxolone, ombitasvir, ombrabulin, omecamtiv mecarbil, omega, omega-3, omega-3 carboxylic acids, omega-3 fatty acids, Omega-3 polyunsaturated fatty acids, omega-3-acid ethyl esters, omega-3-carboxylic acids, omega-6, OmegaMAX, Omegaven, omeprazole, omeprazole and bicarbonate, omeprazole sodium, o-methylphenidate, omidenepag isopropyl, omigapil, Ommaya reservoir, Omri-Hep-B, onalespib, oncovin, ondansetron, ondelopran, opicapone, opipramol, opium, fumagillin, orantinib, orbofiban, Org-9426, orilotimod, oritavancin, orlistat, ornithine phenylacetate, orphenadrine citrate, ortataxel, orteronel, Orthokine, orthosilicic acid, Orthostat, Orthostat-L, Orthovisc, orvepitant, oseltamivir, osemozotan, OSI-632, osilodrostat, ospemifene, OsteoDex, Osteonil, otenabant, oteracil potassium, oteseconazole, otilonium bromide, oxacillin, oxaliplatin, oxandrolone, oxantel pamoate, oxazepam, oxcarbazepine, oxidized glutathione sodium, Oximax, oxitriptan, oxitropium bromide, OX-NLA, oxybuprocaine, oxybutinin, oxybutynin, oxybutynin chloride, oxybutynin hydrochloride, oxycodone, oxycodone CR, oxycodone extended-release, oxycodone hydrochloride, oxycodone IR, Oxycyte, oxygen, oxymetazoline, oxymetazoline hydrochloride, oxymetholone, oxymorphone ER, oxymorphone IR, oxypurinol, oxytocin, ozagrel, ozagrel hydrochloride, ozanimod, ozenoxacin, P276-00, P-53, PAC-14028, paclitaxel, paclitaxel poliglumex, paclitaxel-PM, pacritinib, pactimibe, pafuramidine, pagoclone, palanosetron hydrochloride, palbocichb, palifosfamide, paliperidone, paliperidone ER, paliperidone palmitate, paliroden, palivizumab, palonosetron, palovarotene, pamapimod, pamidronate disodium, PAN-90806, Panavir I, panobinostat, pantoprazole, pantothenic acid, pantovigar, papaverine, paquinimod, paracetamol, pardoprunox, parecoxib, paricalcitol, paritaprevir, parnaparin sodium, parogrelil, paromomycin, paroxetine, paroxetine hydrochloride, paroxetine hydrochloride hemihydrate, paroxetine mesylate, parthenolide, passiflora incarnata, patidegib, patiromer calcium, patupilone, pazopanib, pazufloxacin, pazufloxacin mesylate, PCI-24781, PCI-27483, PD-110843, PD-115934, pectin, pefcalcitol, peficitinib, pegamotecan, pegcantratinib, pegylated liposomal doxorubicin, PEITC, pelitinib, pelitrexol, pelubiprofen, pemafibrate, pemetrexate, pemetrexed, pemetrexed disodium, pemirolast, pemirolast sodium, pemoline, penciclovir, penclomedine, penehyclidine hydrochloride, penicillamine, penicillin, penicillin G, penicillin V, pentaerythritol tetranitrate, PentaLyte, pentamidine, pentamidine isethionate, pentazocine, pentobarbital, pentosan polysulphate sodium, pentostatin, pentothal, pentoxifylline, pentoxyphilline, peramivir, perchlozone, peretinoin, perflubron emulsion, perflutren lipid microsphere, pergolide, perhexiline, perifosine, perillyl alcohol, perindopril, perindopril arginine, permethrin , perospirone, perphenazine, perzinfotel, pethidine, pethidine hydrochloride, petrolatum, pexacerfont, pexidartinib, PF-04447943, PF-05089771, PF-05175157, PF-3654746, PF-3654764, PF-4191834, PF-4531083, PF-4691502, PF-489791, PF-610355, PG-2, PGL-2001, PGP / BCRP inhibitor, PH-797804, phenelzine, phenindione, pheniramine maleate, phenobarbital, phenobarbital sodium, phenoxybenzamine, phenprocoumon, phenserine, phentermine, phentolamme mesylate, phenylbutyrate, phenylephrine, phenylephrine hydrochloride, phenytoin, phloroglucinol, PHN-031, PHN-033, phosphate, phosphatidyl serine, phosphatidylcholine, phosphatidylcholine-associated naproxen, phosphatidylcholine-encapsulated ibuprofen, Phospho-Lax, phosphorus, photopheresis, physostigmine, phytate, phytonadione, phytosterols, piboserod, pibrentasvir, picibanil, piclidenoson, piclozotan, picoplatin, picotamide, picroliv, picropodophyllin, picrorhiza, pictilisib, pilaralisib, pilocarpine, pilocarpine hydrochloride, pilsicainide, PIM-447, pimagedine, pimasertib hydrochloride, pimavanserin, pimecrolimus, pimodivir, pimozide, pindolol, pinocembrin, pioglitazone, pioglitazone hydrochloride, pipamperone, piperacillin, piperacillin sodium, piperacillin-tazobactam, piperaquine, piperaquine phosphate, piperine, piracetam, piragliatin, pirarubicin, pirenzepine, pirfenidone, piribedil, piridoxine, piritramide, piritrexim, piromelatme, piroxicam, pitavastatm, pitavastatin calcium, pitolisant, pivmeciellinam, pivmecillinam, pixantrone, PL-3994, plant sterols, platinum, plazomicin, pleconaril, plenxafor, plevitrexed, plinabulin, PLX-8394, PM-00104 / 50, PMI-001, PMK-N02RS1, pocapavir, polaprezinc, policosanol, polidocanol, polifeprosan 20 with carmustine, polmacoxib, polyethylene glycol, polyethylene glycolated IL-2, polyethylene glycol-citrate-simethicone, polymeric nanoparticle docetaxel, polymyxin B sulphate, polyphenon E, polysaccharide-K, polysorbate 80, polysporin, polytetrafluoroethylene, pomaglumetad methionil, pomalidomide, ponatinib, ponesimod, poractant alpha, porfimer sodium, porfiromycin, posaconazole, posizolid, Posterisan akut, potassium, potassium canrenoate, potassium chloride, Potassium iodide, potassium nitrate, Potassium perchlorate, povidone, povidone iodine, pozamclme, poziotinib, PPA Lux 680, PPA-904, PPD-I0558, PPI, PR-104, pracinostat, pradefovir, pradigastat, pralatrexate, pralidoxime, pralnacasan, pramiconazole, pramipexole, pranlukast, pranlukast hydrate, prasterone, prasugrel, pravastatin, praziquantel, prazosin, prednicarbate, prednisolone, prednisolone acetate, prednisolone phosphate, prednisolone sodium metazoate, prednisolone sodium succinate, prednisone, pregabalin, pregnenolone, preladenant, Premarin, Prempro, Prenatal vitamin, presatovir, pretomanid, prilocame, primaquine, prinaberel, prinomastat, pritelivir, probenecid, Probiotics, probucol, procainamide, procaine, procaine hydrochloride, procarbazine, procarbazine hydrochloride, procaterol, procaterol hydrochloride, prochlorperazine. Procysteine, pro-docosapentaenoic acid, pro-eicosapentaenoic acid, progesterone, progestin, progestogen, progestogen dienogest, proglumide, proguanil, proguanil hydrochloride, Prolarix, promethazine, Prometra, Prometrium, Promisan, propacaine hydrochloride, propacetamol, propafenone, propafenone-SR, propanolol, proparacaine, propionyl-L-carnitine, propiverine, propiverine hydrochloride, propofol, Propofol Lipuro, propofol-lipuro, propranolol, propranolol hydrochloride, propranolol LA, propranolol XL, propylthiouracil, propyphenazone, Prosorba, prostaglandin, prostaglandin-E2, Prostin, Protelos, protriptyline, ProvideXtra, proxymetacaine, proxymetacaine hydrochloride, PRS-211375, prucalopride, prulifloxacin, Prurisol, pruvanserin, PRX-3140, PRX-8066, PSD-508, pseudoephedrine, pseudoephedrine hydrochloride, Pseudomonas aeruginosa mannose-sensitive hemagglutinin (PA-MSHA), PSI-5004, PSI-938, psyllium powder, PTH, p-toluene sulfonamide, puerarin, puerarin sodium phosphate, pumosetrag, PVAC, PVP-ILH liposomes, PX-12, PYN-17, pyrantel-oxantel, pyrazinamide, pyridostigmine bromide, pyridoxal, pyridoxamine dihydrochloride, pyridoxine, pyridoxine hydrochloride, pyrimethamine, pyrimethamine / sulfadoxine, pyrimethamine / sulphadoxine, pyronaridine, Q-301, QAV-680, Qinbudan, Qizhitongluo, quercetin, quetiapine, quetiapine fumarate, quetiapine IR, quinacrine, quinagolide hydrochloride, quinapril hydrochloride, quinfamide, quinidine, quinine, quinolone, quinolones, quinupristin, quisinostat, quizartinib dihydrochloride, R-112, rabacfosadine, rabeprazole, rabeximod, rabusertib, racecadotril, raclopride, radafaxine, radalbuvir, radequinil, radezolid, Radha-108, radioactive iodine, Radioiodine, radiolabeled iodobenzamide, radiprodil, radium Ra 223 dichloride, radotinib, ragaglitazar, ralfinamide, raloxifene, raltegravir, raltitrexed, ramatroban, ramelteon, ramipril, ramosetron, ranibizumab, ranimustine, ranirestat, ranitidine, ranolazine, rapamycin, rasagiline, raseglurant, ravidasvir hydrochloride, ravuconazole, raxatrigme, razupenem, RBP-8000, RBx-10017609, RDEA-806, RDP-58, rebamipide, rebaudioside A, rebimastat, reboxetine, refametinib, reformulated diclofenac, reformulated mebendazole, regadenoson, regorafenib, regrelor, relebactam, relenopride, relugolix, remifentanil, remimazolam, remimazolam tosylate, remogliflozin etabonate, REN-1654, renzapride, repaglinide, reparixin, repinotan, repurposed ajulemic acid, repurposed ondansetron, resatorvid, reserpine, resiniferatoxin, resminostat, Resoferon, Respifor, Respimat, Restylane, Restylane SubQ, resveratrol, retagliptin, retapamulin, retaspimycin, retigabine, retinoic acid, retinoid, retinol, retosiban, retrovir, revamilast, revefenacin, revexepride, reviparin sodium, rezatomidine, RF-07026, rFSH, RG-4929, RG-7234, RG-7795, RGH-478, RGH-507, Rlrenium-188-HEDP, Rhinox, RhuDex, ribavirin, ribociclib, riboflavin, ridaforolimus, ridinilazole, rifabutin, rifalazil, rifampicin, rifampin, rifamycin, rifapentine, rifaximin, rigosertib sodium, rikkunshito, rilapladib, rilmenidine, rilpivirine hydrochloride, riiuzole, rimacalib, rimegepant, rimexolone, rimonabant, Ringer's acetate, Ringer's lactate solution, riociguat, ripasudil hydrochloride hydrate, risedronate sodium, risperidone, ritanserin, ritobegron ethyl ester hydrochloride, ritodrine, ritonavir, rituximab, rivaroxaban, rivastigmine, rivenprost, rivipansel sodium, rivoglitazone, rizatriptan, RLP-068, RNF43, RNS-60, RO-4929097, RO-5036505, robalzotan, rociletinib, rocuronium, rocuronium bromide, rofecoxib, Roferon-A, roflumilast, rolapitant, rolipram, rolofylline, ronacaleret, roniciclib, ronopterin, ropinirole, ropinirole hydrochloride, ropivacaine, roquinimex, rose bengal sodium, rosiglitazone, rosiglitazone maleate, rosiglitazone XR, rosiptor acetate, rostafuroxin, rostaporfin, rosuvastatin, rosuvastatin calcium, rotigotine, rovatirelin, roxadustat, roxithromycin, RP-323, RPh-201, RPL-554, RPM-02 / 08, RQ-00000004, R-salbutamol sulphate, rubitecan, ruboxistaurin, rucaparib, rucaparib camsylate, rucaparib phosphate, rufinamide, rupatadine, ruxolitinib, S Ketamine, S(+)-Ketamine, S-l, S-l 11, S-38093, S-707106, SAB-378, sabarubicin, Saccharomyces boulardii, sacubitril, S-adenosyl methionine, SAF-312, saffron, safmamide, safotibant, sagopilone, salbutamol, salbutamol HFA, salbutamol sulphate, salicylic acid, salicylic acid+benzoic acid, salidroside, saline, salirasib, salmon calcitonin, salsalate, Salubrin, samarium(153Sm) lexidronam, samatasvir, samidorphan, S-amlodipine gentisate, sapacitabine, sapanisertib, sapitinib, sapropterin, sapropterin dihydrochloride, saquinavir, SAR-110894, saracatinib, sarecycline, saredutant, sargramostim, sarizotan hydrochloride, saroglitazar, sarpogrelate hydrochloride, satavaptan, satraplatin, saxagliptin, SB-773812, SBP-002, SC-49483, SCH-002063, SCH-497079, SCH-900776, schisandra sphenanthera extract, scopolamine, SCY-078, SDX-101, secnidazole, Sedlitzia rosmarinus, segesterone acetate, seladelpar L-lysine dihydrate, selegiline, selegiline hydrochloride, selenium, selenium sulfide, selenomethionine, selepressin, seletracetam, selexipag, seliciclib, selinexor, selisistat, selodenoson, selonsertib, Selozok, selumetmib, selurampanel, semagacestat, semapimod, semaxanib, sembragiline, senicapoc, senna, Sensorcaine, Sentra PM, seocalcitol, sepantronium bromide, sepetaprost, sepranolone, septin, SER-150-DN, Serenoa repens, sergliflozin etabonate, serlopitant, serotonin reuptake inhibitors, serotonin / norepinephrme reuptake inhibitors, sertaconazole, sertindole, sertraline, S-ethylisothiourea diethylphosphate, setileuton, setipiprant, S-etodolac, setrobuvir, sevelamer carbonate, sevelamer hydrochloride, sevoflurane, Sevofran, sevuparin sodium, SG-2000, Shanhuang Wuji decoction, SHP-465, sibrafiban, sibutramine, sildenafil, sildenafil citrate, Silexan, silibin, silibinin dihydrogensuccinate, silimarine, silodosin, silver nanoparticle, silver nitrate, silver sulfadiazine, silybin, silymarin, simenepag isopropyl, simeprevir, simethicone, simeticone, simvastatin, Sinbaro, siponimod, sirolimus, sitafloxacin, sitagliptin, sitamaquine, sitaxentan, sitosterol, sivelestat, sivifene, s-ketamine, SKP-1052, SK-PC-B70M, SLx-4090, SMANCS, S-methionyl-L-citrulline, smilagenin, SMP-028, SN-38, SNX-5422, sodelglitazar, sodium, sodium 4-phenylbutyrate, sodium ascorbate, sodium benzoate, sodium bicarbonate, sodium butyrate, sodium carboxymethylcellulose, sodium chloride, sodium chromoglycate, sodium citrate, sodium di chloroacetate, sodium ferric gluconate com plex, sod ium fluoride, sodium folinate, sodium fusidate, sodium hyaluronate, sodium hydroxide, sodium hypochlorite, sodium ketorolac, sodium lactate, sodium nitrate, sodium nitrite, sodium nitroprusside, sodium oxybate, sodium phenylacetate, sodium phenylbutyrate, sodium phosphate, sodium picosulphate hydrate, sodium polystyrene sulfonate, sodium prasterone sulphate, sodium pyruvate, sodium stibogluconate, sodium sulfide, sodium tetradecyl sulphate, sodium thiopental, sodium thiosulphate, sodium valproate, sodiumfluoride, sofinicline, sofosbuvir, sofosbuvir+ daclatasvir, sofpironium bromide, solabegron, solcitinib, Soldesam, solifenacin, solithromycin, soluble ferric pyrophosphate citrate, Solvazinc, somatostatin, sonedenoson, somdegib, sonolisib, sorafenib, soraprazan, sorbitol, sorivudine, sotagliflozin, sotalol, sotrastaurin, sovaprevir, soy isoflavones, sparsentan, spebrutinib, spiramycin, spironolactone, sPLA2 inhibitors, SQ-109, squalamine, SR-T100, SSS, ST-101, STA-4783, standard bicarbonate, standard pneumoperitoneum, stannous compounds, stannsoporfm, statin, stavudme, stearidonic acid, S-tenatoprazole, Sterofundin, steroid, steroids, stiripentol, Stopain, Streptococcus faecium, Streptococcus thermophillus, streptomycin, streptozocin, strontium chloride Sr 89, strontium malonate, strontium ranelate, strontium-89, STW-5, STX-107, SU, SU-101, SU-14813, succimer, succinic acid, succinylcholine, sucralphate, sucralose, sucroferric oxyhydroxide, sucrose, Sufenta, sufentanil, sufentanil citrate, sufentanyl, sugammadex, sulbactam, sulbactam sodium, sulfadiazine, sulfadoxine, sulfadoxine+pyrimethamine, sulfalene-pyrimethamine, sulfamethoxazole, sulfasalazine, sulphate salt solution, sulfonyl urea, sulfonylurea, sulfonylureas, sulforaphane, sulmdac, sulodexide, sulopenem, sulopenem etzadroxil, sulphacetamide sodium, sulphadoxine, sulphadoxine-pyrimethamine, sulphamethoxazole, sulphonylurea, sulpiride, sultamicillin, sumanirole, sumatriptan, sumatriptan succinate, SUN-0597, SUN-1334H, sunitinib, suplatast tosilate, suramin, suramin sodium, surinabant, sutezolid, suxamethonium, SYI-2074, symbiotic, synbiotics, SYNSORB-Pk, synthetic hypericin, T / S, T-1225, T-2000, T3, tacalcitol, tacedinaline, tacrine, tacrolimus, Tacrolimus Hexal, tadalafil, tadekinig alpha, tafamidis, tafenoquine, tafluprost, tafoxipann sodium, TAK-715, TAK-783, talabostat, taladegib, talampanel, talaporfin, talarozole, talazoparib, talc, TALL-104, talmapimod, talnetant, talniflumate, talotrexm, talsaclidme fumarate, taltirelm, tamibarotene, tamoxifen, tamsulosin, tamsulosin hydrochloride, tandospirone, tandutinib, tanespimycin, tanomastat, tanzisertib, tapentadol, taprenepag, Taradyal, tarafenacin, taranabant, tarenflurbil, taribavirin hydrochloride, tariquidar, tarloxotinib bromide, tasidotin HC1, tasimelteon, tasisulam, taspoglutide, tasquinimod, taurolidine, tauroursodeoxycholic acid, tavaborole, tavilermide, Taxol, Taxus, tazarotene, tazobactam, TC-2403, TC-3, TCM-606F, tebipenem pivoxil, tecadenoson, tecalcet, tecarfarin, tecastemizole, technetium bicisate, technetium etarfolatide, technetium Tc 99m tilmanocept, technetium Tc 99m trofolastat, technetium-99, tecovirimat, tedatioxetine, tedisamil, tedizolid phosphate, tegafur, tegaserod, teglarinad chloride, tegobuvir, teicoplanin, telaprevir, telapristone acetate, telatinib, telbivudine, telcagepant, telithromycin, telmisartan, telotristat etiprate, temazepam, temocapril, temocillin, temoporfin, temozolomide, temsirolimus, tenapanor, teneligliptin, teniposide, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir disoproxil fumarate, tenofovir exalidex, tenofovir / emtricitabine, tenoxicam, teprenone, terameprocol, terazosin, terbinafme, terbinafme gel, terbinafme hydrochloride, terbogrel, terbutaline, terbutaline sulphate, terconazole, terguride, teriparatide, terlipressin acetate, terutroban, tesaglitazar, tesetaxel, tesevatinib, tesmilifene, tesofensine, Testagen, testosterone, testosterone cypionate, testosterone enanthate, testosterone undecanoate, Tetanus toxoid, tetomilast, tetrabenazine, tetracaine, tetracaine hydrochloride, tetracycline, tetracycline HC1, tetrahydrobiopterin, tetrahydrocannabinol, tetrathiomolybdate, Tetrodin, tezacaftor, tezacitabine, tezampanel, tezosentan, TG-100-115, TG-100801, thalidomide, THC, theophyllamine, theophylline, theophylline SR, theracurmin, thiamine, thiamine hydrochloride, thiazide, thiazide diuretics, thiazolidinedione, thiazolidinediones, thiocolchicoside, thioctic acid, thioguanine, thiopental, thiopental sodium, thiopentone, thioridazine, thiotepa, thiothixene, THR-0921, THR-4109, thrombin, thrombin microcapsules, thymoctonan, Thymoglobulin, thyroxine, tiagabine, tianeptine, tiapride, tibolone, ticagrelor, ticlopidine, tideglusib, tigecycline, tilapertin, tilarginine acetate, tiludronate disodium, timapiprant, timcodar, timnodonic acid, timolol, timolol, timolol maleate, tinidazole, tinzaparin sodium, tiopronin, tiotropium, tiotropium bromide, tipelukast, tipifamib, tipiracil hydrochloride, tipranavir, tirapazamine, tirasemtiv, tirilazad, tirofiban, tirofiban hydrochloride, titanium dioxide, TIVA, tivantinib, tivozanib, tizanidme, TMC-H4 / RTV, TMC-310911, TMC-647055, TNF-alpha, TNP-470, tobramycin, tocladesine, tocofersolan, tocopherol, tocopherols, tocopheryl phosphate mixture (TPM), tofacitinib, tofimilast, tofogliflozin, tolcapone, tolevamer, tolnaftato, tolperisone, tolterodine, tolterodine tartrate, tolvaptan, TOMM34, tonabersat, Tonalin SG1000T FFA, tonapofylline, Tongxinluo, topiramate, topiroxostat, topotecan, topotecan hydrochloride, torasemide, torcetrapib, toreforant, toremifene, tosedostat, tosufloxacin, tozadenant, tozasertib, trabectedin, trabectome, trabodenoson, tradipitant, tramadol, tramadol hydrochloride, tramazoline, trametinib, tramiprosate, trandolapril, tranexamic acid, tranilast, transcrocetinate-sodium, tranylcypromine, trastuzumab, travoprost, traxoprodil, trazadone, trazodone, trazodone hydrochloride, TRC-101, trehalose, trelagliptin succinate, trelanserin, treosulfan, treprostinil, treprostinil diolamine, tretinoin, triamcinolone, triamcinolone acetonide, triamcinolone hexacetonide, Triapine, Triatec HCT, Triaz, triazavirin, triazolam, tribendimidine, trichlormethiazide, trichlorothiazide, triciribine, tridolgosir, trientine, trientine hydrochloride, trifarotene, trifluoperazine, trifluridine, triflusal, triheptanoin, trihexyphenidyl, triiodothyronine, trilostane, trimebutine, trimebutine 3-thiocarbamoyl-benzenesulfonate, trimegestone, trimetazidine, trimethaphan, trim ethobenzamide, trimethoprim, trimethoprim-sulfa, trimetrexate, trimipramine, trimipramine maleate, trinitrate, Triomune, Triplixam, tripotassium dicitrate bismuthate, tripterygium wilfordii, triptorelin acetate, triptorelin pamoate, trisodium citrate dihydrate, Trivax-AD, trofmetide, trofosfamide, troglitazone, tropicamide, tropisetron, trospium chloride, troxacitabme, troxipide, Trunature, trypsin-EDTA, TS-022, TTK, TTP-054, TTP-399, TTP-435, TTP-889, TTX-9401, tucaresol, tucidinostat, tulobuterol, TV-46763, TV-5010, TY-51924, tylenol, TZD, TZP-102, ubidecarenone, ubiquinol, ubrogepant, UCA-001, UCA-002, UCN-01, udenafil, UFT, UFT / LV, UFUR, UISH-001, UK-390957, UK-432097, UK-447841, ulimorehn, ulinastatin, ulipristal, ulobetasol, ulodesine, umeclidinium, umeclidinium bromide, umirolimus, unfractionated heparin, uniphyllm, upadacitinib, upamostat, uprifosbuvir, uprosertib, UR-906, uracil, urapidil, urea, uridine, uridine triacetate, URLC10, ursodeoxycholic acid, Ursolic acid, Urtica diociea, usistapide, UTD-1, utrogestan, V-l 16517, V-158866, V-404, VA-111913, vabicaserin, vaborbactam, vadadustat, vadimezan, Vagiprost, VAK-694, valaciclovir, valacyclovir, valbenazine, valdecoxib, valerian extract, valganciclovir, valium, valnivudine hydrochloride, valnoctamide stereoisomers, valomaciclovir stearate, valopicitabine dihydrochloride, valproate, valproic acid, valrocemide, valrubicin, valsartan, valsartan trisodium hemipentahydrate, valspodar, valtorcitabine, vancomycin, vancomycin hydrochloride, vandetanib, vaniprevir, vanoxerine, vapendavir, vapitadine, vardenafil hydrochloride, varenicline, varespladib, varespladib methyl, varlitinib, vasopressin, vatalanib, vatiquinone, VDC-2008, vecuronium, vecuronium bromide, vedroprevir, VEGFR1, VEGFR1 peptide, VEGFR1-A02-770, VEGFR2 peptide, VEGFR2-derived HLA-A0201, veliflapon, veliparib, velneperit, velpatasvir, velusetrag, vemurafenib, venetoclax, venlafaxine, venlafaxine hydrochloride, venlafaxine XR, vepoloxamer, verapamil, verapamil hydrochloride, vercimon, verdiperstat, vericiguat, verinurad, vemakalant, vemakalant hydrochloride, verteporfin, verubulin, verucerfont, Verutex, vesatolimod, vesnarinone, vestipitant, vibegron, vicriviroc, Vidoca, vidofludimus, vidupiprant, vigabatrin, viitamin D, vilanterol, vilanterol trifenatate, vilaprisan, vilazodone, vildagliptin, vinblastin, vinblastine, vinblastine sulphate, vincristin, vincristine, vincristine sulphate, vindesine, vinflunine, vinorelbine, vinorelbine ditartrate, vinpocetine, vintafolide, vipadenant, vismodegib, vistusertib, Vit Bl2, Vitamac, vitamin A, vitamin B, vitamin Bl, vitamin Bl2, vitamin B-12, vitamin B2, vitamin B6, vitamin B-6, vitamin C, vitamin D, vitamin D2, vitamin D3, vitamin E, vitamin E succinate derivatives, vitamin K, vitamin KI, vitamins Bl, vitamins B12, vitamins B2, vitamins B6, Vitreosolve, Viusid, Vizomitin, vofopitant, voglibose, volasertib, volmanserin, vonoprazan fumarate, vorapaxar, voriconazole, vorinostat, vortioxetine hydrobromide, vosaroxin, voxilaprevir, voxtalisib, VP-101, VRx-3996, VSL-3, WZ-149, VX-105, VX-135, VX-702, VX-710, Wafermine, warfarin, warfarin sodium, Water, WF-10, WH-1, Wobenzym, WX-554, xaliproden, xemilofiban, xenon, Xiang-sha-liu-jun decoction, xiaoqinglong, Xibrom, Xilei-San, ximelagatran, Xiyanping, XL-139, XP-21279, Xylitol, xylometazoline, Y-39983, Yallaferon, yonkenafil, yttrium clivatuzumab tetraxetan, yttrium Y 90 anti-CD66 monoclonal antibody BW 250 / 183, zabofloxacin, zafirlukast, zalcitabine, zaleplon, zaltoprofen, zanamivir, ZD-6126, zeaxanthm, zibotentan, zicronapine, zidovudine, zileuton, zinc, zinc acetate, zinc oxide, zinc picolinate, zinc sulphate, zinc supplement, Zincas Forte, Zinthionein, ziprasidone, zofenopril, zoledronate, zoledronic acid, zoliflodacin, zolmitriptan, zolpidem, zolpidem tartrate, Zometa, zonampanel, zonisamide, zonisamide SR, zopiclone, zosuquidar, zotarolimus, zotepine, zucapsaicin, zuclopenthixol, and zuretinol acetate. 10191] In some embodiments, the cargo of the engineered platelets descried herein is a small molecule such as, but not limited to, those from the CeMM Library of Unique Drugs (CLOUD), as shown in Licciardello et al., Nat Chem Biol; Vol. 13, pages 781-780 (2017)), which is hereby incorporated by reference in its entirety. For example, the small molecule may be, but it not limited to, Pinacidil, Altretamine, Pipobroman, Uracil Mustard, Trioxsalen, Plicamycin, Ambenonium, Edrophonium, Hexafluorenium, Oxtriphylline, Arbutamine, Guanabenz, Mephentermine, Methoxamine, Phenylpropanolamine, Protokylol, Tetrahydrozoline, Tolazoline, Bethanidine, Ergoloid, Oxprenolol, Penbutolol, Phentolamine, Propiomazine, Thiethylperazine, Fomepizole, Triamterene, Stanozolol, Dromostanolone, Ethylestrenol, Fluoxymesterone, Methyltestosterone, Deserpidine, Quinapril, Rescinnamine, Spirapril, Testolactone, Ethionamide, Sulfameter, Sulfacytine, Sulfamerazine, Sulfamethazine, Sulfamethizole, Sulfaphenazole, Sulfapyridine, Sulfathiazole, Sulfisoxazole, Sulfoxone, Cefmenoxime, Amdinocillin, Azlocillin, Bacampicillin, Carbenicillin, Cefalotin, Cefamandole, Cefditoren, Cefonicid, Ceforanide, Cefotiam, Cefpiramide, Cefradine, Ceftizoxime, Cephaloglycin, Cephapirin, Cyclacillin, Hetacillin, Loracarbef, Methicillin, Mezlocillin, Moxalactam, Nafcillin, Ticarcillin, Capreomycin, Demeclocycline, Dirithromycin, Methacycline, Oxytetracycline, Spectinomycin, Troleandomycin, Viomycin, Enoxacin, Novobiocin, Alatrofloxacin, Cinoxacin, Lomefloxacin, Nalidixic Acid, Sparfloxacin, Trovafloxacin, Acetohydroxamic Acid, Marinol, Ethoxzolamide, Acetohexamide, Fenoprofen, Oxyphenbutazone, Carprofen, Oxaprozin, Phenylbutazone, Tolmetin, Meclofenamic Acid, Methylergonovine, Acetophenazine, Carphenazine, Chlorprothixene, Mesoridazine, Tnflupromazine, Promazine, Benzphetamine, Phenmetrazine, Chlorotrianisene, Estrone, Mestranol, Polyestradiol, Quinestrol, Cortisone, Fluprednisolone, Meprednisone, Paramethasone, Oxamniquine, Azatadine, Bromodiphenhydramine, Buclizine, Carbinoxamine, Chlophedianol, Dexbrompheniramine, Diphenylpyraline, Mepyramine, Methdilazine, Trimeprazine, Tripelennamme, Triprolidine, Romidepsin, Primidone, Butabarbital, Chlormezanone, Flurazepam, Glutethimide, Halazepam, Meprobamate, Metharbital, Methyprylon, Prazepam, Quazepam, Secobarbital, Talbutal, Thiamylal, Gamma Hydroxy butyric Acid, Memantine, Triclofos, Piperazine Hexahydrate, Desoxycorticosterone Pivalate, Pargyline, Carbachol, Oxyphenonium Bromide, Anisotropine, Clidinium, Cycrimine, Dicyclomine, Diphemanil, Ethopropazine, Fesoterodine, Hexocyclium, Isopropamide, Mepenzolate, Methanthelme, Methylscopolamine, Metixene, Orphenadrine, Oxyphencyclimine, Procyclidine, Propantheline, Tridihexethyl, Trospium, Decamethonium, Pentolinium Tartrate, Cisatracurium Besylate, Succinylcholine Chloride, Doxacurium, Gallamine, Metocurine, Pancuronium, Pipecuronium, Rapacuronium, Tubocurarine, Guanadrel, Phendimetrazine, Anileridine, Difenoxin, Diphenoxylate, Levomethadyl, Oxymorphone, Propoxyphene, Levallorphan, Methylnaltrexone, (+ / -)-Sulfinpyrazone, Pamidronic Acid, Risedronate, Tiludronate, Clofibrate, Dyphylline, Inamrinone, Vardenafil, Ethynodiol, Hydroxyprogesterone, Norethynodrel, Ulipristal Acetate, Carboprost, Etretinate, Methysergide, Chlorphentermine, Acetyldigitoxin, Deslanoside, Chlorpropamide, Tolazamide, Tolbutamide, Methyclothiazide, Benzthiazide, Chlorothiazide, Cyclothiazide, Hydroflumethiazide, Polythiazide, Quinethazone, 5-Fluorouracil, Dextrothyroxine, Metyrosine, Rimantadine, Adefovir, Anisindione, Dicumarol, Nisoldipine, Trimethadione, Bepridil, Paramethadione, Bretylium Tosylate, Mephenytoin, Benzonatate, Ethotoin, Indecainide, Moricizine, Phenacemide, Tocainide, Pyrvinium Chloride Dihydrate, Halofantrine, Metaxalone, Diphenidol, Mebutamate, Chlorphenesin, Phensuximide, Thiabendazole, Benzquinamide, Piperacetazine, Ethchlorvynol, and Ethinamate. IV. PRODUCTION

[0192] In some embodiments, the engineered platelets described herein may be produced using the technique described in Ito et al. (Cell, 174(3): 636-648.e!8, 2018, which is hereby incorporated by reference in its entirety). Ito provides a method of clinical scale production of platelets from iPSC progenitors. Turbulence was observed to activate platelet biogenesis for clinical scale ex vivo production of platelets from human-induced pluripotent stem cells (iPSCs) (Ibid.). iPSCs derived from immortalized megakaryocyte progenitor cell lines (imMKCLs) were combined with soluble factors insulin Like Growth Factor Binding Protein 2 (IGFBP2), macrophage migration inhibitory factor (MIF), and nardilysm convertase (NRDC) in a bioreactor with control over the physical parameters of turbulent energy and shear stress (Ibid.). Production of greater than 1011 platelets were observed (Ibid.). Platelets were observed to function analogously to those derived from donors (Ibid.).

[0193] In certain embodiments of the invention herein, the imMKCL may be established by introducing cancer-derived MYC (c-MYC) / polycomb ring finger proto-oncogene (BMI-1) and BCL2 1 like 1 (BCL-XL) genes into the iPSC using a lentivirus. Additional genes may be introduced or deleted resulting in an edited megakaryocyte, in fact even platelet specific promoters have been previously characterized. These genes provide inducible gene expression in the presence of an agent, such as doxorubicin (DOX). The imMKCL may be cyropreserved until cultivation is desired. Megakaryocyte expansion is stimulated by contacting the cell line with the agent resulting expression of the inserted genes. The agent is removed to halt gene expression and allow platelet production.

[0194] Current Federal Drug Administration (FDA)-approved rules for storage of platelets for transfusion require storage at 22°C and must be used within 6 days. Slichter et al. “Treatment of Bleeding in Severely Thrombocytopenic Patients with Transfusion of Dimethyl Sulfoxide (DMSO) Cryopreserved Platelets (CPP) Is Safe - Report of a Phase 1 Dose Escalation Safety Trial”. Blood, 2016, which is hereby incorporated by reference in its entirety, hypothesizes cry opreservation is possible for two years when frozen with DMSO. After a positive phase 1 trial, phase 2 and 3 trials are underway. Infusion of up to three sequential units of cryopreserved platelets (CPP) in patients with severe thrombocytopenia and active bleeding appeared to be “safe and without any evidence of thrombotic complications despite CPP having a procoagulant phenotype resulting from the cryopreservation process.” Therefore, cryopreserved platelets likely have efficacy for stabilizing, reducing, or stopping bleeding in thrombocytopenic patients as measured using the World Health Organization (WHO) bleeding grades. No evidence was found to undermine the hypothesis that cryopreserved platelets used for non-clotting purposes would be as effective as platelets stored according to the present FDA rules, V. PHARMACEUTICAL COMPOSITIONS

[0195] The present teachings further comprise pharmaceutical compositions comprising one or more of the engineered platelets of the present invention, and optionally at least one pharmaceutically acceptable excipient or inert ingredient. Further, a pharmaceutical may comprise the therapeutic delivery system described herein.

[0196] As used herein the term “pharmaceutical composition” refers to a preparation of one or more of the engineered platelets described herein, or pharmaceutically acceptable salts thereof, optionally with other chemical components such as physiologically suitable carriers and excipients.

[0197] The term “excipient” or “inactive ingredient” refers to an inert or inactive substance added to a pharmaceutical composition to further facilitate administration of a compound. Non-limiting examples of such inert ingredients are disclosed herein under Formulations.

[0198] In some embodiments, compositions are administered to humans, human patients or subjects. For the purposes of the present disclosure, the phrase “active ingredient” generally refers to any one or more of the engineered platelets to be delivered as described herein.

[0199] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to any other animal, e.g., to non-human animals, e.g. non-human mammals. Subjects to which administration of the pharmaceutical compositions is contemplated include, but are not limited to, non-human mammals, including agricultural animals such as cattle, horses, chickens and pigs, domestic animals such as cats, dogs, or research animals such as mice, rats, rabbits, dogs and nonhuman primates.

[0200] A pharmaceutical composition in accordance with the invention may be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. As used herein, a “unit dose” is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is general ly equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

[0201] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient or inert ingredient, and / or any additional ingredients in a pharmaceutical composition in accordance with the invention will vary, de...

Claims

1. An engineered megakaryocyte or progenitor thereof that has reduced thrombogenic potential; and / or is capable of producing a platelet that has reduced thrombogenic potential, comprising a disruption of or deletion in at least two of the following:a) a gene that encodes a protein involved in recognition of primary stimuli of thrombus formation, selected from the group consisting of: GPIb / V / IX and GPVI (GP6), ITGA2B, CLEC2, integrins s aIIbp3, a2p1, a5p1 and a6P1,, or from the group consisting of GPVI and ITGA2B;b) a gene that encodes a protein involved in recognition of secondary mediators of thrombus formation, selected from the group consisting of Par1, Par4, P2Y12, GPIb / V / IX, the Thromboxane receptor (TBXA2R), P2Y1, P2X1 and integrin aIIbp3 or from the group consisting of Pari, Par4 and P2Y12; and / orc) a gene that encodes a protein involved in the release of secondary mediators of thrombus formation, selected from the group consisting of Cox1, HPS and thromboxane-A synthase (TBXAS1) or from the group consisting of Cox1 and HPS,and wherein the disruption or deletion is a disruption of the function of the protein.

2. The engineered megakaryocyte or progenitor thereof of claim 1, wherein the engineered megakaryocyte or progenitor thereof comprises at least three disruptions of, or deletions in, two or more of the pathways specified in (a), (b), and (c).

3. The engineered megakaryocyte or progenitor thereof according to claim 1 or 2, wherein each of the following genes is disrupted or deleted: GPVI, ITGA2B, Par1, Par4, P2Y12, Cox1 and HPS.

4. The engineered megakaryocyte or progenitor thereof of any of claims 1-3, wherein the disruption of said gene comprises altering expression of the said gene(s), optionally with RNA interference construct (RNAi), small interfering RNA (siRNA), microRNA (miRNA), or short hairpin RNA (shRNA).2020407437   05 Aug 20265. An engineered platelet produced by the engineered megakaryocyte or progenitor thereof according to any one of claims 1-4.

6. The engineered megakaryocyte or progenitor thereof according to any one of claims 1-4, or the engineered platelet of claim 5, further comprising a cargo, optionally wherein:a) the cargo is:i)      a protein or peptide;ii)     a therapeutic drug;iii)     a toxin;iv) a nucleic acid, optionally a therapeutic RNA or an mRNA;v)     a cosmetic agent;vi)    a soluble cargo;vii) a membrane-bound cargo;viii) an imaging agent;ix)    a CRISPR / Cas system;x)    a guide RNA;xi) a small molecule, optionally a small molecule drug;xii) a passively loaded therapeutic agent;xiii) a genetically encoded therapeutic agent;xiv) a passively loaded imaging agent; and / orxv) a genetically encoded imaging agent; and / orb) the cargo comprises an alpha-granule localisation signal.

7. A delivery system comprising the engineered megakaryocyte according to any one of claims 1 to 4 and 6, or the engineered platelet according to any one of claims 5 and 6, and a cargo, optionally where the cargo is a therapeutic agent.

8. A targeted delivery system comprising the engineered megakaryocyte according to any one of claims 1 to 4 and 6, or the engineered platelet according to any one of claims 5 and 6, and a cargo, wherein the megakaryocyte further comprises:a) a chimeric platelet receptor, wherein the chimeric platelet receptor comprises: i) an intracellular domain that is a platelet stimulation domain and comprises domains from an immunoreceptor tyrosine-based activation motif (ITAM) receptor; and2020407437   05 Aug 2026ii) a heterologous targeting domain that recognizes and binds a target;b) a nucleic acid encoding a chimeric platelet receptor wherein the chimeric platelet receptor comprises:i) an intracellular domain that is a platelet stimulation domain and comprises domains from an immunoreceptor tyrosine-based activation motif (ITAM) receptor; andii) a heterologous targeting domain that recognizes and binds a target;c) a vector that comprises a nucleic acid encoding a chimeric platelet receptor wherein the chimeric platelet receptor comprises:i) an intracellular domain that is a platelet stimulation domain and comprises domains from an immunoreceptor tyrosine-based activation motif (ITAM) receptor; andii) a heterologous targeting domain that recognizes and binds a target; and / ord) a viral vector or viral particle that comprises a nucleic acid encoding a chimeric platelet receptor wherein the chimeric platelet receptor comprises: i) an intracellular domain that is a platelet stimulation domain and comprises domains from an immunoreceptor tyrosine-based activation motif (ITAM) receptor; andii) a heterologous targeting domain that recognizes and binds a target.

9. A therapeutic delivery system comprising the engineered megakaryocyte according to any one of claims 1 to 4 and 6, the engineered platelet according to claim 5 or 6, and a cargo, the delivery system of claim 7, or the targeted delivery system of claim 8, optionally wherein the cargo is a therapeutic agent.

10. The therapeutic delivery system according to claim 9, wherein the cargo, optionally the therapeutic agent:a)     is packaged within an a-granule;b)     comprises an a-granule localization signal;c) coats the surface of the megakaryocyte or platelet;d)     is a proteine)     is a nucleic acid; and / orf) is a small molecule, optionally coating the surface.2020407437   05 Aug 202611. A method of using the megakaryocyte or progenitor thereof according to any one of claims 1 to 4 and 6 to produce platelets, comprising the step of incubating said megakaryocyte or megakaryocyte progenitor under conditions that cause production of platelets.

12. The method according to claim 11:a) further comprising the step of loading a therapeutic agent onto the platelets by incubating the platelets with the therapeutic agent; and / orb) wherein the platelet has reduced thrombogenic potential.

13. Use of the engineered megakaryocyte according to any one of claims 1 to 4 and 6, or the engineered platelet according to any one of claims 5 and 6, in the manufacture of a medicament for delivering a cargo.

14. A method of delivering a cargo comprising administering an effective amount of any one or more of the engineered megakaryocyte according to any one of claims 1 to 4 and 6, or the engineered platelet according to any one of claims 5 and 6 to a subject.

15. The use according to claim 13, or the method according to claim 14 , wherein the cargo is a therapeutic cargo, optionally a therapeutic agent, or an imaging cargo.

16. A non-therapeutic method of delivering cargo to a subject in need thereof, comprising administering any one or more of the engineered megakaryocyte according to any one of claims 1 to 4 and 6, or the engineered platelet according to any one of claims 5 and 6.

17. A method for the treatment or prevention of any one or more of cancer, an autoimmunity disease, and / or an infection, the method comprising administering an effective amount of any one or more of the engineered megakaryocyte according to any one of claims 1 to 4 and 6, or the engineered platelet according to any one of claims 5 and 6.

18. Use of one or more of the engineered megakaryocyte according to any one of claims 1 to 4 and 6, and / or the engineered platelet according to any one of claims 5 and 6 in the2020407437   05 Aug 2026manufacture of a medicament for the treatment or prevention of any one or more of cancer, an autoimmunity disease, and / or an infection.

19. A kit comprising any two or more of the following:the engineered megakaryocyte according to any one of claims 1 to 4 and 6;the engineered platelet according to any one of claims 5 and 6; and a therapeutic agent and / or an imaging agent.

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