Fusion proteins for imaging and treatment of infectious diseases and cancer

Abstract

Disclosed are proteins that bind to structures associated with numerous pathogenic microorganisms and tumors. The disclosed proteins are pan-therapeutic anti-microbials and anti-cancer agents and are useful as imaging agents suitable to detect and monitor infections and tumors or the progress of infections and tumors in mammals including human beings.

Description

[0001] 10255 / PC Fusion proteins for imaging and treatment ofinfectious diseases and cancerThe present specification comprises a sequence listing in computer readable format, submitted together with the application. The sequence listing forms part of the disclosure and is incorporated in the specification in its entirety.The present invention relates to the use of phosphatidylserine or pathogenic sugar targetedprotein therapeutics for the management and treatment of human and animal microbialinfections and cancer.The present invention also relates to the use of these targeting proteins as imaging agentsfor real time in vivo detection and localization of infection and cancer in humans andanimals. This invention may inter alia be used for diagnosis of infection and cancer, forselection of subjects that may benefit from therapies, such as interventional therapies, andfor assessment of therapeutic response. Provided are compositions related to novel, therapeutic proteins including pathogen neutralizing proteins from different species, including human, monkey, dog, cat, chicken, cow and pig, that may be conjugated to furin protease inhibitors, T cell engagers, platformswith cytotoxic functions, monovalent and multivalent molecules, drug conjugates andadjuvants, carriers and methods of administration, in particular subcutaneous, oral or nasal administration. This invention further relates to a companion diagnostic as a method of selection of subjects that may benefit from such therapies and a blood biomarker fordetection of early and repeat infection, as well as monitoring response of treatment.Technical BackgroundAccording to WHO, the Arboviruses, Zika Virus (ZIKV), Chikungunya (CHIKV), Dengue (DENV),West Nile (WNV), as well as Ebola (EBLV) and SARS are relatively recent, life-threatening, rare diseases prone to pandemic spread that pose a high global public health risk (WHOreport 2020). The development of therapeutics that are not strain or pathogen specific and 10255 / PC are readily available for new pandemics is a priority. Many diseases with pandemic potentialare vector-borne, requiring a vector such as a mosquito or tick to transmit an infection fromanimals to humans, and this includes Lyme, WNV, ZIKV and DENV. Others, such as rotavirus,rabies, influenza and Ebola, are transmitted from vertebrate animals to humans and vice-versa through food, water, and bites. 2022 outbreaks of highly transmissible avian Influenza(H5N1) in poultry, and monkeypox in human, in non-endemic areas, underscore theimportance of preventing and mitigating their occurrence in animals. In addition, there areno drugs to treat common, life-threatening animal infections such as rabies, canineparvovirus, and distemper nor broad spectrum anti-virals available (Adalja and Inglesby,2019). Most anti-virals are designed to block the function of one specific viral protein uniqueto a specific virus or viral family. A few antibodies and RNAi compounds have beencommercialized that treat specific viruses. Acyclovir, valacyclovir, and famciclovir arethymidine kinase inhibitors indicated for herpes family viruses such as herpes simplex virus 1(HSV-1), HSV-2, and varicella-zoster virus (VZV) with a very narrow spectrum. Similarly, anti-HIV medications are highly specific to HIV viral proteins such as the reverse transcriptase,protease, integrase, and gp41. Hepatitis C (HCV) protease (NS3 / 4A) inhibitors, such as simeprevir, have activity only against specific genotypes (e.g.1 and 4 for simeprevir) of HCV.At most, a pan-genotypic combination regimen for HCV has been developed(http: / / www.hcvguidelines.org). Attempts to develop drugs that target a protein universal toRNA viruses have been made. Favipiravir, an RNA polymerase inhibitor, exhibits activityagainst Influenza, Ebola and Lassa, however failed to benefit COVID19 patients.Ribavirin, a nucleoside analog that inhibits viral polymerase enzymes, has activity against RNA viruses such as RSV, hepatitis C, influenza A and B, parainfluenza viruses, hepatitis E, metapneumovirus, Crimean-Congo Hemorrhagic Fever (CCHF) and New and Old-WorldHemorrhagic Arenaviruses (e.g. Lassa Fever, Junin). However, these antivirals are alsoassociated with serious toxicity concerns.Host immunomodulatory compounds such as interferon and imiquimod can be conceptually thought of as broad spectrum. However, they do not target a virus directly as they augment intrinsic antiviral activities possessed by the immune system of the host.Therefore, there is an unmet need for pan-microbial therapeutics. 10255 / PCThere is a similar unmet need in the field of oncology. Cancer cells present aberrantglycosylation profiles that affect the metastatic process. Gangliosides such as GD2 areenriched in several solid tumors, such as neuroblastoma and sarcoma, and both anti-GD2therapeutic antibodies and a GD2 vaccine have been successful to manage neuroblastoma, apediatric cancer (Danyelza®, YmAbs Therapeutics, and Unituxin®, United Therapeutics,Cheung, 2021). Targeting glycan signatures that are not expressed in normal cells and arecommon structures on several proteins and lipids on cancer and bacterial cells such as the N-glycan Mannose 9 broadens the spectrum of cancers recognized by the immune system andhas therapeutic potential against resistant tumors due to loss of a protein antigen as well asprotein heterogeneous cancers.Mannose 9 accumulates on advanced, metastatic breast and prostate cancers (de Leoz,2011, Bhat 2017, Scupakova 2021). This is in part due to reduced expression or processing ofmannose-trimming enzymes during cancer progression (Bhat 2017). Therefore, Mannose 9 isan attractive target for pan-therapy and a potential biomarker of disease progression and treatment response.Another surface molecule with pan-potential is phosphatidylserine (PS). In normal cells,phosphotidylserine is present in the inner leaflet of the plasma membrane. In microbes andtumors, PS exposure on the surface leads to immune suppression, cell infection and thepromotion of tumor growth. Imaging agents are key to understanding the pathophysiology, localization and severity ofinfection as well as evaluating response to therapies in both animal models and humansubjects. Several strategies to image pathogens have been explored including labelling antimicrobialpeptides, antibiotics, anti-fungals, anti-virals (Di Mascio 2009, Hatori, 2009, Bergstrom 1999,Cass 1999), substrates of bacterial metabolic pathways (for review see Bray 2010) andthymidine or guanosine analogs such as [124I]-2-fluoro-1-h-D-arabino-furanosyl-5- iodo-uracil([124I] FIAU), [18F]-2-fluoro-2-deoxy1-h-D-arabionofuranosyl-5-ethyl-uracil ([18F] FEAU),fluoroganciclovir or 9-[(3-18F-fluoro-1-hydroxy-2-propoxyl)methyl]guanine([18F] (Ady andFong 2014). 10255 / PC Due to the detection of high-energy photons emitted by radionuclides, PET and SPECT have no tissue depth penetration limits, spatial resolution between 1-12 mm and are also highly sensitive (10-10–10-12M) compared to other imaging modalities such as MRI (10-3–10-5M). After injection, as few as 1x 107viral particles in a 0.5-cm diameter tumor can be detected by [124I] FIAU-PET imaging. Furthermore, PET scanning can detect changes in viral concentrationreliably and sensitively (Bennett 2001).Exceptionally bright near-infrared imaging has been achieved by encapsulating Cyanine dyes in inert < 10 nm silica shells compared to dye alone. These stable and renally cleared C dots can be functionalized at the surface and multiplexed and have been translated clinically for lymph node mapping and the detection of disease lesions in cancer (Phillips 2014, Yoo, 2015, Chen 2017, Chen 2019).Zhang et al (Zhang 2014) showed that the liposomal nanoprobe PGN-L-IO / DiR, which bindsspecifically to PS and is subsequently internalized into cells, was a feasible imaging contrastagent in mice bearing MDA-MB231 breast tumors (Zhang 2014). Kannadorai et al (Kannadorai2016) showed that Indocyanine green (ICG) bound to PS antibodies was useful to track andimage apoptosis in triple-negative breast cancer cells (Kannadorai 2016). Phosphatidylcholine-stearylamine (PC-SA) is a cationic liposomal carrier that specifically bindsto PS on cancer cells and tumors (De 2018). PC-SA showed anticancer effects as a single agentand additional efficacy when loaded with camptothecin or doxorubicin in mouse tumormodels. PC-SA enhanced the half-life of the antitumor drugs and showed no remarkabletoxicity. DPA-Cy3 is a lipid-soluble zinc(II)-bis-dipicolylamine derivative that contains the fluorophore cyanine 3 (Cy3) and two 22-carbon chains that can be anchored into liposomal membrane bilayers. DPA-CY3 and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) liposomeswere shown to bind to PS-enriched cancer cells (Ayesa 2017) and exert an antitumor effectwithout any drugs loaded.Bavituximab, is a human-mouse chimeric monoclonal antibody that binds to PS indirectlythrough binding to β2GP1, a PS binding glycoprotein, with high affinity. It has been shown thatbavituximab blocks PS and promotes M1 macrophage maturation and cellular cytotoxicityagainst tumors. Bavituximab is being evaluated in several clinical trials as a monotherapy and 10255 / PCin combination with chemotherapy and immune checkpoint inhibitors (for review Chang2020). US 2023 / 0338465 discloses fusion proteins comprising a PS-binding domain an a domaincapable of binding a pathogen associated molecular pattern and the use therefore fortreatment of infectious diseases. WO20257011639 discloses fusion protein comprising an antibody binding domain capable of binding a lectin, CLEC5A, and an antibody domain binding a tumor associated antigen, and theuse of such a fusion protein for the treatment of certain cancers.WO 2023 / 150672 discloses fusion proteins capable of binding phosphatidyl serine and animmunostimulatory domain, and the use thereof for the treatment of certain cancers.Summary of the inventionThe invention relates to a method of treating, diagnosing or imaging cancer using a proteincomprising a polypeptide capable of binding to phosphatidylserine (PS) and / or a polypeptidecapable of binding a pathogen associated molecular pattern (PAMP).The invention further relates to a method of treating, diagnosing or imaging microbialinfections or infectious agents using a protein comprising a polypeptide capable of binding to phosphatidylsering (PS) and / or a polypeptide capable of binding a pathogen associatedmolecular pattern (PAMP).The polypeptide capable of binding PS and / or the polypeptide capable of binding a PAMP may be of human or animal origin, or it may be synthetic polypeptides designed based on knowledge of the sequences of such polypeptides. The polypeptide is typically prepared as a fusion protein linking one or more polypeptides having different functionality such as binding to PS or PAMP, antibody effector functions, immune cell recruiting domain, payloads etc. In a further aspect the invention relates to the use of the protein of the invention for imaging, detecting or localizing microbial infections or cancer in a sample, typically a tissue sample. 10255 / PCThe invention further relates to compositions comprising the protein of the inventions,nucleic acids encoding the protein, expression vectors and host cells comprising such nucleic acids, as well as method for producing the protein of the invention.According to an aspect, the invention concerns a method of treating, diagnosing or imagingcancer, infectious agents or tissues infected with an infectious microorganism using fusionconstruct comprising an Ig-Fc domain or other protein scaffold, such as albumin, and a. a peptide, protein, or antibody fragment binding to phosphatidylserineand / or b. a peptide or protein binding to and / or recognizing a PAMP expressed by amicrobe. In some embodiments the fusion protein used according to the invention is in form of a chimeric antigen receptor (CAR) or an immune cell comprising such a CAR. In some embodiments the fusion protein used according to the invention is in form of a small polypeptide comprising a. a peptide, protein, or antibody fragment binding to phosphatidylserineand / or b. a peptide or protein binding to and / or recognizing a PAMP expressed by amicrobe; additionally comprising one or more amino acid residue, such as a cysteine residue, allowing attachment of a payload, e.g. a nanoparticle optionally loaded with other functional agents; to the protein. PAMP refers to Pathogen-associated molecular pattern: conserved molecular structures produced by microbial pathogens, but not by the host organism that are recognized by the host innate immune system. According to another aspect, the invention concerns a fusion construct comprising an IgG-Fc domain or other protein scaffold and a. a human, monkey, cow, dog, cat, pig or chicken TIM1 fragment and / orb. a human, monkey, cow, dog, cat, pig or chicken CD209 fragment. 10255 / PC According to another aspect, the invention concerns a fusion construct comprising an IgG-Fc domain or other protein scaffold and a. a human, monkey, cow, dog, cat, pig or chicken TIM1 fragment and / orb. a human, monkey, cow, dog, cat, pig or chicken CD209 fragmentand wherein said fusion construct provides enhanced ADCC, ADCP and / or CDC. ADCC may be defined as Antibody-Dependent Cellular Cytotoxicity. ADCP may be defined as Antibody-Dependent Cellular Phagocytosis. CDC may be defined as Complement-dependent cytotoxicity. According to another aspect, the invention concerns a fusion construct comprising an IgG-Fc domain or other protein scaffold and a. a human, monkey, cow, dog, cat, pig or chicken TIM1 fragment and / orb. a human, monkey, cow, dog, cat, pig or chicken CD209 fragmentand wherein said fusion construct additionally comprises a CD3 binding site. According to another aspect, the invention concerns a fusion construct comprising an IgG-Fc domain or other protein scaffold and a. a human, monkey, cow, dog, cat, pig or chicken TIM1 fragment and / orb. a human, monkey, cow, dog, cat, pig or chicken CD209 fragmentand wherein said fusion construct additionally comprises a CD16 binding site.According to another aspect, the invention concerns a fusion construct comprising an IgG-Fc domain or other protein scaffold and a. a human, monkey, cow, dog, cat, pig or chicken TIM1 fragment and / orb. a human, monkey, cow, dog, cat, pig or chicken CD209 fragmentand wherein said fusion construct further comprises a Furin inhibitor.Preferably the Furin inhibitor is selected among chloromethylketone and D-arginine derivatives such as hexa-D-arginine and dec-RVKR-cmk The linker and spacers that may be used in connection with furin Inhibitors are disclosed in WO2022040436A1. The disclosure of this document is incorporated by reference. 10255 / PCAccording to another aspect, the invention concerns a fusion construct, wherein said fusionconstruct comprises an IgG1 homodimer or an IgG1 heterodimer.According to another aspect, the invention concerns use of a fusion construct according tothe invention for the treatment of an infection or a cancer.According to another aspect, the invention concerns use, wherein said infections areselected among viral, bacterial, fungal and protozoan infections.According to another aspect, the invention concerns use, wherein the treatment comprisingadministration of the fusion construct with an administration form selected among subcutaneous, intradermal, intramuscular, oral and nasal.According to another aspect, the invention concerns use of IgG4 or a part of IgG4 for payloaddelivery, wherein said IgG4 has been modified to comprise no Fc or wherein the activity of the Fc of said IgG4 has been nullified or diminished by one or more mutations.According to another aspect, the invention concerns use of IgG1 or a part of IgG1 for payloaddelivery, wherein said IgG1 has been modified to comprise no Fc or wherein the activity ofthe Fc of said IgG1 has been nullified or diminished by one or more mutations.Despite great advances in the field of imaging devices, there is a paucity of approved fluorescence-based imaging agents and a great unmet need for non-invasive, targeted fluorescence-based technologies to study and treat diseases.According to an aspect the invention relates to a protein comprising a polypeptide capable ofbinding to phosphatidylserine (PS) and / or a polypeptide capable of binding a pathogen-associated molecular pattern (PAMP).The protein and / or the liposomes of the invention are useful for binding to infectious agentsand infected tissues and are useful for generating images showing the degree and location ofinfections by use of a device detecting the label. According to an aspect the invention relates to methods for in vivo or in vitro detection and localization of infections, as well as compositions, in particular pharmaceutical compositions for use in such methods. 10255 / PC According to an additional aspect the invention relates to nucleic acids and expression vectors encoding the proteins of the invention, host cells comprising such nucleic acids or expression vectors and methods of producing the proteins using such host cells. Detailed Disclosure Fusion proteins Similarities in the way pathogens bind to permissive human or animal cells offer opportunities to develop non-invasive, real time, and highly specific imaging agents for the study of new or re-emerging infectious diseases vital to accelerated drug development. Host C-type lectin receptors that recognize specific glycans have been shown to bind pathogens and to play a role in host defense. Glucans, polysaccharide moieties derived from D-glucose and linked to surface proteins or lipids, are prominent constituents of the cell walls of fungi, plants, and mycobacteria. High-mannose containing structures (mannans) are expressed by many viruses, fungi, and bacteria, and fucose structures (fucans) are found on the surface of helminths and some bacteria (Geijtenbeek and Gringhuis, 2009; Robinson et 25 al., 2006). Microbes are extensively glycosylated to facilitate several functions during infection (Watanabe 2019). Many have evolved to exploit host-cell glycosylation pathways anddecorate the surface of their proteins with “self” glycan moieties mainly of the O- and N-linkage type. For example, glycans on viral glycoproteins aid in folding and trafficking through the host secretory pathway. Influenza viruses have carbohydrate cleaving ability to modulate viral release. HIV, Dengue, RSV, Lassa and Ebola viruses evade the immune system by shedding glycoproteins that act as decoys or enhance infection, and HIV, Ebola, Coronavirus and Influenza, among others, shield their immunogenic surface with heavily glycosylated viral entry proteins. Viral glycans are also attachment factors that facilitate cell uptake by immune or target host cells, increasing infection. The myeloid, dendritic and macrophage cell specific C-type lectin receptor CD209 (also known as DC-SIGN), (Zelensky and Gready, 2005) is an important host cell receptor for entry of ZIKV (Perera Lecoin, 2013, Osorio and Sousa 2011), Influenza (Gillespie 2016), DENV (Cruz- Oliveira, 2015), WNV (Davis 2006), Ebola (Alvarez 2002), enterovirus (REN 2014), 10255 / PC mycobacterium tuberculosis (Tailleux 2003) and mycobacterium Leprae (Barreiro 2006) and SARS-COV2 / COVID19 (Amraei 2020, Cai 2020, Jeffers 2004). The protozoan vector borne disease Leshmaniasis and Malaria are non-viral pathogens that may exploit CD209 for host entry (Colmenares 2002, Morenikeji 2020). CD209 binds to both mannan (Oligomannose (Man5-8GlcNAc2) or high-mannose (mannose 9 or Man9GlcNAc2) glycans) and fucan moieties that comprise viral signatures or pathogen associated molecular patterns (PAMPs). The binding occurs within a compact protein region with a unique structural fold that became known as the ‘‘C-type carbohydrate recognition domain’’ or ‘‘C-type lectin domain(CTLD)’’ (Weis and Drick- Amer, 1996).Specifically, DC-SIGN binds to the Manα1-3(Manα1-6)-Manα, tri-mannose structure and additional affinity enhancements are observed in the presence of one or more Manα1-2Manα- moieties on the non-reducing termini of oligomannose structures (Feinberg 2007).Specificity to oligomannose-type glycans is conferred by the presence of a phenylalanine side chain in the CRD (C-type carbohydrate recognition domain) that acts as a steric block obstructing the GlcNAc residues of the N-linked glycan core, when a core mannose residue of a complex-type glycan attempts to bind. This selectivity to oligomannose-type glycans ensures that DC-SIGN interactions are predominantly with foreign pathogens, due to the rarity of oligomannose-type glycans expressed on correctly processed host glycoproteins (Doores, 2010). The outer virus membrane layer of several viruses is rich in phospholipid phosphatidylserine (PS) whereas in the host cell membrane, PS is normally restricted to the inner membrane layer. TIM-1 (also known as HAVCR1) is a viral entry cofactor for several viruses (Ebola, Zika, Dengue, West Nile, HIV, Hepatitis A and C, RSV, Lassa, JEV, Marburg, Chikungunya, COVID19)(Jemielity, 2010), plasmodium (malaria), and bacteria (Streptococcus pneumonia) due to itsextended stalk and PS-binding capacity through a conserved N-terminal IgV extracellular domain. While TIM-1 binding to PS facilitates pathogen entry through endocytosis or membrane fusion, TIM-1 also has an inhibitory function on viral release from the infectedcell (Moller-Tank, 2014; Evans and Liu, 2019). In normal human tissues, TIM-1 expression isrestricted to CD4+ T cells in particular T-helper 2 (Th2) cells, mast cells and regulatory B cells(Freeman, 2010) and has a potent stimulatory effect on T-cells (Kane, 2010). 10255 / PCIt has been shown that TIM-1 is an entry factor for highly divergent viruses (Jemielity, 2013),including Zika (Lee, 2018), Ebola (Brunton, 2019), Dengue (Chu, 2019; Amara; 2015), WestNile (Richard, 2015), Hepatitis A and possibly Malaria (Nuchnoi, 2020). TIM-1 (also known asHAVCR1) is a type I transmembrane glycoprotein that contains an extracellular domain composed of an N-terminal immunoglobulin variable (IgV)-like domain followed by a glycosylated mucin domain, a single transmembrane domain, and a short cytoplasmic tail with tyrosine phosphorylation motifs. The binding of TIM-1 with PS on apoptotic cells through its metal ion-dependent ligand binding site (MILIBS) within IgV domain promotes apoptotic clearance. TIM-1 is a well-known PS receptor although other PS receptors have been described to a lesser extent such as Tyro3, Axl and Mer of the TAM family of proteins.According to an embodiment, the invention relates to the use of a protein comprising apolypeptide capable of binding to phosphatidylserine (PS) and / or a polypeptide capable ofbinding a pathogen-associated molecular pattern (PAMP).The polypeptide used according to the invention has the ability to bind PS and / or PAMP andit will therefore after in vivo administration to a subject bind to PS and / or PAMP and will therefore be located on surfaces where PS and / or PAMP are present which will mainly beinfectious microorganisms, tumors and apoptotic cells. Consequently, the polypeptide will,after in vivo administration, mainly bind to infected cells or tumor cells and the localizationof the polypeptide will give a picture of an infection and the affected tissues. Thepolypeptide may also be used ex vivo, e.g., administered to a tissue sample, e.g. a biopsy ora blood sample, in order to assess an infection and / or to follow the development of aninfection in the subject from which the sample was taken.The polypeptide capable of binding to PS and the polypeptide capable of binding PAMP areconnected via covalent or non-covalent bindings or consists of a single polypeptidecomprising a part capable of binding PS and a part capable of binding PAMP. In principle, anytechnique to attach one polypeptide to another polypeptide may be used to connect thepolypeptide capable of binding PS to the polypeptide capable of binding PAMP as long as theconnection is stable after administration, and the capability of binding PS and the capabilityof binding PAMP is not impeded by the connection. It is preferred that the polypeptideconsists of a single polypeptide comprising a part capable of binding PS and a part capable ofbinding PAMP because this provides for a stable connection between the two parts, and it is 10255 / PCfurther convenient to produce the polypeptide as a single polypeptide chain without theneed of any steps for connecting the parts.The part capable of binding PS and the part capable of binding PAMP may be two distinctparts of the polypeptide or they may be partially or completely overlapping.In one preferred embodiment, the polypeptide for use according to the invention consists ofa single polypeptide comprising a domain capable of binding PS and a domain capable ofbinding PAMP, optionally separated by a linker.In another embodiment, the polypeptide capable of binding to PS is selected among TIM-1,TIM-3, TIM-4 and the Tyro3, Ax1 and Mer of the TAM family. Preferably, the polypeptidecapable of binding to PS is derived from TIM-1, a fragment thereof or a polypeptide havingTIM-1, a fragment thereof. The TIM-1 polypeptide may be human TIM-1 or derived from an animal e.g. a mammal such as monkey, pig, cow, dog, cat or mouse, or from a bird, such as a chicken and comprise a sequence selected among SEQ ID NO: 1 or one of SEQ ID NO: 43-49. The polypeptide capable of binding to PS may be a variant of a natural TIM-1 generatedusing knowledge of the structure and sequence of natural TIM-1 sequences. Preferably suchvariants have at least 80% sequence identity, at least 85%, at least 90%, at least 95%, at least96%, at least 97%, at least 98% or at least 99% sequence identity to one of SEQ ID NO: 1 orSEQ ID NO: 43-49. The skilled person will appreciate that a multisequence alignment of natural TIM-1 fragments, such as disclosed in figure 8, can assist in designing variants, because the molecule can afford substitutions in positions that differs between species and still provide a functional molecule, whereas it is not known if change can be tolerated in invariant positions, and therefore should the invariant positions not be altered. Thus, in one embodiment a TIM-1 variant comprises a sequence of XXXVXGVXGXXVTLPCXYRVSTXXXITTMCWGRGCXXXXXCXXXIIWTNGXXVTXXKXXRYXLKGXLXXGDVSLTIX NXXXSDSGXYCCRVEXXGWFNDXKXTXSLXIX (SEQ ID NO: 73) wherein X can be any amino acid, preferably where: the amino acid in position 1 is selected among S, Y, H, and G; the amino acid in position 2 is selected among V, T, S, K, and L; 10255 / PC The amino acid in position 3 is selected among K, N, E, Q, and L; The amino acid in position 5 is selected among G, D, T, N and K; The amino acid in position 8 is selected among A, E, T, and V; The amino acid in position 10 is selected among P, L, Q, E, and H; The amino acid in position 11 is selected among S, P, and N; The amino acid in position 17 is selected among H, R, T, L, A, and F; The amino acid in position 19 is R or absent; The amino acid in position 20 is V or absent; The amino acid in position 21 is S, K or absent; The amino acid in position 23 is selected among G, A, E, and Y; The amino acid in position 24 is S, K, Y, R or absent; The amino acid in position 25 is selected among A, S, E, G, and D; The amino acid in position 35 is selected among S, T, A, E, V, and Q; The amino acid in position 37 is selected among S and P; The amino acid in position 38 is selected among L, A, T, W, I, V, and S; The amino acid in position 39 is selected among F, W, and S; The amino acid in position 40 is selected among T, S, H, Q, K, and A; The amino acid in position 42 is selected among Q, P, S, R, and L; The amino acid in position 43 is selected among N, D, E, and Q; The amino acid in position 44 is selected among G, Y, D, E, V, P, and T; The amino acid in position 51 is selected among T, Y, S, R, and H; The amino acid in position 52 is selected among H, N, K, and R; The amino acid in position 55 is selected among Y, F, and E; The amino acid in position 56 is selected among R and Q; The amino acid in position 58 is selected among D, E, H, and S; The amino acid in position 59 is selected among T, P, R, L, and S; The amino acid in position 62 is selected among K, L, Q, V, and N; The amino acid in position 66 is selected among D, N, Y, K, and H; The amino acid in position 68 is selected among S, G, and L; The amino acid in position 69 is selected among R, H, E, and K; The amino acid in position 77 is selected among E, A, V, K, and L; The amino acid in position 79 is selected among T, V, A, and S; 10255 / PC The amino acid in position 80 is selected among A, K ,D, Q, and V; The amino acid in position 81 is selected among V, L, P, Q, and E; The amino acid in position 86 is selected among V, I, L, Q, and T; The amino acid in position 93 is selected among H, L, K, and I; The amino acid in position 94 is selected among R, S, A, K, and P; The amino acid in position 100 is selected among M, L, I, E, and Q; The amino acid in position 102 is selected among I, V, L, and T; The amino acid in position 104 is selected among V, I, Y, Q, L, and F; The amino acid in position 107 is selected among E, K, S, V, and Q; and / orThe amino acid in position 109 is selected among V, G, R, K, and E. Similar to TIM-1, TIM-3 and TIM-4, belonging to the same family as TIM-1, can bind to PS. There is evidence that TIM-1, TIM-3 and TIM-4 have calcium dependent binding to carbohydrate signatures in cells. There are also high sequence similarities among theseproteins, see alignment in figure 12.TIM-1 and TIM-3 Ig-like V domain sequences have: Sequence identity = 40.4% Sequence similarity = 60.6% TIM-1 and TIM-4 Ig-like V domain sequence have: Sequence identity = 47.2% Sequence similarity = 62.0% As such, the Ig like V-domains of TIM-3 and TIM-4 can be used in place of TIM-1 for generating TIM-3 x CTLD and TIM-4 x CTLD constructs. The TIM-3 polypeptide may be human TIM-3 or derived from an animal e.g. a mammal such as monkey, pig, cow, dog, cat or mouse, or from a bird, such as a chicken and comprise a sequence selected among the sequence of human TIM-3 polypeptide (SEQ ID NO: 80), animal analogues thereof, or it may be a variant of a natural TIM-3 generated using knowledge to the structure and sequence of natural TIM-3 sequences. Preferably such variants have at least 80% sequence identity, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to SEQ ID NO: 80. The skilled person will appreciate that a multisequence alignment of natural TIM-3 fragments, can assist in designing variants, because the molecule can afford substitutions in positions that differs between species and still provide a functional molecule, whereas it is 10255 / PC not known if change can be tolerated in invariant positions, and therefore should the invariant positions not be altered. The TIM-4 polypeptide may be human TIM-4 or derived from an animal e.g. a mammal such as monkey, pig, cow, dog, cat or mouse, or from a bird, such as a chicken and comprise a sequence among the sequence of human TIM-4 polypeptide (SEQ ID NO: 81), animal analogues thereof, or it may be a variant of a natural TIM-4 generated using knowledge to the structure and sequence of natural TIM-4 sequences. Preferably such variants have at least 80% sequence identity, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to SEQ ID NO: 81. The skilled person will appreciate that a multisequence alignment of natural TIM-4 fragments, can assist in designing variants, because the molecule can afford substitutions in positions that differ between species and still provide a functional molecule, whereas it is not known if change can be tolerated in invariant positions, and therefore should the invariant positions not be altered.In another embodiment of the invention, the PAMP, recognized by the polypeptide, isselected among microbial glycans, such as mannans, oliogomannans and fucans; and glycoproteins. Preferably, PAMP is selected among Man5-8GlcNAc2, Man9GlcNAc2, Manα1- 3(Manα1-6)-Manα, tri-mannose structure and oligomannans comprising one or moreManα1-2Manα- moieties on the non-reducing termini of the oligomannose structure.In another embodiment of the invention the polypeptide capable of binding PAMP isselected among lectins. In a preferred embodiment, the polypeptide capable of binding PAMP is selected among a DC-SIGN C-Type lectin polypeptide or a L-SIGN C-type lection polypeptide, a fragment thereof or a polypeptide having at least 80% sequence identity, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%sequence identity to one of SEQ ID NO: 2 and SEQ ID NO: 50-56.The DC-SIGN C-Type Lectin polypeptide may be human DC-SIGN C-Type Lectin or derived from an animal e.g. a mammal such as monkey, pig, cow, dog, cat or mouse, or from a bird,such as a chicken and comprise a sequence selected among SEQ ID NO: 2 or one of SEQ IDNO: 50-56. 10255 / PC The polypeptide capable of binding to PAMP may be a variant of a natural DC-SIGN C-TypeLectin generated using knowledge of the structure and sequence of natural DC-SIGN C-TypeLectin sequences. Preferably such variants have at least 80% sequence identity, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequenceidentity to one of SEQ ID NO: 2 or SEQ ID NO: 50-56.The skilled person will appreciate that a multisequence alignment of natural DC-SIGN C-Type Lectin fragments, such as disclosed in figure 9, can assist in designing variants, because the molecule can afford substitutions in positions that differs between species and still provide a functional molecule, whereas it is not known if change can be tolerated in invariant positions, and therefore should the invariant positions not be altered. Thus, in one embodiment a DC-SIGN C-Type Lectin variant comprises a sequence of XXLCXPCPWXWEXFQGXCYFFSXXQXXWXXSXXACXXXGAQLVXIXSXEEQXFLXXXXXRXNXXTWIGLSDXXXEGXWXWVDXSPLXLSFXQYWKXGEPNNXGXNEDCAEXXXDGQWNDXXCXXEXFWICXKXXXXCP (SEQ ID NO:74)wherein X can be any amino acid, preferably where:the amino acid in position 1 is selected among E, A, D, and L; the amino acid in position 2 is selected among R, G, and F; the amino acid in position 5 is selected among H, R, and G; the amino acid in position 10 is selected among E, H, N, K, D, and Q; the amino acid in position 13 is selected among F, L, H, and Y; the amino acid in position 17 is selected among N, R, and S; the amino acid in position 23 is selected among N, Q, W, L, and V; the amino acid in position 24 is selected among S, T, and A; the amino acid in position 26 is selected among R, S, N, K, and M; the amino acid in position 27 is selected among N, D, T, and S; the amino acid in position 29 is selected among H, K, R, and N; the amino acid in position 30 is selected among D, S, E, and K; the amino acid in position 32 is selected among I, L, V, A, and K; the amino acid in position 33 is selected among T, S, and A; the amino acid in position 36 is selected among K, Q, L, H, and E; the amino acid in position 37 is selected among E, D, L, and N; 10255 / PC the amino acid in position 38 is selected among V, I, L, and M; the amino acid in position 44 is selected among V and I; the amino acid in position 46 is selected among K, N, E, and D; the amino acid in position 48 is selected among A, T, D, and Y; the amino acid in position 52 is selected among N and K; the amino acid in position 55 is selected among Q, K, N, and M; the amino acid in position 56 is L, S, F or absent; the amino acid in position 57 is selected among Q, W, and R; the amino acid in position 58 is selected among S, Y, N, and T; the amino acid in position 59 is selected among S, V, P, T, and R; the amino acid in position 61 is S, Y, N, K or absent; the amino acid in position 63 is selected among R, K, Q, G, and E; the amino acid in position 64 is selected among F, A, P, R, and Y; the amino acid in position 72 is selected among L, D, H, M, and E; the amino acid in position 73 is selected among N, T, H, and S; the amino acid in position 74 is selected among Q, H, N, S, and K; the amino acid in position 77 is selected among T, S, and E; the amino acid in position 79 is selected among Q, R, K, and Y; the amino acid in position 83 is selected among G, N, and D; the amino acid in position 87 is selected among L, Q, T, and R; the amino acid in position 91 is K, M, T, or absent; the amino acid in position 92 is Q, K, or absent; the amino acid in position 93 is Y, F, or absent; the amino acid in position 96 is selected among R, K, and E; the amino acid in position 102 is selected among V, I, H, L, and R; the amino acid in position 104 is selected among E, D, and F; the amino acid in position 105 is N or absent; the amino acid in position 111 is selected among F, L, and V; the amino acid in position 112 is selected among S, H, Y, R, and W; the amino acid in position 113 is selected among G, N, S, D, and T; the amino acid in position 120 is selected among D, S, G, N, T, and V; the amino acid in position 121 is selected among K, R, and Y; 10255 / PC the amino acid in position 123 is selected among N, T, V, and S; the amino acid in position 124 is selected among L, V, T, N, and Y; the amino acid in position 126 is selected among K, N, and C; the amino acid in position 131 is selected among K, E, and L; the amino acid in position 133 is selected among S, P, G, and L; the amino acid in position 134 is selected among A, S, T, and L; the amino acid in position 135 is selected among A, S, V, P, and T; the amino acid in position 136 is selected among S, P, N, and K; the amino acid in position 137 is C or absent; and / or the amino acid in position 138 is S, P, or absent. The L-SIGN C-Type Lectin polypeptide may be human L-SIGN C-Type Lectin or derived from an animal e.g. a mammal such as monkey, pig, cow, dog, cat or mouse, or from a bird, such as a chicken and comprise a sequence selected among SEQ ID NO: 57-64. The polypeptide capable of binding to PAMP may be a variant of a natural L-SIGN C-Type Lectin generated using knowledge to the structure and sequence of natural L-SIGN C-Type Lectin sequences. Preferably such variants have at least 80% sequence identity, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to one of SEQ ID NO: 57-64. The skilled person will appreciate that a multisequence alignment of natural L-SIGN C-Type Lectin fragments, such as disclosed in figure 10, can assist in designing variants, because the molecule can afford substitutions in positions that differs between species and still provide a functional molecule, whereas it is not known if change can be tolerated in invariant positions, and therefore should the invariant positions not be altered. Thus, in one embodiment a L-SIGN C-Type Lectin variant comprises a sequence of XXLCRXCPWXWEFFQGXCYFFSXXQXXWXXSXXACXXXXAQLVIIXSXEEQXFLXXXXXRXNXXTWIGLSDXXXEGXWXWVDXSPLXXSFXXYWKXGEPNNXGFXEDCVEXXXDGQWNDXXCXXENXWICKKPXXPCPXXE (SEQ ID NO:75) wherein X can be any amino acid, preferably where: the amino acid in position 1 is selected among E, A, F, and L; the amino acid in position 2 is selected among R, G, and F; the amino acid in position 6 is selected among H, P, L, and A; 10255 / PC the amino acid in position 10 is selected among D, E, H, N, K, and Q; the amino acid in position 17 is selected among N, R, and S; the amino acid in position 23 is selected among N, Q, W, L, and K; the amino acid in position 24 is selected among S and T; the amino acid in position 26 is selected among R, S, N, and M; the amino acid in position 27 is selected among N, D, T, and S; the amino acid in position 29 is selected among H, K, R, and N; the amino acid in position 30 is selected among D, S, E, and K; the amino acid in position 32 is selected among V, I, L, and K; the amino acid in position 33 is selected among T, S, and A; the amino acid in position 36 is selected among Q, K, L, and E; the amino acid in position 37 is selected among E, D, L, and N; the amino acid in position 38 is selected among V, I, L, and M; the amino acid in position 39 is selected among R, G, K, and H; the amino acid in position 46 is selected among K, N, E, and D; the amino acid in position 48 is selected among A, T, D, and Y; the amino acid in position 52 is selected among N, K, and T; the amino acid in position 55 is selected among Q, K, N, and M; the amino acid in position 56 is L, S, F, or absent; the amino acid in position 57 is selected among Q, W, and R; the amino acid in position 58 is selected among T, S, Y, and N; the amino acid in position 59 is selected among S, V, P, T, and R; the amino acid in position 61 is S, Y, N, A, or absent; the amino acid in position 63 is selected among R, K, Q, G, and E; the amino acid in position 64 is selected among F, A, P, and R; the amino acid in position 72 is selected among L, D, H, and E; the amino acid in position 73 is selected among N, T, H, and K; the amino acid in position 74 is selected among Q, N, S, and K; the amino acid in position 77 is selected among T, M, S, and E; the amino acid in position 79 is selected among Q, R, L, and K; the amino acid in position 83 is selected among G, D, and N; the amino acid in position 87 is selected among S, Q, and R; 10255 / PC the amino acid in position 88 is selected among P, T, L, and S; the amino acid in position 91 is Q, K, T, or absent; the amino acid in position 92 is R, Q, K, or absent; the amino acid in position 93 is Y, F, or absent; the amino acid in position 96 is selected among S, R, E, and K; the amino acid in position 102 is selected among S, I, H, and R; the amino acid in position 104 is F or absent; the amino acid in position 105 is selected among N, E, and D; the amino acid in position 111 is selected among F, L, and V; the amino acid in position 112 is selected among S, N, H, Y, A, and W; the amino acid in position 113 is selected among G, N, S, and T; the amino acid in position 116 is Q or absent; the amino acid in position 120 is selected among N, D, S, G, and V; the amino acid in position 121 is selected among R, K, and Y; the amino acid in position 123 is selected among D, S, T, V, and E; the amino acid in position 124 is selected among V, A, T, L, and Y; the amino acid in position 127 is selected among Y, F, A, and P; the amino acid in position 134 is selected among A, S, and L; the amino acid in position 135 is selected among A, S, V, T, and P; the amino acid in position 139 is R, M, V, G, E, or absent; the amino acid in position 140 is D, L, P, G, or absent; and / orthe amino acid in position 141 is E or absent. In addition to the polypeptide capable of binding PS and the polypeptide capable of binding PAMP, the protein of the invention may comprise additional elements that may have a structural or a functional role. Examples of elements having a functional role includes Fc parts, having effector functions as known in the art; furin protease inhibitors, T cell engagers and cytotoxic elements. Examples of elements having a structural role includes linker sequences having the role of separating other elements of the protein allowing these elements to exert their intended function. 10255 / PC The Fc parts may be selected among known Fc elements. The Fc parts may be derived from any antibody as known in the art, such as IgG, IgG1, IgG3, IgG4, IgA, IgD, IgE, and the skilled person will appreciate that selecting a particular Fc part leads to the protein of the invention obtains the effector function usually associated with the particular selected Fc part. Fc Parts typically also has the ability to dimerize. The numbering of amino acid positions in antibodies or antibody fragments, such as Fc parts mentioned throughout the application is based on EU number of the Fc. All mutations made in the design of protein constructs at the IgG Fc region are written using the EU numbering system. (https: / / www.imgt.org / IMGTScientificChart / Numbering / Hu_IGHGnber.html) Th Fc part may be of human, mammalian or avian origin, preferably from human, monkey,pig, cow, dog, cat, mouse or chicken.The Fc part may be provided with one or more amino acid substitution as known in the art. For example, substitutions that can enhance hinge stability; substitutions having the abilityto knock out ADCC or complement are known and may be used according to the invention.Suitable Examples of Fc part sequences for use according to the invention are SEQ ID NO: 65- 72.If the protein for use according to the invention is intended for use in a particular species it ispreferred to use elements derived from that particular species in order to avoid any inadvertent immune reactions.The protein for use according to the invention may further comprise an additional elementcapable of binding T-cells or otherwise recruit / activate the immune system. One preferred such element is a CD3 binding site. Examples of suitable CD3 binding sites that may be used according to the invention are shown in table 7. The protein of the invention may further comprise an additional element capable of binding NK-cells or otherwise recruit / activate the NK-cells. One preferred such element is a CD16 binding site. Examples of suitable CD16 binding sites that may be used according to the invention are shown in table 4. 10255 / PCIn some embodiments the protein comprises a scaffold protein in addition to thepolypeptide capable of binding PS and the polypeptide capable of binding PAMP. In this connection a scaffold protein is intended to mean a protein that carries the polypeptide capable of binding PS and the polypeptide capable of binding PAMP, whereas the scaffold protein has no impact on the binding properties thereof. Examples of scaffold proteins include plasma proteins, preferably albumins, that in addition to the function as carrier alsomay provide for a longer plasma half-life compared to a protein comprising the samepolypeptide capable of binding PS and the same polypeptide capable of binding PAMP, would have without the albumin. Other examples include transferrin and lactoglobulins.In another preferred embodiment the fusion protein for use according to the inventionconsists of the polypeptide of a single polypeptide comprising a domain capable of bindingPS and a domain capable of binding PAMP, separated by a linker.The linker has the purpose of separating the two domains and is therefore typically of a length between 4 and 30 amino acids, preferably in the range of 5-25 amino acids, and is mainly composed of small hydrophilic amino acids and glycine, which residues are supposed to be fully hydrated in an aqueous environment without strong secondary structures. Thus, preferably, the linker consists of amino acid residues selected among serine, threonine and glycine. A preferred linker has the sequence of GGGGS (SEQ ID NO: 5), or two or more repeats thereof.In another preferred embodiment, the polypeptide further comprises a membrane bindingpolypeptide or a tag selected among poly histidine tag, and biotin binding polypeptides. The membrane binding polypeptide or tag, preferably selected among poly histidine tag and biotin binding polypeptides, provides for a convenient way to attach the polypeptide of the invention to a lipid surface, preferably a liposome according to the present invention. Membrane binding polypeptides are known in the art and any such membrane bindingpolypeptides known in the art may in principle be used according to the invention. Preferredexamples of membrane binding polypeptides for use according to the invention include the membrane binding polypeptide selected among peptides comprising or consisting of thesequences disclosed in SEQ ID NO; 9 or SEQ ID NO: 10, and variants thereof, e.g. variantshaving at least 80% sequence identity, at least 85%, at least 90%, at least 95%, at least 96%, 10255 / PC at least 97%, at least 98% or at least 99% sequence identity to one of SEQ ID NO: 9 and SEQ ID NO: 10.Histidine tags are also known in the art and consist in general of a stretch of 4-12 histidineresidues. Preferably the histidine tag is selected among SEQ ID NO: 6 or SEQ ID NO: 7. Biotin binding polypeptides are known in the art and any such biotin binding polypeptide may in principle be used according to the invention. A preferred biotin binding polypeptidesare streptavidin, variants or fragments thereof, such as the polypeptide having the aminoacid sequence disclosed is SEQ ID NO: 8 or a polypeptide having at least 80% sequence identity, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or atleast 99% sequence identity to SEQ ID NO: 8; because streptavidin is known to bindspecifically to biotin with a very high affinity. The membrane binding polypeptides or the biotin binding polypeptide may, if present, be separated from the other parts of the polypeptide by a linker that may or may not be identical to the linker separating the polypeptide binding PS and the polypeptide capable ofbinding PAMP.The present invention is not limited to any particular architecture of the elements of the used fusion protein. On the contrary it is envisaged that the order of the elements can be varied.For example, figure 2 discloses constructs where a TIM-1 fragment and a CTLD fragment areboth linked at the N-terminal of a Fc fragment that provides for dimerization, and constructs where a TIM-1 and a CTLD fragment are located at each end of the Fc fragment. Other contemplated constructs comprise a polypeptide capable of binding PS bound to a first Fc part and a polypeptide capable of binding PAMP bound to a second Fc part, where the first and the second Fc parts dimerizes. One or both Fc Parts may additionally be bound to an additional functional element such as an anti-CD3 site, see figure 6 and 7, or an anti-CD16 site.Preferred examples of proteins for use according to the invention includes polypeptidescomprising or consisting of the amino acid sequences disclosed in SEQ ID NO: 3, SEQ ID NO:4, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO:15, SEQ ID NO: 23; SEQ ID NO:24, SEQ ID NO: 23 and SEQ ID NO: 24; SEQ ID NO: 25 and SEQ ID NO: 26, SEQ ID NO: 27 and 10255 / PC SEQ ID NO: 28, SEQ ID NO: 29 and SEQ ID NO: 30, SEQ ID NO: 31 and SEQ ID NO: 32; SEQ ID NO: 31 and SEQ ID NO: 82, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, SEQ ID NO: 96 and SEQ ID NO: 98, SEQ ID NO: 118 and SEQ ID NO: 119, SEQ ID NO: 118 and SEQ ID NO: 121, SEQ ID NO: 118 and SEQ ID NO: 122, SEQ ID NO: 1183 and SEQ ID NO: 124, SEQ ID NO: 125 and SEQ ID NO: 124, SEQ ID NO: 127 and SEQID NO: 128; SEQ ID NO: 118 or SEQ ID NO: 130.In another embodiment of the invention, the fusion protein can carry a payload, which canbe used to diagnose, image, treat or prevent an infectious disease or cancer. The payloadcan be a cytotoxic drug (such as microtubule inhibitors or DNA-damaging agents),radionuclide, fluorescent dye, or other imaging agents. The fusion protein can be conjugatedto desferrioxamine (DFO), DOTA, or another suitable chelator for the purpose of radiolabeling, wherein the conjugated protein demonstrates enhanced stability, targeted binding specificity, and favorable radiolabeling efficiency, making it suitable for diagnostic imaging or targeted radiotherapy applications in oncology or other diseases where specific targeting is critical. Examples of preferred radionuclides include Zirconium-89, Copper-64, Fluorine-18 and Lutetium-177. The label or chelator may be attached to the fusion proteins using methods known in the art. In some embodiments, the label is conjugated to the fusion protein e.g. via a natural or engineered cysteine residue.In another preferred embodiment, the fusion protein may be used to functionalizeliposomes, lipid nanoparticles (LNP), or other nanoparticles, wherein the fusion proteinenhances the stability, targeted delivery, and therapeutic efficacy of the liposomes or nanoparticles, making it suitable for drug delivery, diagnostic imaging, or targeted therapy applications in oncology or other diseases requiring precise cellular targeting.Functionalizing the liposomes, lipid nanoparticles or other nanoparticles with the fusionproteins comprises the steps of covalently attaching the fusion proteins to the liposomes or nanoparticles using carbodiimide chemistry or maleimide chemistry, non-covalently binding proteins to the liposomes or nanoparticles through adsorption or biotin-streptavidin interactions, and optionally introducing functional groups to the nanoparticle / liposome or 10255 / PC fusion protein to facilitate said attachment, wherein the functionalized liposomes or nanoparticles retain protein activity and are stable for use in research, diagnostic or therapeutic applications. In another embodiment, the invention relates to a method of detecting exosomes, which are small vesicles secreted by cells that transport bioactive molecules between cells. In cancer, exosomes carry molecules that contribute to tumor growth, metastasis and drug resistance, and regulate the immune response. Phosphatidylserine is exposed on the surface of exosomes, facilitating delivery of their cargo and modulating the immune system. Therefore, the invention may be used to further research into the mechanism of action of exosomes in health and disease. It may also be used as a liquid biopsy in fluids such as blood and urine. In another embodiment, the invention relates to a method of screening and / or monitoring progression of a disease in a subject, comprising the steps of: a. providing a blood sample from the subject;b. contacting the blood sample with a protein of the invention;c. prepare images of the blood sample showing the distribution of the protein;and d. based on the distribution of the protein as shown in the images of step c)evaluating the progression of the disease in the subject. Treatment The invention also relates to the use of the protein of the invention in a method for treatinginfectious diseases or cancer.The infectious disease may be any viral, bacterial, and protozoan infections, where theinfecting microorganisms or the infected cells disclose PS and / or PAMP on their surface.Examples of infectious diseases include but are not limited to: Arborviruses Zika Virus (ZIKV),Chikungunya (CHIKV), Dengue (DENV), West Nile (WNV), Ebola (EBLV), SARS, Lyme, WestNile, Zika and Dengue, enteroviruses, rotavirus, rabies, distemper, parvovirus and influenza.The cancer may be any human cancer carrying PS and / or a glycan on the surface that is recognized by the PAMP of the particular selected fusion protein of the invention. 10255 / PC It is contemplated that the fusion protein of the invention binds to the cancer cells and is capable of recruiting effector cells that can eliminate or inhibit cancer cells binding the fusion proteins.Examples of effector cells include the immune effector cells such as a T cell, a Natural Killer(NK) cell, a cytotoxic T lymphocyte (CTL), a regulatory T cell, or an embryonic or a pluripotent stem cell. Preferably, fusion proteins of the invention for treatment of cancer comprises a domaincapable of recruiting effector cells selected among a Fc domain, a CD3 binding site or a CD16binding site.The cancer may be any solid or non-solid cancer such as leukemia, AML (acute myeloidleukemia), multiple myeloma, B-cell lymphoma, pancreatic cancer, breast cancer, bladder cancer, colon cancer and lung cancer. The protein of the invention may be formulated for subcutaneous, intradermal,intramuscular, oral and nasal administration.The subject to be treated may be a human being, an animal, preferably a mammal or a bird, preferably selected among cow, monkey, horse, goat, pig, dog, cat, mouse, chicken, duck, goose or turkey.The protein of the invention may be prepared using methods well known in the art.Nucleic acidsNucleic acids encoding the protein may be provided as known in the art. For example,nucleic acids encoding parts of the protein may be provided by cloning, e.g., by PCRamplification of the desired sequences, and the parts be joined using methods known in the art. The obtained nucleic acids are inserted in suitable expression constructs provided withthe required regulatory sequences, such as promoter, terminator, ribosome binding sites,Kozak sequence, intron, enhancers etc. to allow the sequence to be expressed in the selected host cell.Alternatively, nucleic acids encoding the protein may be deduced based on the desiredamino acid sequence and nucleic acids, optionally including regulatory and vector sequences, synthesized using methods known in the art, or ordered at a provider of such 10255 / PC services. This procedure also allows the sequence to be codon-optimized to the selected host cell, which may result in a better expression of the protein. The host with the encoding nucleic acid inserted together with suitable regulatory sequences are grown in a suitable growth medium inducing the expression of the protein, and the protein is subsequent recovered from the broth using a number of well know separation and purification methods.In another embodiment the invention related to compositions, preferably pharmaceuticalcompositions, comprising the protein of the invention, comprising one or more excipientssuch as diluents, binders or carriers in addition to the protein. Compositions Pharmaceutical compositions are made of pharmaceutically acceptable ingredients inaddition to the active components, i.e. the fusion protein or the invention. Thepharmaceutical composition may be formulated for oral, inhalation, nasal or intravenous administration. The pharmaceutical composition may be intended for human use or for veterinary use. If the pharmaceutical composition is intended for human use it comprises in addition to theone or more fusion proteins of the invention, at least one pharmaceutically acceptableingredient approved for human use. If the pharmaceutical composition is intended for veterinary use it comprises in addition tothe one or more fusion proteins of the invention, at least one pharmaceutically acceptableingredient approved for veterinary use. The pharmaceutical composition may comprise one or more pharmaceutically acceptableingredients selected among well-known ingredients such as: diluents, fillers, pH regulators,salt, stabilizers, antioxidants, viscosity regulating agents, flavorings and colorings.The pharmaceutical compositions may be formulated in single dose formulations or as multi dose formulations. The veterinary formulations may be formulated of administration to any animal or livestock such as cattle, sheep, horses, dogs, cats, birds etc. 10255 / PC Chimeric Antigen receptorsThe invention is also related to novel chimeric antigen receptors (CAR), that target PAMPS and PS.CAR are receptor proteins that have been engineered to give T-cells the ability to target a specificantigen and be activated upon binding to the antigen. CARs are in nature chimeric in that theycombine the ability to bind an antigen with the T cell activating function, which typically is accommodated by a chimeric molecule comprising an antigen binding domain and a T-cell activating domain. CARs typically comprise an extracellular portion capable of binding the antigen, an intracellular portion capable of activating the T-cells, a hinge and transmembrane domain and optionally a co- stimulatory domain.CARs are known in the art and the skilled person knows how to apply the general knowledge of CARsto the specific requirements provided by the present invention.The novel chimeric antigen receptors (CARs) are designed to transduce human effector cells, such as Tcells, to express these receptors of their surface allowing these cells to directly kill tumor cells, infected cells or pathogens that contain cell surface PAMPs and PS. Thus, the CAR of the invention comprises a polypeptide capable of binding to phosphatidylserine (PS) and a polypeptide capable of binding apathogen-associated molecular pattern (PAMP).In a preferred embodiment a polypeptide capable of binding to phosphatidylserine (PS) and apolypeptide capable of binding a pathogen-associated molecular pattern (PAMP) are selected amongpolypeptides capable of binding to phosphatidylserine (PS) and polypeptides capable of binding apathogen-associated molecular pattern (PAMP) as described elsewhere in this specification.Further the CARs of the invention comprises a domain capable of activating T-cells. A preferred example of such a domain is the CD3-zeta chain as known in the art.Preferred examples of CAR molecules of the invention comprise nine CAR formats (VC300 – VC308) asshown in Figure 20. VC300 and VC301 are single-targeting CARs that have either TIM-1 or CTLD on the extracellular domains. VC302 and VC303 have tandem TIM-1 x CTLD or CTLD x TIM-1 targeting domains, respectively. VC304-VC308 have two separate CAR chains (each chain containing TIM-1 or CTLD) that can be co-transduced into the immune effector cells. VC304 has equal co-stimulatory (co-stim)domains on each chain, whereas VC305 and VC306 have co-stimulatory domains only on one of thechains, allowing for attenuated activity to the PAMP and PS targets. VP307 and VP308 have one chain with co-stimulation and no CD3-zeta function (necessary to have T cell activation), and one chain with CD3-zeta and no-stimulation. It has previously been shown that the separating the co-stimulation and 10255 / PC CD3-zeta chain can lead to higher specificity where binding by both chains is necessary for activations(Nat Biotechnol. 2013 January ; 31(1): 71–75). The sequences of the components used for eachCAR construct are listed in Table 1 and the full sequences are listed in Table 2.Domain SequenceCD8 leader MALPVTALLLPLALLLHAARP (SEQ ID NO: 85)TIM-1 Amino acids 1-105 of SEQ ID No: 1 CTLD Amino acids 1-136 of SEQ ID NO: 2 TIM-1 x CTLD (Amino acids 1-105 of SEQ ID No: 23 or any sequence fromTable 9)-GGGGS-(Amino acids 1-136 of SEQ ID NO: 24 or any DC-SIGN or L-SIGN sequences from Table 10 or 11) CTLD x TIM-1 (Amino acids 1-136 of SEQ ID NO: 24 or any DC-SIGN or L-SIGNsequences from Table 10 or 11)-GGGGS-(Amino acids 1-105 of SEQ ID No: 23 or any sequence from Table 9) CD8 hinge and TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFA transmembrane CDIYIWAPLAGTCGVLLLSLVIT (SEQ ID NO: 86) CD28 hinge and KGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWV transmembrane (SEQ ID NO: 87) CD28 co-stimulatory RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS (SEQ ID domain NO: 88) 4-1BB co-stimulatory KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL (SEQ ID domain NO: 89) 2B4 co-stimulatory domain WRRKRKEKQSETSPKEFLTIYEDVKDLKTRRNHEQEQTFPGGGSTIYSMIQSQSSAPTSQEPAYTLYSLIQPSRKSGSRKRNHSPSFNSTIYEVIGKS QPKAQNPARLSRKELENFDVYS (SEQ ID NO: 114)CD28 x 41-BB tandem co- RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS- stimulatory domains GGGGS-KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL (SEQ ID NO: 90) CD3-zeta RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLY QGLSTATKDTYDALHMQALPPR (SEQ ID NO: 91) Table 1. Sequences of component domains to engineer chimeric antigen receptors that target PAMP and PS. 10255 / PCConstruct Leader Extracellular Domain Hinge andCo- CD3 Sequence Transmembrane stimulatory Zeta domain / sVC300 SEQ IDAmino acids 1-105 of SEQ ID NO: 86 SEQ ID NO: 88 SEQ NO: 85 SEQ ID No: 23 or any or SEQ ID NO: or SEQ ID NO: ID sequence from Table 9 87 89 or SEQ ID NO: NO: 90 91VC301 SEQ IDAmino acids 1-136 of SEQ ID NO: 86 SEQ ID NO: 88 SEQ NO: 85 SEQ ID NO: 24 or any or SEQ ID NO: or SEQ ID NO: ID DC-SIGN or L-SIGN 87 89 or SEQ ID NO: sequences from Table NO: 90 91 10 or 11VC302 SEQ ID(Amino acids 1-105 of SEQ ID NO: 86 SEQ ID NO: 88 SEQ NO: 85 SEQ ID No: 23 or any or SEQ ID NO: or SEQ ID NO: ID sequence from Table 87 89 or SEQ ID NO: 9)-GGGGS-(Amino NO: 90 91 acids 1-136 of SEQ ID NO: 24 or any DC-SIGN or L-SIGN sequences from Table 10 or 11)VC303 SEQ ID(Amino acids 1-136 of SEQ ID NO: 86 SEQ ID NO: 88 SEQ NO: 85 SEQ ID NO: 24 or any or SEQ ID NO: or SEQ ID NO: ID DC-SIGN or L-SIGN 87 89 or SEQ ID NO: sequences from Table NO: 90 91 10 or 11)-GGGGS-(Amino acids 1-105 of SEQ ID No: 23 or any sequence from Table 9) VC304- SEQ ID Amino acids 1-105 of SEQ ID NO: 86 SEQ ID NO: 88 SEQ chain 1 NO: 85 SEQ ID No: 23 or any or SEQ ID NO: or SEQ ID NO: ID sequence from Table 9 87 89 or SEQ ID NO: NO: 90 91 VC304- SEQ ID Amino acids 1-136 of SEQ ID NO: 86 SEQ ID NO: 88 SEQ chain 2 NO: 85 SEQ ID NO: 24 or any or SEQ ID NO: or SEQ ID NO: ID DC-SIGN or L-SIGN 87 89 or SEQ ID NO: NO: 90 91 10255 / PC sequences from Table 10 or 11VC305- SEQ ID Amino acids 1-105 of SEQ ID NO: 86none SEQchain 1 NO: 85 SEQ ID No: 23 or any or SEQ ID NO: ID sequence from Table 9 87 NO: 91 VC305- SEQ ID Amino acids 1-136 of SEQ ID NO: 86 SEQ ID NO: 88 SEQ chain 2 NO: 85 SEQ ID NO: 24 or any or SEQ ID NO: or SEQ ID NO: ID DC-SIGN or L-SIGN 87 89 or SEQ ID NO: sequences from Table NO: 90 91 10 or 11VC306- SEQ ID Amino acids 1-105 of SEQ ID NO: 86 SEQ ID NO: 88 SEQ chain 1 NO: 85 SEQ ID No: 23 or any or SEQ ID NO: or SEQ ID NO: ID sequence from Table 9 87 89 or SEQ ID NO: NO: 90 91 VC306- SEQ ID Amino acids 1-136 of SEQ ID NO: 86none SEQchain 2 NO: 85 SEQ ID NO: 24 or any or SEQ ID NO: ID DC-SIGN or L-SIGN 87 NO: sequences from Table 91 10 or 11VC307- SEQ ID Amino acids 1-105 of SEQ ID NO: 86 SEQ chain 1 NO: 85 SEQ ID No: 23 or any or SEQ ID NO: ID sequence from Table 9 87 NO: 91 none VC307- SEQ ID Amino acids 1-136 of SEQ ID NO: 86 SEQ ID NO: 88 none chain 2 NO: 85 SEQ ID NO: 24 or any or SEQ ID NO: or SEQ ID NO: DC-SIGN or L-SIGN 87 89 or SEQ ID sequences from Table NO: 90 10 or 11VC308- SEQ ID Amino acids 1-105 of SEQ ID NO: 86 SEQ ID NO: 88 none chain 1 NO: 85 SEQ ID No: 23 or any or SEQ ID NO: or SEQ ID NO: sequence from Table 9 87 89 or SEQ ID NO: 90 VC308- SEQ ID Amino acids 1-136 of SEQ ID NO: 86none SEQchain 2 NO: 85 SEQ ID NO: 24 or any or SEQ ID NO: ID DC-SIGN or L-SIGN 87 NO: 91 10255 / PC sequences from Table 10 or 11Table 2. Sequences of PAMP and PS targeting chimeric antigen receptors.In another preferred embodiment of the invention, a fragment of the human protein 2B4 isused as a co-stimulatory domain for generating CAR constructs with the fusion proteins,preferably when generating CAR-NK cells, since 2B4 has been shown to enhance NK cell activity (Tangye SG, Cherwinski H, Lanier LL, Phillips JH.2B4-mediated activation of human natural killer cells. Mol Immunol.2000;37(9):493–501.) It has been shown that engineered immune cells that express chimeric antigen receptors can also be engineered to secrete cytokines, such as IL-12, IL-18, IL-15, IL-7 and IL-21, which can enhance the immune cell’s proliferation, persistence and efficacy. [Reviewed in Jin et al (https: / / pmc.ncbi.nlm.nih.gov / articles / PMC7783740 / )]. The engineered immune cell can be transduced with genetic material (cytokine producing material) to produce and secrete these cytokines.Such engineered immune cell capable of expressing a CAR according to the invention andfurther capable of sectrting one of more cytokines may also be contemplated according to the invention. Heterodimeric Chimeric Antigen Receptors The invention further relates to heterodimeric chimeric antigen receptors comprising two or more different CARs, each comprising an extracellular portion capable of binding the antigen, an intracellular portion optionally comprising a domain capable of activating the T- cells and / or a co-stimulatory domain, a hinge and transmembrane domain; wherein the transmembrane domain is able to heterodimerize; and wherein at least one of the two or more CARs comprises a domain capable of activating the T-cells located in the intracellular portion.Examples of transmembrane domains able to heterodimerize includes transmembranedomains based on human or animal integrin alpha-IIb and Beta-III. Preferred examples of transmembrane domains able to heterodimerize is the transmembrane domain of humanIntegrin alpha-IIB with the sequence of amino acids 5-30 of SEQ ID NO: 92 or thetransmembrane domain of human Integrin beta-III with the sequence of amino acids 6 – 28of SEQ ID NO: 93. Even more preferred is to use both the hinge and transmembrane domain of human Integrin alpha-IIB with the sequence of SEQ ID NO: 92 or the hinge and transmembrane domain of Integrin beta-III with the sequence of SEQ ID NO: 93. 10255 / PC In some embodiments the heterodimeric chimeric antigen receptor of the invention comprises two CARs, where one of the CARs comprises an extracellular portion capable of binding PS and the other CAR contains an extracellular domain capable of binding a PAMP. The NMR solution structure of the integrin alpha-IIb and integrin beta-III transmembrane heterodimer had previously been solved (Protein Data Bank entry ID 2K9J). Hinge and transmembrane domain of Integrin alpha-IIB, where the transmembrane domainis underlined: LEERAI PIWWVLVGVLGGLLLLTILVLAMW (SEQ ID NO: 92)Hinge and transmembrane domain of Integrin beta-III, where the transmembrane domain isunderlined: PKGPDILVVLLSVMGAILLIGLAALLIW (SEQ ID NO: 93)The integrin alpha-IIb / beta-III transmembrane domains were used to design the 2-chain CARconstructs shown in Figure 21 and Table 3.Construct Leader Extracellular Domain Hinge andCo- CD3 Sequence Transmembrane stimulatory Zeta domain / s VC309- SEQ ID Amino acids 1-105 ofSEQ ID NO: 92 SEQ ID NO: 88SEQ chain 1 NO: 85 SEQ ID No: 23 or any or SEQ ID NO: ID sequence from Table 9 89 or SEQ ID NO: NO: 90 91 VC309- SEQ ID Amino acids 1-136 ofSEQ ID NO: 93 SEQ ID NO: 88SEQ chain 2 NO: 85 SEQ ID NO: 24 or any or SEQ ID NO: ID DC-SIGN or L-SIGN 89 or SEQ ID NO: sequences from Table NO: 90 91 10 or 11VC310- SEQ ID Amino acids 1-105 ofSEQ ID NO: 92 none SEQchain 1 NO: 85 SEQ ID No: 23 or any ID sequence from Table 9 NO: 91 VC310- SEQ ID Amino acids 1-136 ofSEQ ID NO: 93 SEQ ID NO: 88SEQ chain 2 NO: 85 SEQ ID NO: 24 or any or SEQ ID NO: ID DC-SIGN or L-SIGN 89 or SEQ ID NO: sequences from Table NO: 90 91 10 or 11VC311- SEQ ID Amino acids 1-105 ofSEQ ID NO: 92 SEQ ID NO: 88SEQ chain 1 NO: 85 SEQ ID No: 23 or any or SEQ ID NO: ID sequence from Table 9 89 or SEQ ID NO: NO: 90 91 10255 / PC VC311- SEQ ID Amino acids 1-136 ofSEQ ID NO: 93 none SEQchain 2 NO: 85 SEQ ID NO: 24 or any ID DC-SIGN or L-SIGN NO: sequences from Table 91 10 or 11VC312- SEQ ID Amino acids 1-105 of SEQ ID NO: 92 SEQ chain 1 NO: 85 SEQ ID No: 23 or any ID sequence from Table 9 NO: none 91 VC312- SEQ ID Amino acids 1-136 ofSEQ ID NO: 93 SEQ ID NO: 88none chain 2 NO: 85 SEQ ID NO: 24 or any or SEQ ID NO: DC-SIGN or L-SIGN 89 or SEQ ID sequences from Table NO: 90 10 or 11VC313- SEQ ID Amino acids 1-105 ofSEQ ID NO: 92 SEQ ID NO: 88none chain 1 NO: 85 SEQ ID No: 23 or any or SEQ ID NO: sequence from Table 9 89 or SEQ ID NO: 90 VC313- SEQ ID Amino acids 1-136 ofSEQ ID NO: 93 none SEQchain 2 NO: 85 SEQ ID NO: 24 or any ID DC-SIGN or L-SIGN NO: sequences from Table 91 10 or 11Table 3. Sequences of PAMP and PS targeting heterodimeric chimeric antigen receptors.In Vivo Engineered CAR Immune Cells and In Vivo delivery of Immune Cell Engager MoleculesThe invention further relates to a delivery system of the genetic material of the selected CAR protein(s) in vivo, allowing for in vivo engineering of immune cells, such as T or NK cells, using target-specific nanoparticles, liposomes, viral vectors and other vehicles, administeredsubcutaneously, intravenously, orally or nasally. For example, liposomes or lipid nanoparticlesor silica nanoparticles containing any of DNA or RNA sequences for proteins in Table 3 andfunctionalized on its surface with anti-CD3 domains (shown in Table 7) or functionalized withanti-CD16 molecules (shown in Table 4) to deliver the genetic material to T cells (using anti-CD3 molecules) or to NK cells (using anti-CD16 molecules) for in vivo engineering andactivation of CAR T or CAR NK cells. This invention greatly reduces the cost and safety concernsof ex vivo CAR T (and CAR NK) engineering. A similar method can be used for in vivo delivery 10255 / PC of TIM-1 x CTLD x anti-CD3 or TIM-1 x CTLD x anti-CD16 immune engaging molecules, where DNA or RNA can be encapsulated in liposomes or lipid nanoparticles or silica nanoparticles for expression in patients with cancer or infectious diseases.Methods known from the art allow in vivo expression of CARs on immune cells(https: / / www.cell.com / trends / pharmacological-sciences / fulltext / S0165-6147(24)00052-X,Short et al. Trends Pharmacol Sci. 2024 May;45(5):406-418. doi: 10.1016 / j.tips.2024.03.004).An embodiment of the invention is use of the fusion proteins according to the invention for in vivo engineering of CARs using the principles described in the methods known from the art. Also known from the art, are methods for in vivo delivery of immune cell engaging molecules. (An example is shown here: https: / / www.cell.com / molecular-therapy-family / oncology / fulltext / S2372-7705(23)00012-8 Park et al. Mol Ther Oncolytics.2023 Feb16:28:249-263. doi: 10.1016 / j.omto.2023.02.004.)An embodiment of the invention is in vivo delivery of immune cell engaging molecules suchas the T- and NK-cell engaging fusion proteins of the invention.Definitions The term “Sequence identity” is according to the invention used as a measure of the similarity of two amino acid sequences. In order to determine the sequence identity between twosequences the sequences are aligned, the optimal overlap is identified, and the sequenceidentity is calculated as the number of positions where the same amino acid residue is present in the two sequences divided by the total length of the overlap. The term “Structural lipid” is according to the invention intended to mean lipids contributing to forming the lipid bilayer structure of the liposomes. Structural lipids have a bipolar structurewith a lipophilic character in one part of the molecule and a hydrophilic character in anotherpart of the molecule. Examples of structural lipids include phospholipids and steroids such as cholesterol, ergosterol and phytosterol. The term “functionalized lipid” is according to the invention intended to mean a lipid that has modified by attachment of an atom, a chemical group or a moiety in order to provide the functionalized lipid with a function that the lipid by itself do not have. Examples of functionalized lipids include lipids with an attached chelator, which enables the functionalized 10255 / PC lipid to bind a metal ion, a property not shared by the original lipid; or a biotinylated lipid, which is capable of binding to streptavidin, a property not shared by the original lipid.The term “recombinant protein” refers to a protein, which is or may be encoded byrecombinant DNA. The recombinant protein of the invention may be an artificial protein i.e. not identical to any protein found in nature, and it may be provided by fusing parts of proteins found in nature and / or artificial peptides or combinations thereof. The term “Targeting protein” is intended to mean a protein capable of attachment, bycovalent or non-covalent binding, to a specific target. According to the invention, a targetingprotein is a protein capable of attaching to a pathogen associated molecular pattern (PAMP)and / or to phosphatidylserine (PS). A targeting protein of the invention is preferably a recombinant protein. The term “Imaging agent” is according to the invention intended to mean a molecule or structure that can be detected by a detecting device forming an image. One preferred imaging agent according to the invention is a targeting agent provided with a label, because the targeting agent will attach to the target, the label allows the detecting device to register the targeting agent and thereby the location of the target and generate an image showing the abundance and location of targets. The term “Pathogen associated molecular pattern (PAMP)” is according to the invention intended to mean a molecular structure or pattern that is abundant on pathogens but rarely found in the normal tissues of the host. Examples of PAMP include oligosaccharide structures, such as high mannose carbohydrates, frequently found on the surface of pathogens but only rarely found in the host as higher eukaryotes typically have carbohydrates of the complex type attached to its proteins and surfaces. The term “tag” is according to the invention intended to mean a small chemical group that can be attached to a protein in order to give the protein the ability to bind to a specific chemical structure. Examples of tags suitable for the present invention include a his-tag, a repeat of histidine residues, typically 6 to 10 histidine residues, that can form a complex with certain metal ions, and which can provide binding to other molecules via metal complexes. Another example is biotinylation where a biotin group is attached to a protein, which allowsthe protein to bind with high affinity to streptavidin or derivatives thereof. 10255 / PC Several numbering systems for antibodies and antibody fragments have been developed and used throughout the scientific community. In this specification the numbering of amino acid positions in antibodies and antibody fragments; e.g. the Fc region; is based on EU numbering (IMGT numbering), also described in as found in: https: / / www.imgt.org / IMGTScientificChart / Numbering / Hu_IGHGnber.html. Design of proteins of the invention. Design of Bivalent TIM-1 x CTLD IgG1-Fc Fusion Proteins As an alternative to using IgG4 Fc domains which inherently do not have high levels of ADCC, ADCP and CDC activity, bivalent TIM-1 x CTLD Fc fusions were designed using IgG1 Fc domains containing knobs-in-hole mutations to facilitate Fc heterodimer formation (See Figure 6 and Table 6). Five different constructs were designed with either active Fc (VP304), silent Fc (VP305), silent Fc with thiol-conjugation site for linking payload or imaging agent (VP306), silent Fc with monovalent anti-CD3 moiety to activate T cells (VP307 and VP308). Specific engineered Fc domains are used and shown in Table 5, including ‘knob’ mutation T366W, the ‘hole’ mutations T366S, L368A and Y407V, silencing mutations N297G and K322A, and the thiol-conjugation site mutation A339C, where the numbering is according to the EU numbering (IMGT). The anti-CD3 moieties are exemplified in Table 7, includinghumanized OKT3 and the nanobody F10. All of the constructs shown in Table 7 can bemodified to treat animals using the sequences shown in Example 5. In addition, the CTLD of L-SIGN can be used in place of DC-SIGN, as also shown in Example 5. Silencing mutations in the Fc portion of the fusion proteins that engage immune cells are important for preventing the fusion proteins from re-directing an engaged immune cell (for example a T cell engaged via CD3 or NK cell engaged via CD16) from killing other immune cells containing FcγRs that normally interact with an Fc for the processes of antibodydependent cellular cytotoxicity and antibody dependent cellular phagocytosis. Silencingmutations can also prevent Fc-mediated complement activation. Silencing the Fc is also important when the fusion proteins carry a payload or have a mechanism of action that doesnot require the binding of FcγR or complement. Established silencing mutations include the 10255 / PC following Fc modifications: N297G, N297A, N297Q, L234A, L235A, L235E, K322A, P329G,S267K, and D265A (IMGT numbering).Design of Tetravalent TIM-1 x CTLD IgG1-Fc Fusion Proteins For enhanced avidity and active Fc function, tetravalent TIM-1 x CTLD Fc fusions were designed using IgG1 Fc domains and shown in Figure 7 and Table 8. Each construct has 2 TIM-1 Ig-like V domains and 2 CTLD moieties and either an active Fc (VP309), silent Fc (VP310), silent Fc with thiol-conjugation site for linking payload or imaging agent (VP311),silent Fc with bivalent anti-CD3 moieties to activate T cells (VP312), and silent Fc withmonovalent anti-CD3 moiety to activate T cells (VP313). All of the constructs shown in Table 8 can be modified to treat animals using the sequences shown in Example 5. In addition, the CTLD of L-SIGN can be used in place of DC-SIGN, as also shown in Example 5. Design TIM-1 x CTLD Fusion Proteins for animal use TIM-1 x CTLD fusion proteins can be used to PS and pathogenic sugar antigens for infectious diseases and cancer in humans and animals. The human TIM-1 Ig-like V-domain sequenceutilized in the constructs of this invention (from Tables 13, 6 and 8) can be replaced fully orin part using animal sequences shown in Figure 8 and Table 9, to reduce the potential immunogenicity to the treated animal. The alignment consensus sequence for human monkey, pig, cow, dog, cat, mouse, and chicken Ig-like V domain of TIM-1 is as follows: XXXVXGVXGXXVTLPCXYRVSTXXXITTMCWGRGCXXXXXCXXXIIWTNGXXVTXXKXXRYXLKGXLXXGDVSLTIXNXXXSDSGXYCCRVEXXGWFNDXKXTXSLXIX (SEQ ID NO: 73 )Similarly, the CTLD of human DC-SIGN sequence utilized in the constructs of this invention(from Tables 13, 6 and 8) can be replaced fully or in part using animal sequences shown inFigure 9 and Table 10, to reduce the potential immunogenicity to the treated animal. Thealignment consensus sequence for human monkey, pig, cow, dog, cat, mouse, and chickenCTLD of DC-SIGN is as follows:XXLCXPCPWXWEXFQGXCYFFSXXQXXWXXSXXACXXXGAQLVXIXSXEEQXFLXXXXXRXNXXTWIGLS DXXXEGXWXWVDXSPLXLSFXQYWKXGEPNNXGXNEDCAEXXXDGQWNDXXCXXEXFWICXKXXXXCP (SEQ ID NO: 74) 10255 / PC The CTLD of human DC-SIGN sequence utilized in the constructs of this invention (fromTables 13, 6 and 8) can also be replaced by the CTLD of L-SIGN which shares 79.4% identityand 91.2% similarity to the CTLD of human DC-SIGN, or it can be replaced fully or in partusing animal sequences of L-SIGN shown in Figure 10 and Table 11, to reduce the potentialimmunogenicity to the treated animal. The alignment consensus sequence for human monkey, pig, cow, dog, cat, mouse, and chicken CTLD of L-SIGN is as follows: XXLCRXCPWXWEFFQGXCYFFSXXQXXWXXSXXACXXXXAQLVIIXSXEEQXFLXXXXXRXNXXTWIGLSD XXXEGXWXWVDXSPLXXSFXXYWKXGEPNNXGFXEDCVEXXXDGQWNDXXCXXENXWICKKPXXPCPXXE (SEQ ID NO: 75)The hinge-Fc scaffolds utilized in constructs VP300 to VP313 can also be replaced with the animal sequences shown in Figure 11 and Table 12, to again reduce the potential immunogenicity in the treated animal. As noted in Tables 6 and 8, the animal hinge-Fc domains would need to include the specific knob, hole, silencing and thiol-conjugation mutations for their respective functions. The human hinge sequence can be retained in the animal-specific therapeutic for enhanced stability, while replacing the human CH2-CH3 domains with the homologous animal sequences. Design of TIM-1 x CTLD x anti-CD16 trispecific molecules Additional constructs were designed where the anti-CD3 domains found in VP307, VP308, VP312 and VP313 can be replaced with anti-human CD16 scFv fragments derived from the sequence of NM3E2, in order to engage NK and NKT cells for cytotoxic activity. Table 4: CD16 binding sequences Construct SequenceEVQLVESGGGVVRPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLE NM3E2 VH WVSGINWNGGSTGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTA VYYCARGRSLLFDYWGQGTLVTVSS (SEQ ID NO: 76) SSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIY GKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCNSRDSSGNH NM3E2 VL VVFGGGTKLTVL (SEQ ID NO: 77) 10255 / PC EVQLVESGGGVVRPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLE WVSGINWNGGSTGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTA VYYCARGRSLLFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGS NM3E2 scFv (VH-linker-VL) GGGGSSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAP VLVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCNSRDS SGNHVVFGGGTKLTVL (SEQ ID NO: 78) EVQLVESGGGVVRPGGSLRLSCAASGFTFDDYGMSWVRQAPGKCLE WVSGINWNGGSTGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTA VYYCARGRSLLFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGS NM3E2 scFv (VH-linker-VL) GGGGSSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAP disulfide stabilized VLVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCNSRDS SGNHVVFGCGTKLTVL (SEQ ID NO: 79) Table 5. Engineered human IgG1 hinge-Fc domains Construct SequenceIgG_Fc (SEQ ID NO: 104)IgG_Fc_knob (SEQ ID NO: 105)IgG_Fc_knob_null (SEQ ID NO: 106)IgG_Fc_knob_null_conj (SEQ ID NO: 107)IgG_Fc_hole (SEQ ID NO: 108)IgG_Fc_hole_null (SEQ ID NO: 109)IgG_Fc_hole_null_conj (SEQ ID NO: 110)

[0002] 10255 / PC Table 6. Sequences of Bivalent TIM-1xCTLD-Fc Fusion Proteins Construct andChain name Variable linker Constant FusionDescription VP304 VP304 Chain Amino acids 1- Amino acids Amino acids 111-337 of SEQ ID TIM1XCTLD Knob in 1 105 of SEQ ID 106-110 of SEQ NO: 23 or any Fc from Table hole Fc fusion (SEQ ID NO: No: 23 or any ID NO: 23 10 and containing Ser heterodimer 23) sequence from 366+Ala368+Val407 Table 9 VP304 Chain Amino acids 1- Amino acid Amino acid 142-368 of SEQ ID 2 136 of SEQ ID 137-141 of SEQ NO: 24 or any Fc from Table (SEQ ID NO: NO: 24 or any ID NO: 24 12 and containing Trp336 24) DC-SIGN or L- SIGN sequences from Table 10 or 11 VP305 VP305 Chain Amino acids 1- Amino acids Amino acids 111-337 of SEQ ID TIM1 x CTLD Knob-in- 1 105 of SEQ ID 106-110 of SEQ NO: 25 or any Fc from Table hole Fc fusion (SEQ ID NO: No: 25 or any ID NO: 25 12 and containing Ser 25) sequence from 366+Ala368+Val407+ Table 9 Gly297+Ala322

[0003] 10255 / PC heterodimder with VP305 Chain Amino acids 1- Amino acid Amino acid 142-368 of SEQ ID silent Fc 2 136 of SEQ ID 137-141 of SEQ NO: 26 or any Fc from Table (SEQ ID NO: NO: 26 or any ID NO: 26 12 and containing 26) DC-SIGN or L- Trp336+Gly297+Ala322 SIGN sequences from Table 10 or 11 VP306 VP306 Chain Amino acids 1- Amino acids Amino acids 111-337 of SEQ ID TIM1 x CTLD Knob-in- 1 105 of SEQ ID 106-110 of SEQ NO: 27 or any Fc from Table hole Fc fusion (SEQ ID NO: No: 27 or any ID NO: 27 12 and containing Ser heterodimder with 27) sequence from 366+Ala368+Val407+ silent Fc and thiol- Table 9 Gly297+Ala322+Cys339 conjugation site VP306 Chain Amino acids 1- Amino acid Amino acid 142-368 of SEQ ID 2 136 of SEQ ID 137-141 of SEQ NO: 28 or any Fc from Table (SEQ ID NO: NO: 28 or any ID NO: 28 12 and containing 28) DC-SIGN or L- Trp336+Gly297+Ala322+ SIGN sequences Cys339 from Table 10 or 11 VP307 VP307 Chain Amino acids 1- Amino acidsAmino acids 111-335 of SEQ ID Amino acids 351-605 of SEQ IDTIM1 x CTLD Knob-in- 1 105 of SEQ ID 106-110 of SEQ NO: 29 or any Fc from TableNO: 32 or any anti-human CD3hole Fc fusion (SEQ ID NO: No: 29 or any ID NO: 29 12 and containing Ser sequence from Table 7 or anti- heterodimder with 29) sequence from 366+Ala368+Val407+ mammal / bird CD3 sequence silent Fc and anti- Table 9 Gly297+Ala322

[0004] 10255 / PC CD3 fragment on VP307 Chain Amino acids 1- Amino acid Amino acid 142-368 of SEQ ID Chain 1 2 136 of SEQ ID 137-141 of SEQ NO: 30 or any Fc from Table (SEQ ID NO: NO: 30 or any ID NO: 30 12 and containing 30) DC-SIGN or L- Trp336+Gly297+Ala322 SIGN sequences from Table 10 or 11 VP308VP308 ChainAmino acids 1- Amino acids Amino acids 111-337 of SEQ ID TIM1 x CTLD Knob-in- 1 105 of SEQ ID 106-110 of SEQ NO: 31 or any Fc from Table hole Fc fusion (SEQ ID NO: No: 31 or any ID NO: 31 12 and containing Ser heterodimder with 31) sequence from 366+Ala368+Val407+ silent Fc and anti- Table 9 Gly297+Ala322 CD3 fragment onVP308 ChainAmino acids 1- Amino acid Amino acid 142-366 of SEQ IDAmino acids 382-636 of SEQ IDChain 2 2 136 of SEQ ID 137-141 of SEQ NO: 32 or any Fc from TableNO: 32 or any anti-human CD3(SEQ ID NO: NO: 32 or any ID NO: 32 12 and containing sequence from Table 7 or anti- 32) DC-SIGN or L- Trp336+Gly297+Ala322 mammal / bird CD3 sequence SIGN sequences from Table 10 or 11

[0005] 10255 / PCTable 7. Anti-CD3 sequencesConstruct Description SequencehOKT3 huOKT3 C114S scFv SEQ ID NO:33F10-FC Alpaca Anti-CD3 nanobody F10 SEQ ID NO: 34HUF10-A-FC humanized Anti-CD3 nanobody F10 with free Cys removed SEQ ID NO: 35HUF10-FC humanized Anti-CD3 nanobody F10 (contains free Cys) SEQ ID NO: 36Table 8. Sequences of Tetravalent TIM-1 X CTLD IgG1-Fc Fusion proteins Construct andChain name Variable Seq 1 Linker Variable Seq 2 Constant FusionDescription VP309 VP309 Chain Amino acid 1- Amino acid Amino acid Amino acid 252-478 Tetravalent TIM1 x 1 105 of SEQ ID 106-115 of 116-251 of SEQ of SEQ ID NO: 37 or CTLD - Fc fusion(SEQ ID NO: NO: 37 or any SEQ ID NO: 37 ID NO: 37 or any sequences from 37) TIM-1 any DC-SIGN or Table 12 sequence from L-SIGN Table 9 sequences from table 10 or 11 VP309 Chain Same as Chain 1 2

[0006] 10255 / PC VP310 VP310 Chain Amino acid 1- Amino acid Amino acid Amino acid 252-478 1 105 of SEQ ID 106-115 of 116-251 of SEQ of SEQ ID NO: 38 or Tetravalent TIM1 x (SEQ ID NO: NO: 38 or any SEQ ID NO: 38 ID NO: 38 or any sequences fromCTLD - Fc fusion with38) TIM-1 any DC-SIGN or Table 12 and silent Fc sequence from L-SIGN containing Gly Table 9 sequences from 297+Ala322 table 10 or 11 VP310 Chain Same as Chain 1 2 VP311 VP 311 Chain Amino acid 1- Amino acid Amino acid Amino acid 252-478 1 105 of SEQ ID 106-115 of 116-251 of SEQ of SEQ ID NO: 39 or Tetravalent TIM1 x (SEQ ID NO: NO: 39 or any SEQ ID NO: 39 ID NO: 39 or any sequences fromCTLD – Fc fusion with39) TIM-1 any DC-SIGN or Table 12 and silent Fc andThiol- sequence from L-SIGN containing Gly conjugation site Table 9 sequences from 297+Ala322+Cys339 table 10 or 11 VP311 Chain Same as Chain 1 2 VP312 VP312 Chain Amino acid 1- Amino acid Amino acid Amino acid 252-476 Amino acids 492-746 1 105 of SEQ ID 106-115 of 116-251 of SEQ of SEQ ID NO: 40 or of SEQ ID NO: 40 or Tetravalent TIM1 x (SEQ ID NO: NO: 40 or any SEQ ID NO: 40 ID NO: 40 or any sequences from any anti-human CD3CTLD – Fc fusion with40) TIM-1 any DC-SIGN or Table 12 and sequence from table 7 silent Fc and bivalent sequence from L-SIGN containing Gly anti-CD3 Table 9 sequences from 297+Ala322 or anti-mammal / bird table 10 or 11 CD3 sequence VP312 Chain Same as Chain 1 2

[0007] 10255 / PC VP313 VP313 Chain Amino acid 1- Amino acid Amino acid Amino acid 252-476 Amino acids 492-746 1 105 of SEQ ID 106-115 of 116-251 of SEQ of SEQ ID NO: 41 or of SEQ ID NO: 41 or Tetravalent TIM1 x (SEQ ID NO: NO: 41 or any SEQ ID NO: 41 ID NO: 41 or any sequences from any anti-human CD3 CTLD - Fc fusion with41) TIM-1 any DC-SIGN or Table 12 and sequence from table 7 silent Fc and sequence from L-SIGN containing monovalent anti-CD3Table 9 sequences from Ser366+Ala368+ or anti-mammal / bird table 10 or 11 Val407+Gly CD3 sequence 297+Ala322 VP313 Chain Amino acid 1- Amino acid Amino acid Amino acid 252-478 2 105 of SEQ ID 106-115 of 116-251 of SEQ of SEQ ID NO: 42 or (SEQ ID NO: NO: 42 or any SEQ ID NO: 42 ID NO: 42 or any sequences from 42) TIM-1 any DC-SIGN or Table 12 and sequence from L-SIGN containing Table 9 sequences from Trp336+Gly table 10 or 11 297+Ala322 Table 9. Ig-like V-domain of TIM-1 (HVACR1 / KIM-1) Sequences Animal Species Reference SequenceHuman Homo sapiens Uniprot Q96D42 SEQ ID NO: 1Monkey Macaca fascicularis Uniprot A0A2K5WXJ6 SEQ ID NO: 43Pig Sus scrofa Uniprot F1RQD3 SEQ ID NO: 44Cow Bos Taurus Uniprot Q2KII3 SEQ ID NO: 45Dog Canis lupus familiaris Uniprot A0A8C0MZ91 SEQ ID NO: 46

[0008] 10255 / PC Cat Felis catus Uniprot A0A024A8A5 SEQ ID NO: 47Mouse Mus musculus Uniprot Q5QNS5 SEQ ID NO: 48Chicken Gallus gallus Uniprot A0A1D5PPR4 SEQ ID NO: 49Table 10. CTLD of DC-SIGN (CD209) Sequences Animal Species Reference SequenceHuman Homo sapiens Uniprot Q9NNX6 SEQ ID NO: 2Monkey Macaca fascicularis Uniprot Q95J96 SEQ ID NO: 50Pig Sus scrofa Uniprot B3FVQ2 SEQ ID NO: 51Cow Bos indicus x Bos Taurus Uniprot A0A4W2FD42 SEQ ID NO: 52Dog Canis lupus familiaris Uniprot A0A8C0T4Z9 SEQ ID NO: 53Cat Felis catus Uniprot M3WYX9 SEQ ID NO: 54Mouse Mus musculus Uniprot Q91ZX1 SEQ ID NO: 55Chicken Gallus gallus NCBI NP_990815.1 SEQ ID NO: 56

[0009] 10255 / PC Table 11. CTLD of L-SIGN(DC-SIGNR / DC_SIGN2 / CD209L / CD299) sequences Animal Species Reference SequenceHuman Homo sapiens Uniprot Q9H2X3 SEQ ID NO: 57Monkey Macaca fascicularis Q8MIS5 SEQ ID NO: 58Pig Sus scrofa NP_001123444.1 SEQ ID NO: 59Cow Bos Taurus NP_001139228.1 SEQ ID NO: 60Dog Canis lupus familiaris NP_001124304.1 SEQ ID NO: 61Cat Felis catus XP_003981851.2 SEQ ID NO: 62Mouse Mus musculus Uniprot Q8CJ91 SEQ ID NO: 63Chicken Gallus gallus NP_990815.1 SEQ ID NO: 64

[0010] 10255 / PCTable 12- Antibody hinge-Fc sequences for mammals (IgG) and bird (IgY)Animal Species Reference SequenceHuman Homo sapiens Uniprot P01857 SEQ ID NO: 65Monkey Macaca fascicularis NCBI AGC00820.1 SEQ ID NO: 66Pig Sus scrofa NCBI AAA52219.1 SEQ ID NO: 67Cow Bos Taurus NCBI AAB37381.2 SEQ ID NO: 68Dog Canis lupus familiaris NCBI AAL35301.1 SEQ ID NO: 69Cat Felis catus NCBI BAA32230.1 SEQ ID NO: 70Mouse Mus musculus Uniprot P01868 SEQ ID NO: 71Chicken Gallus gallus NCBI AHX37590.1 SEQ ID NO: 72

[0011] 10255 / PC Figures Fig.1 shows schematic representation of fusion proteins with DC-SIGN and TIM-1. Solid dots indicate calcium ions used to bind C-type lectin domains (CTLD) of DC-SIGN to carbohydrate antigens. For more information see example 1.Fig. 2 shows the designs of tetravalent TIM-1 x CTLD fusions with IgG4-Fc scaffolds.Fig. 3A-C shows the SEC-HPLC profiles for VP300, VP301 and BioRad Sec std. respectivelyafter a single step protein A purification. For more information, see example 2.Fig. 4 shows the SEC-HPLC profiles for VP302 and VP303 after a single step protein Apurification. For more information, see example 2.Fig. 5 shows the viral antigen ELISA of VP303 binding to viral surface protein of RSV, SARS-COV-2 (Wuhan and Delta strains), CMV and Zika. For more information, see example 2.Fig. 6 shows the designs of bivalent TIM-1 x CTLD IgG1-Fc fusion proteins.Fig. 7 shows the designs of tetravalent TIM-1 x CTLD IgG1-Fc fusion proteins.Fig. 8 shows the sequence alignment of TIM-1 Ig-like V domain from several species. Line 1:Human. Line 2: Monkey. Line 3: Pig. Line 4: Cow. Line 5: Dog. Line 6: Cat. Line 7: Chicken. Line 8: Mouse. Line 9: Alignment consensus.Fig. 9 shows the sequence alignment of DC-SIGN C-Type Lectin Domain from several species.Line 1: Human. Line 2: Monkey. Line 3: Pig. Line 4: Cow. Line 5: Dog. Line 6: Cat. Line 7: Mouse. Line 8: Chicken. Line 9: Alignment consensus.Fig. 10 shows the sequence alignment of L-SIGN C-Type Lectin Domain from several species.Line 1: Human. Line 2: Monkey. Line 3: Pig. Line 4: Cow. Line 5: Dog. Line 6: Cat. Line 7: Mouse. Line 8: Chicken. Line 9: Alignment consensus. Fig.11 shows the sequence alignment of the hinge sequences (in bold) and Fc sequences (CH2 and CH3) of IgG for human, monkey, pig, cow, dog, cat, mouse and IgY for chicken. Line1: Human. Line 2: Monkey. Line 3: Pig. Line 4: Cow. Line 5: Dog. Line 6: Cat. Line 7: Mouse.Line 8: Chicken.Fig. 12 shows the sequence alignment of the TIM-1 family. Line 1: TIM1. Line 2: TIM2. Line 3:TIM3. Line 4: Alignment Consensus. 10255 / PCFig. 13. Schematic of fusion proteins that were functionally characterized. For further detailssee example 3.Fig. 14A-D. Oligomannose and PS targeting fusion proteins bind to AML cells and spare non-apoptotic healthy cells. Mean and SEM are presented. AML cell lines with the highest levels of binding (>5000 MFI) in panels A and B are shown in light gray. Full data set including the AML lines shown in Figure 14D. Binding to annexin-negative PBMC is shown asrepresentative of normal cells for further details see example 4. Figure 14A shows the datafor VP020: Figure 14B shows the data for VP025. Fig.15. Binding to normal cells, human AML cell lines, and patient primary AML tumor cells.A: VP025 used to determine binding to other human blood tumors in addition to the 9 AMLcancer cell lines, including multiple myeloma and B Cell lymphomas, as well as human solidtumors, including pancreatic, lung and colon cancer. B: Binding of AML cell lines with Man9 xPS targeting molecule by flow cytometry. C: Binding of various tumor samples with Man9 xPS targeting molecules by flow cytometry. AML: acute myeloid leukemia; ALL: acute lymphoblastic leukemia; MM: multiple myeloma; DLBCL: diffuse large B cell lymphoma. D: Binding of Man9 x PS targeting molecules and Man9 or PS monospecific molecules to AMLcell line SET-2. For further details see Example 4.Fig.16. VP020, VP304-TM and VP025 bind to AML patient cells while sparing healthy PBMC. Mean and SEM are presented. For further details see example 4. Fig.17. Immune cell engaging molecules targeting oligomannose and PS mediate killing ofAML cell lines in vitro. Mean and SEM of relative luminescence units (RLU) are presented.For further details see example 5. Fig.18. Immune cell engaging molecules targeting Man9 and PS mediate killing of AML celllines in vitro. Mean and SEM of % Cytotoxicity are presented. For further details see example6. Fig.19. Frequency T cells, B cells and myeloid cells on day 7 post treatment. For further details see example 7.Fig. 20A-C. Schematic of PAMP and PS targeting chimeric antigen receptors.Fig.21. Schematic of PAMP and PS targeting heterodimeric chimeric antigen receptors. 10255 / PCFig. 22A-D. Product profiles of VP304 (22A and 22B) and VP308 (22C and 22D) after 2-steppurification. Analytical SEC-HPLC profiles are shown in 22 A and C. SDS-PAGE gel analysesare shown in 22B and D.Fig. 23A-B. Glycan binding profile of VP304-CT. A: VP304-CT (50 μg / mL) + Anti-human IgG Fc– Cy3 (5 μg / mL). B: VP304-CT (5 μg / mL) + Anti-human IgG Fc – Cy3 (5 μg / mL). For moreinformation, see example 9.Fig. 24A-B. Glycan binding profile of VP304. A: VP304 (0.16 μg / mL) + Anti-human IgG Fc –Cy3 (5 μg / mL). B: VP304 (0.032 μg / mL) + Anti-human IgG Fc – Cy3 (5 μg / mL). For moreinformation, see example 9.Fig. 25. Neutralization of CMV infection with VP304. In vitro infectivity of human CMV onhuman lung fibroblast cells MRC-5 (left) and neutralization of CMV infectivity with VP304 (VIT-GLT) at Day 1, 3 and 5 post infection. For further details see example 10.Fig. 26. Day 5 inhibition of CMV infection by VP304 compared to anti-CMV control mAb.Comparison of neutralization efficacy of VP304 and anti-CMV PC0034 control mAb. Forfurther details see example 10.Fig. 27A-B. T cell mediated killing of two human AML cell lines with VP308. Fig 27 A: THP-1;Fig 27B: SET-2. For further details see example 11.Fig. 28. Design of VP304-CL and VP308-CL. For more information, see example 13.Fig. 29. Design of VP320. For more information, see example 14.Fig. 30A-B. In vitro killing of human AML cell line SET-2 by VP308, VP308-CL and VP320. Formore information, see example 14.Fig. 31A-G. In vivo efficacy of VP320 in syngeneic mouse AML tumor model. A:Bioluminescence imaging of mice treated with control or VP320. In vivo anti-tumor efficacyof VP320 immunotherapy in a syngeneic AML mouse model. Bioluminescence imaging ofC57BL / 6 huCD3e transgenic mice implanted with C1498 mouse AML tumors with luciferasereporter and treated with 3 doses of VP320 at 1.6 or 4.8 mg / kg. B: Survival curve of threecohorts. C-F: Fold change in bioluminescence signal. G: AUC of tumor fold change for 10255 / PCtreatment cohorts. Data is shown as mean ± SEM, with individual data points shown. Formore information, see example 15.Fig. 32A-B. IHC staining profile of VP320 on human lung cancer and triple negative breastcancer. Positive: primary and secondary. Negative control: secondary only. A: HuCAT232(lung adenocarcinoma, stage IV) - 5μg / mL VP320. B: HuCAT292 (triple negative breastcancer) - 5μg / mL VP320. For more information, see example 16.Fig. 33A-B. IHC staining profile of VP320 on invasive ductal carcinoma and normal mammarygland tissue. Positive: primary and secondary. Negative control: secondary only. A:HuCAT300 (invasive ductal carcinoma) - 5μg / mL VP320. B: HuFPT130 (normal mammarygland) - 5μg / mL VP320. For more information, see example 16.Fig. 34A-D. IHC staining profile of VP320 on matched normal tissue and tumor tissue frompancreas, lung, bladder, and breast. Staining: Blue / purple - Hematoxylin staining on nucleifor structure delineation. Green - Specific VP320 staining overlaid on Hematoxylinbackground. Negative control: Secondary antibody. For more information, see example 16.Fig. 35. Design of chimeric antigen receptors for engineered immune effector cells. For moreinformation, see example 17.Fig. 36A-B. Expression of VC001 in NK-92 cells transduced with CAR-encoded lentivirus. A:Non-transduced NK-92. B: VC001 NK-92 cell (MOI 1.7). For more information, see example 17.Fig. 37A-B. Expression of VC001 in T cells transduced with CAR-encoded lentivirus. A: Non-transduced T cells. B: VC001 T-cells (MOI 2.4). For more information, see example 17.Fig. 38A-B. Real time killing assay of breast and lung cancer cell lines by VC001 CAR-T cells. A:Real-time cytotoxicity assay of MDA-MB-231 breast cancer cells. B: Real-time cytotoxicity assay of NCl-H460 lung cancer cells. For more information, see example 17.Fig. 39. Binding of VP304 to pediatric AML tumors (top) and leukemic stem cells (bottom).For more information, see example 18. 10255 / PC Fig.40. Co-staining of human pancreatic tumor sections and normal human pancreas withVP320 and anti-CD133 (cancer stem cell marker CD133). Red: CD133. Green: VP320 stainingfor PS x Man9 x CD3. For more information, see example 22. Fig.41. Average tumor burden by bioluminescence measurements of mice implanted with human AML cell line and treated with Tim-1 x CTLD x anti-CD3 molecule. For more information, see example 23. Fig.42. Bioluminescence imaging of study cohorts of mice implanted with human AML cell line and treated with Tim-1 x CTLD x anti-CD3 molecule at Day 55 post treatment initiation. For more information, see example 23. Fig.43. AUC of tumor burden for treatment cohorts from mice implanted with human AML cell line and treated with Tim-1 x CTLD x anti-CD3 molecule. For more information, see example 23. Fig.44. Survival curves of study cohorts of mice implanted with human AML cell line and treated with Tim-1 x CTLD x anti-CD3 molecule. For more information, see example 23.Fig. 45. Additional Tim-1 x CTLD x anti-CD3 molecules. For more information, see example24. Fig.46A-E. Characterization of VP321 and VP323.A: Binding of VP321 and VP323 to recombinant human and cynomolgus CD3de fragments by ELISA. B: Binding of VP321 and VP323 to AML cell line OCI-AML3 (Top) and human CD8 T cells (bottom) by flow cytometry.C: In vitro cytotoxicity of VP321 and VP323 using AML tumor cell line THP-1 (top) andMultiple Myeloma cell line NCI-H929 (bottom), using human CD8 T cells at a 5:1 effector-to-target ratio. D: In vitro cytotoxicity of VP321 and VP323 using pancreatic cancer cell lineAsPC-1 and human pan T cells at a 3:1 effector-to-target ratio E: Pilot in vivo anti-tumorefficacy of VP321 immunotherapy in a pediatric AML patient derived xenograft mousemodel. E: Top) Average tumor burden by bioluminescence measurements of CD34+ hu-SGM3 mice implanted human PBMC and human AML cell line SET-2 with luciferase reporterand treated with VP321 (twice weekly for 3 weeks) at 0.07 mg / kg VP321. E: Bottom)Bioluminescence imaging of study cohorts of mice implanted with human AML cell line SET-2 10255 / PCand treated with VP321 molecule at Day 17 post treatment initiation. For moreinformation, see example 25.Fig. 47. Design of Tim-1 x anti-CD3 / CTLD x anti-CD3 bispecific molecules. For moreinformation, see example 26. Fig.48. In vitro cytotoxicity of VP321, VP321-TM and VP321-CT using AML tumor cell line THP-1 and human CD8 T cells at a 5:1 effector-to-target ratio.Fig. 49. Design of Fc-containing payload carrying agents with Tim-1 and CTLD domains. Formore information, see example 28.Fig. 50. Binding of VP601 to Phosphatidylserine (PS), Lewis X (LewX), and Mannose-9 (Man9)by ELISA. For more information, see example 28.Fig.51. Immunofluorescence of mouse salivary gland tissue with Man9xPS bispecificmolecule VP601 (green) and nuclear stain (blue). For more information, see example 29.Fig.52. Immunofluorescence of human tumor and normal tissues with Man9xPS bispecific molecule VP601 (green) alone and nuclear stain (blue) (Top panel), or with Man9xPSbispecific molecule VP601 (green) alone (Bottom panel). Tumor from patient with Stage IIinvasive breast ductal adenocarcinoma (left panels).Tumor and adjacent normal tissuesections from patient with high-grade pancreatic ductal adenocarcinoma (the two most right panels). For more information, see example 30. Fig.53. FDA panel of normal human tissues. Immunofluorescence of human tumor and normal tissues with Man9xPS bispecific molecule VP601 (green) and nuclear stain (blue) (Toppanel), or with Man9xPS bispecific molecule VP601 (green) alone (Bottom panel). For moreinformation, see example 30.Fig. 54. SEC-HPLC profiles VP601-DFO radiolabeled with Zirconium-89. For more information,see example 31.Fig. 55A-C. Functional activity of Fc-containing payload carrying agents with Tim-1 and CTLDdomains. A: Immunofluorescence imaging of AML cell line THP-1 with VP601 (left) or VP602(right) directly conjugated to FITC. B: Immunofluorescence imaging of pancreatic cancer cellline AsPC-1 with VP601 (left) or VP602 (right) directly conjugated to FITC. C: 10255 / PCImmunofluorescence imaging of AML cell line SET-2 with VP601 (left), VP602 (middle) andVP603 (right) directly conjugated to FITC. For more information, see example 32.Fig. 56. Binding of VP601, VP602 and VP603 to tumor exosomes. Top: U87-MG exosomes.Bottom: HCT-116 exosomes. For more information, see example 33.Fig. 57. Design of mini-protein payload carrying agents with Tim-1 and CTLD domains. Formore information, see example 34.Fig. 58A-B. Conjugation of VP701, VP702, VP701xVP702, or VP703 to fluorescently labeledpolymer nanoparticles and immunofluorescence imaging. A: AML cell line THP1. B:pancreatic cancer cell line AsPC-1. For more information, see example 35. Fig.59. Design of murine chimeric antigen receptor construct with Tim-1 and CTLD domains. For more information, see example 36. Fig.60. Real Time Cytotoxicity Assay with liver cancer cell line Hep3B treated with mVC302 T cells at various Effector to Target (ET) ratios. Target cells are allowed to adhere for 20hbefore T cells were added. Normalized cell index indicates that cells are viable and adhere tothe sensor surface. For more information, see example 36. Fig.61. Cytotoxicity Assay with murine pancreatic cancer cell line Panc-02 treated withmVC302 T cells at various Effector to Target (ET) ratios. For more information, see example36. Fig.62. Cytotoxicity Assay with murine AML cell line C1498 (top) and MM cell line 5TGM1 treated with mVC302, mVC302-TM or mVC302-CT T cells at various Effector to Target (ET) ratios. For more information, see example 36. Fig.63. Results from pilot study of subcutaneous Panc02-luc tumors in C57 / BL6 mice treatedfor 3 days with untransduced or mVC302 transduced T cells. For more information, seeexample 36. Fig.64. Results from pilot study of orthotopic Panc02-luc tumors in C57 / BL6 mice treated for7 days with untransduced or mVC302 transduced T cells. For more information, see example36. 10255 / PC Fig.65. Design of human chimeric antigen receptor constructs with Tim-1 and CTLD domainsas a single chain. For more information, see example 37.Fig. 66. CAR T potency. In vitro killing to AML tumor cell line THP-1 with hVC302a, hVC302bor hVC302c transduced T cells. For more information, see example 37.Fig. 67. Binding of Man9 x PS targeting molecules to A: Glioblastoma cell line U-87 MG(using VP601), and B: liver cancer cell line Hep-G2 (using VP304 and VP601). For moreinformation, see example 38. All cited references are incorporated by reference. The accompanying Figures and Examples are provided to explain rather than limit the present invention. It will be clear to the person skilled in the art that aspects, embodiments,claims and any items of the present invention may be combined.Unless otherwise mentioned, all percentages are in weight / weight. Unless otherwise mentioned, all measurements are conducted under standard conditions (ambienttemperature and pressure). Unless otherwise mentioned, test conditions are according toEuropean Pharmacopoeia 8.0. Examples Example 1. Design of TIM1 x CTLD for targeting infectious disease and cancerMolecular modelling was utilized to design the fusion constructs of the Ig-like V-type domainof human TIM-1 (SEQ ID NO:1) with the C-type lectin domain of human (CTLD) of DC-SIGN(SEQ ID NO:2), as depicted in Figure 1. The TIM-1 xCTLD fusion sequences (SEQ ID NO:3 andSEQ ID NO:4) were designed with a flexible Gly-Ser linker between the two domains and aHis tag for purification. These his-tagged protein fusions can then be used for targetingimaging liposomes. The TIM-1 x CTLD sequences can be put onto an human IgG4 Fc scaffoldfor therapeutic and imaging applications by fusing the sequences to an additional Gly-Serlinker, human IgG4 hinge and Fc domains (V-IGG4-ADC-A-Fc, SEQ ID NO: 13), which has additional mutations to enhance hinge stability (S228P), knock out ADCC (F234A, L235A), knock out complement (K322A) and an engineered Cys (A339C) to allow for site-specificthiol-conjugation of imaging agents and other payloads (mutations are in standard EU 10255 / PCnumbering (IMGT)). The design of tetravalent TIM-1 x CTLD fusions with IgG4-Fc scaffoldsare shown in Figure 2. Exemplary sequences are shown in Table 13 (SEQ ID NO:11, SEQ IDNO:12), below. TIM-1 x CTLD bispecific molecules can also be generated where the TIM-1and CTLD are on opposite ends of the Fc domain (SEQ ID NO:14, SEQ ID NO:15). Table 13: Protein sequences Construct Description SequenceVIT-006-1 TIM-1 Ig-likeSVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIV V domain WTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCR Residues 21- VEHRGWFNDMKITVSLEIV (SEQ ID NO: 1) 125 VIT-006-2 CD209 (DC-ERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQ SIGN) C-type LVVIKSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVD lectin GSPLLPSFKQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLA domain KFWICKKSAASCS Residues (SEQ ID NO: 2) 250-385 VIT-006-3 TIM1-CD209-SVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIV fusion WTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCR VEHRGWFNDMKITVSLEIV-GGGGSGGGGSGGGGS- ERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQ LVVIKSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVD GSPLLPSFKQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLA KFWICKKSAASCSHHHHHH (SEQ ID NO: 3, the construct without the his-tag is disclosed as SEQ ID NO: 14) VIT-006-4 CD209-TIM1-ERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQ fusion LVVIKSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVD GSPLLPSFKQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLA KFWICKKSAASCS GGGGSGGGGSGGGGS- 10255 / PC SVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIV WTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCR VEHRGWFNDMKITVSLEIVHHHHHH (SEQ ID NO: 4, the construct without the his-tag is disclosed as SEQ ID NO: 15) VIT-006-5 TIM-1 and DC- SVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIV (VP300) SIGN with V- WTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCR IGG4-ADC-A- VEHRGWFNDMKITVSLEIVGGGGSGGGGSGGGGSERLCHPCP Fc WEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVIKSAEE QNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPSFK QYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLAKFWICKKSA ASCSGGGGSGGGGSGGGGSKYGPPCPPCPAPEAAGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKGLP SSIEKTISKCKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 11)VIT-006-6 DC-SIGN and ERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQ (VP301) TIM-1 with V- LVVIKSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVD IGG4-ADC-A- GSPLLPSFKQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLA Fc KFWICKKSAASCSGGGGSGGGGSGGGGSSVKVGGEAGPSVTL PCHYSGAVTSMCWNRGSCSLFTCQNGIVWTNGTHVTYRKDTR YKLLGDLSRRDVSLTIENTAVSDSGVYCCRVEHRGWFNDMKITV SLEIVGGGGSGGGGSGGGGSKYGPPCPPCPAPEAAGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKGL PSSIEKTISKCKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 12) 10255 / PC V-IGG4-ADC-A- GGGGSGGGGSGGGGSKYGPPCPPCPAPEAAGGPSVFLFPPKPKFc Linker, hingeDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTK and Fc of PREEQFNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKGLPSSIEK human IgG4 with S228P, TISKCKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAV F234A, EWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV L235A, FSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 13) K322A, A339C mutations VIT-006-7 TIM-1 with V- SVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIV (VP302) IGG4-ADC-A- WTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCR Fc and DC-VEHRGWFNDMKITVSLEIV SIGN GGGGSGGGGSGGGGSKYGPPCPPCPAPEAAGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTK PREEQFNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKGLPSSIEK TISKCKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV FSCSVMHEALHNHYTQKSLSLSLGK GGGGSGGGGSGGGGSERLCHPCPWEWTFFQGNCYFMSNSQ RNWHDSITACKEVGAQLVVIKSAEEQNFLQLQSSRSNRFTWM GLSDLNQEGTWQWVDGSPLLPSFKQYWNRGEPNNVGEEDCA EFSGNGWNDDKCNLAKFWICKKSAASCS (SEQ ID NO: 14) VIT-006-8 DC-SIGN with ERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQ (VP303) V-IGG4-ADC- LVVIKSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVD A-Fc and DC- GSPLLPSFKQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLA SIGN KFWICKKSAASCS GGGGSGGGGSGGGGSKYGPPCPPCPAPEAAGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTK PREEQFNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKGLPSSIEK TISKCKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV FSCSVMHEALHNHYTQKSLSLSLGK 10255 / PC GGGGSGGGGSGGGGSSVKVGGEAGPSVTLPCHYSGAVTSMC WNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVS LTIENTAVSDSGVYCCRVEHRGWFNDMKITVSLEIV (SEQ ID NO: 15) Linker Gly-Ser linker GGGGS (SEQ ID NO: 5)6His 6X His tag HHHHHH (SEQ ID NO: 6)10His 10X His tag HHHHHHHHHH (SEQ ID NO: 7)Streptavidin CoreAEAGITGTWYNQLGSTFIVTAGADGALTGTYESAVGNAESRYVL Streptavidin TGRYDSAPATDGSGTALGWTVAWKNNYRNAHSATTWSGQYV Residues 13- GGAEARINTQWLLTSGTTEANAWKSTLVGHDTFTKVKPSAAS 139) (SEQ ID NO: 8) MBP-1 MembraneRPPGFSPFR (SEQ ID NO: 9) binding peptide 1 from Bradykinin (residues 381-389) MBP-2 MembraneKKKKKRFSFKKSFKLSGFSFKKNKK (SEQ ID NO: 10) binding peptide 2 from MARCKS protein (residues 151–175)Example 2: Expression, Purification and Characterization of Tetravalent TIM-1 x DC-SIGNIgG4-Fc Fusion ProteinsPlasmid DNA for the fusion constructs shown in Figure 2 (VP300 – VP303) were generatedand used to transfect CHO cells. Supernatant was harvested and purified using MabSelect 10255 / PC Sure protein A resin (Cytiva). Analytical SEC-HPLC was run to assess purity and shown in Figures 3 and 4. After the single step protein A purification, all constructs had a mixture ofthe expected monomeric species (~110 KDa) and a multimer (>600 KDa), with VP301 andVP302 having predominant multimer. VP303 was selected for a second step SEC purification resulting in 70% monomer content, which was then assessed for binding to viral surfaceproteins by ELISA.Figure 5 shows the ELISA binding of the 70% pure VP303 to the following viral surfaceproteins coated onto a polystyrene ELISA plate: RSV Glycoprotein G, SARS-Cov-2 S (Wuhanand Delta), Zika Virus Envelope Protein, and CMV gH pentamer. All tested viral antigenswere recognized by VP303. Example 3. Expression and Purification of Fusion Protein ConstructsFusion protein constructs listed in Table 14 were expressed and purified. The sequences ofVP304, VP306, VP308 and VP309 were described in Table 6. VP304-TM and VP304-CT and the monospecific homodimeric parent molecules that comprise the heterodimeric VP304. VP308-CD16 is a version of the VP308 format where an anti-CD16 scFv (SEQ ID NO: 78 from Table 4)is used instead of an anti-CD3 scFv, in order to engage NK cells for the killing of tumors, infected cells or pathogens. VP020 and VP025 are IgG4 version of DC-SIGN and / or TIM-1 fusion protein described previously in US 11,197,910 B1. The sequences of VP308-CD16, VP020 and VP025 are shown in Table 14. For each heterodimeric construct, the plasmids which contained either the TIM-1 fusion gene or the DC-SIGN fusion gene were mixed in a 1:1 ratio or a single plasmid was used (in the case of homodimeric constructs) to co-transfect 250 mL of Expi-CHO expression cells (Invitrogen / ThermoFisher). Cells were harvested after 6 days of culturing at 37 deg C and the filtered supernatant was used for protein purification by Protein A (ProtA) affinity chromatography on at Akta Start FPLC system (Cytiva). The sample column contained 1mL Prot A Mab Select Sure resin (Cytiva) which was first equilibrated with 6 column-volumes of PBS at 1mL / min. Filtered cultured media was then loaded over Prot A Mab Select Sure resin (Cytiva) at 3mL / min and washed with 15 column volumes of PBS at 1mL / min. Purified protein was then eluted off the column using 6 column-volumes of 0.1 M Glycine pH 2.7 at 1mL / min. 10255 / PC 1mL elution fractions were collected and neutralized with 100uL of 1M Tris pH 8.0 and 100uL of 10 x PBS. Construct Format Sequence for Chain 1 Sequence for Chain 2Name VP304- TIM-1 IgG1-Fc fusion SEQ ID NO: 23 SEQ ID NO: 23TM homodimer CTLD IgG1-Fc fusion VP304-CTSEQ ID NO: 24 SEQ ID NO: 24homodimer VP304 TIM1 x CTLD SEQ ID NO: 23 SEQ ID NO: 24(VIT-GLT) heterodimer TIM1 x CTLD VP306 heterodimer withSEQ ID NO: 27 SEQ ID NO: 28conjugation site VP308 TIM1 x CTLD x anti-CD3 (VIT-SEQ ID NO: 31 SEQ ID NO: 32trispecific GLT3) VP308- TIM1 x CTLD x anti- SEQ ID NO: 31 (SEQ ID NO: 82)CD16 CD16 trispecific TIM1 x CTLD VP309SEQ ID NO: 37 SEQ ID NO: 37tetravalent homodimer CTLD IgG4-Fc fusion VP020SEQ ID NO: 83 (SEQ ID NO: 83)homodimer TIM1 x CTLD IgG4-Fc VP025(SEQ ID NO: 84) SEQ ID NO: 83fusion heterodimer Table 14. Protein fusion products that were expressed and purified. Six of the expressed and purified proteins (depicted in Figure 13) were then functionally characterized for their ability to bind and kill tumor cells. The purity and expected MW of the constructs are shown in Table 15.Sample ID: VP020 VP025 VP304-TM VP304-CTVP304 VP308 (VIT-GLT) (VIT-GLT3) 1.4 2.5 Concentration0.2 mg / mL 5.5 mg / mL 0.2 mg / mL 1.1 mg / mLmg / mL mg / mLPurity 92.9% 83.4% >95%* 91% >95% 42% 10255 / PC Calculated 86.6 KDa 82.6 KDa 77.3 KDa 85.9 KDa 81.6 KDa 109.1 KDaMW Table 15. Summary of characteristics of characterized fusion proteins.*Presents as a high molecular weight multimer. Example 4. Binding to normal cells, human AML cell lines, and patient primary AML tumor cellsThe expressed and purified constructs from Table 15 were used to stain human PBMC, humanBMMC, mouse splenocytes, nine human AML (Acute Myeloid Leukemia) cell lines and eight human primary tumors from AML patients by flow cytometry. Secondary staining was done using Southern Biotech Mouse Anti-Human IgG Fc-FITC (JDC-10) (Cat. No.: 9040-02) as a 1:200 dilution. Samples were incubated for 15 minutes at 4 °C in the dark, washed in staining buffer and resuspended in 300 µl of staining buffer. Phosphate buffered saline, pH 7.4 (Thermo Fisher Scientific) with 0.5% bovine serum albumin (Equitech-Bio) containing 2.5mM of Calcium Chloride (Sigma Aldrich) was used as staining buffer for both the primary and secondary staining steps. Multiparameter flow cytometry was performed using a BD LSRFortessa Cell Analyzer and FCS files were analyzed by FlowJo (v10) software. Readout was done by looking at percent FITC positive cells and FITC median fluorescence intensity (MFI). Apoptotic versus non-apoptotic cells were determined by Annexin staining. Cells were washed with PBS, resuspended in Annexin V binding buffer (BioLegend), stained with Annexin V-FITC (BioLegend) for 15 minutes at 4 deg C in the dark, and analyzed immediately by flow cytometry. Binding of AML cell lines and normal cells by FACS analysis VP020 (DC-SIGN homodimer-hIgG4 fusion protein, targeting high mannose glycan) and VP025 (DC SIGN / TIM-1 heterodimer-hIgG4 fusion protein, targeting high mannose glycan andphosphatidylserine) were used to stain 9 human AML cell lines (Figure 14A and 14B). BothVP020 and VP025 had moderate to high binding to seven out of nine tested AML cell lines and did not bind to healthy control cells (PBMC, BMMC). VP020 or VP025 primary staining was followed by anti-hIgG-FITC secondary staining. Negative control was anti-hIgG4-FITC staining alone. 10255 / PC Healthy cells (mouse splenocytes or human PBMC) were stained with VP020, VP025 or VP304- TM (TIM-1 homodimer-hIgG4 fusion protein) and counterstained with Annexin V. VP020 does not bind to apoptotic healthy cells but VP025 and VP304-TM binding to healthy cells correlateswith apoptosis. Representative contour plots are presented (Figure 14C). Non apoptotichuman PBMC, apoptotic PBMC and HL-60 human AML cells were then stained with VP020, VP304-CT, VP025, VP304, or VP304-TM (Figure 14D). Control conditions included unstained cells and anti-hIgG4-FITC stained cells. The experiments showed that the cells stained with the fusion of the invention stained well, whereas the control cells contained little or no stain.Binding to human blood and solid tumor cell lines by flow cytometryIn addition to the 9 AML cancer cell lines, VP025 was used to determine binding other human blood tumors, including multiple myeloma and B Cell lymphomas, as well as human solidtumors, including pancreatic, lung and colon cancer (see Figure 15A and Figure 15B). Alltumor types showed positive binding as compared to normal PBMC. Percent binding to tumorsamples with VP025 (for tumor cell lines) or VP304 (for primary tumor samples) are shown inFigure 15C. The binding to VP304 compared to VP304-TM and VP304-CT for AML cell line SET-2 is shown in Figure 15D. VP304 has superior binding to the monospecific VP304-TM and VP304-CT. Binding to human AML primary tumors Human PBMC (n=4) and human AML patient cells (n=8) were stained with VP020 (CTLD only), VP304-TM (TIM-1 only) or VP025 (TIM1 x CTLD) (see Figure 16). All three test articles showed significant binding to the patient AML tumors, with the highest binding observed in the dual targeting VP025 molecule. Example 5. Immune cell mediated killing of AML tumor cells with Fc-active test articles VP304, VP304-TM and VP304-CT VP304, VP304-TM and VP304-CT (all having active IgG1-Fc domains) were assessed for the ability to recruit effector cells from healthy donor PBMC to kill human AML tumor cells. AML target cells with stable luciferase expression were seeded at 20,000 cells / well in 96 well plates 10255 / PC and mixed with human PBMC effectors cells at an Effector:Target ratio of 5:1 at a volume of 200 µL / well with RPMI (Gibco) / 10% FBS (Gemini Bio) or MEM-ɑ (Gibco) / 10% FBS. Plates were sealed with a Breathe-Easy sealing membrane (Sigma Aldrich) and cultured for 72h at 37 deg C. At 24, 48 and 72 h, D-Luciferin potassium salt (Goldbio) was added at a concentration of 30ug / 200µL / well and luciferase activity (bioluminescence) was measured using a multimodalplate reader (TECAN Infinite 200 PRO). THP-1-luc human AML cells were cultured in the presence of whole PBMC effector target cells at an effector:target (E:T) ratio of 5:1. VP304-CT, VP304-TM and VP304 were added to the media at a concentration of 1.4 pM and luciferase activity was measured at 24, 48 and 72 hours. High potency killing of the AML cells was observed with all three test articles (VP304- CT, VP304-TM and VP304) only in the presence of PBMC effectors cells (see Figure 17). Example 6. T-cell mediated killing of AML tumor cells with VP308 VP308 is a trispecific molecule (PS x oligomannose x CD3) engineered to re-direct T cells to tumor cells. Quick purification by protein A affinity chromatography resulted in ~42% purity which was considered sufficient for this pilot study to test its ability to re-direct T cells to kill human AML tumor cells. The human AML cell line OCI-AML-3 was chosen as the target cell,which had significantly less target expression (see Figure 15) than other AML cell lines testedsuch as HEL, SET-2 and THP-1. The human AML cells were cultured in the presence of wholePBMC effector target cells at an effector:target (E:T) ratio of 5:1 (equivalent to a T cell:targetratio of 1:1). VP308 was added to media at concentrations of 0.1, 0.3 and 1.0 nM, and luciferase activity was measured after incubation for 24h. High levels of AML cell cytotoxicity were observed in a dose dependent manner (see Figure 18). Summary of Binding and Cytotoxicity Data The PS and oligomannose targeting molecules were shown to bind human AML cells (both cell lines and cells from young adult high-risk AML patients) and spare healthy cells (PBMC, BMMC). The dual-targeting VP304 (VIT-GLT) which binds PS and oligomannose showed higher binding to patient AML tumor samples than the single-targeting VP304-CT (binds only oligomannose) 10255 / PC or the single-targeting VP304-TM (binds only PS). All three Fc-active molecules (VP304, VP304-TM, VP304-CT) showed killing of high target expressing human AML tumor cell lineTHP-1 in the presence of PBMC effector cells and at ultra-low concentration (1.4 pM). A tri-specific (PS x oligomannose x CD3) targeting molecule VP308 (VIT-GLT3) showed the ability to re-direct T cells to kill low target expressing human AML tumor cell line OCI-AML3. Example 7. In vivo safety study of VP304 C57BL / 6J immunocompetent mice were used in the study according to Table 16. Two micewere administered PBS vehicle control, and 3 mice were treated with 1 μg of VIT-GLT (0.04mg / kg) in PBS by intravenous injection on day 1. Body weights were measured at baseline and day 7. Mortality and clinical signs were monitored at baseline, during injection and at 1, 8, 24, 48h and day 7. Mice were sacrificed on day 7 post-injection and the spleen and blood were collected for immune cell profiling. Mice were anesthetized using 2-4% vaporized isoflurane and blood collection was done by cardiac puncture, collecting 200 µl per mouse in EDTA tubes. Following cardiac puncture, the mice were euthanized by cervical dislocation and splenectomies were performed via a 0.5-cm skin incision made in the lateral abdomen; the spleens were then separated from the stomach, removed from the abdominal cavity and transferred to a 5 mm Petri dish with PBS+0.5% BSA. TA Total Test Article Volume of Group Group Vehicle Dose Dosing doses / (TA) single dose (ml) size route animal1 PBS - 0.1 i.v. 2 1VP304 (VIT- 2PBS 1 μg 0.1 i.v. 3 1GLT)Table 16. Study designA rodent severity scoring method was used for clinical signs at each of the time points, which is described in Table 17. Key Normal (0) Mild (1) Moderate (2) Substantial (3) 10255 / PC ANormal weightReduced Weight loss up Weight loss gain weight gain to 20% greater than 25% BLittleinteraction with peers CHunchedHunched Hunched transiently intermittently persistently or after dosing frozen DIntermittentlyLabored abnormal breathing breathing pattern ETransientProlonged prostration prostration (less than 1 (more than 1 hour) hour) FTransientIntermittent Persistent tremors tremors tremors GIntermittentPersistent convulsions convulsions HSelf-mutilationI PartialStaring coat- Staring coat- piloerection marked marked piloerection piloerection and other signs of dehydration JSubdued Subdued andUnresponsive non-responsive to extraneous activity and provocation Table 17. Rodent Severity of Clinical Signs Scoring Body Weight and Clinical Scores No mortality was observed in any of the study animals. Body weights and clinical scores foreach study animal showed no significant changes in body weight in the Group 1 or Group 2animals. No clinical signs were observed at any of the time points for any of the animals. As 10255 / PC such, no changes in body weight and clinical scores were not significantly different between the control and VIT-GLT treated groups. Immune Cell ProfilingTerminal blood and spleen were collected 7-days post injection and profiled for the frequencyof CD4+ T cells, CD8+ T cells, B cells and myeloid cells by FACS analysis. 200 μl of blood per sample was transferred from EDTA tubes to FACS tubes for red blood cell lysis with ACK lysing buffer and antibody labeling. Spleens were homogenized using frostedslides and cell suspensions were passed through a 70-micron cell strainer. All PBMCs and onemillion splenocytes per sample were stained with an antibody cocktail containing the following mouse-specific monoclonal antibodies from Biolegend: CD3-APC (clone 145-2C11), CD4-BV605 (clone RM4-5), CD19 (clone 6D5), CD8-PE (clone 53-6.7), CD11b-APC-Cy7 (clone M1 / 70). Multiparameter flow cytometry was performed using a BD LSRFortessa Cell Analyzer and FCS files were analyzed by FlowJo (v10) software.The frequency of Frequency T cells, B cells and myeloid cells on day 7 after injection of PBScontrol or VIT-GLT for all study mice are shown in Figure 19. No significant differences were observed between the two groups, and the values were within the normal range. No mortality, abnormal body weights or clinical signs were observed in any group. Immunecell profiles were normal in both the treated and control groups. VP304 (VIT-GLT)administered intravenously at a dose level of 0.04 mg / kg was well-tolerated in immunocompetent mice. Example 8. Expression and purification of VP304 and VP308 using 2-step protein A and cation exchange chromatography VP304 (Tim-1 x CTLD bispecifc with active IgG1 Fc) and VP308 (Tim-1 x CTLD x anti-CD3 trispecifc with silenced IgG1 Fc) were expressed and purified using an optimized 2-step purification method. Gene inserts for VP304 and VP308 were cloned into PCDNA3.4 10255 / PC plasmids (Thermo Fisher Scientific) and used to transiently transfect ExpiCHO cells for 7 days. Supernatant was harvested and purified using MabSelect Sure protein A resin (Cytiva) and then polished with a cation exchange column. Analytical SEC-HPLC and SDS-PAGE was run to assess purity and shown in Figure 22A-D VP304 had a purity of 86% by SDS-PAGE and 85% by analytical SEC-HPLC. VP308 had a purity of 65% by SDS-PAGE and 64% by analytical SEC- HPLC Example 9. Glycan binding profile of VP304 and VP304-CTTo characterize the PAMP recognition by VP304 (containing the IgV domain of Tim-1 and theCTLD of DC-SIGN) and VP304-CT (containing only the CTLD of DC-SIGN), the CatchAll glycan microarray (Z Biotech, Aurora CO, USA) was utilized. The CatchAll glycan array contains 166 glycans that represent a diverse collection of carbohydrate structures, ranging from mammalian oligosaccharides, N-glycans, O-glycans, glycosphingolipid glycans, blood group antigen glycans, glycosaminoglycans, sialylated glycans to human milk oligosaccharides. For each test article, the glycan array was treated with glycan array blocking buffer and allowed to incubate at room temperature for 30 minutes. Subsequently, the samples were diluted fivefold in glycan array assay buffer for 7 times, applied to the microarray slide, and incubated at room temperature for one hour. Following this incubation period, the microarray slide underwent thorough washing to remove unbound substances. Next, a secondary antibody targeting human IgG Fc, at a concentration of 5 µg / mL, was applied to the microarray and incubated for an additional hour under the same conditions. After a final wash to remove any non-specific binding, the microarray was scanned to analyze the glycan binding interactions. The microarray slide was scanned at 532 nm using high-intensity settings (1 PMT). Innopsys's Mapix software was used to analyze the array scan. This software assesses binding signals by subtracting background signals and those from negative controls. The glycan profile of VP304-CT is shown in Figure 23A-B. VP304-CT exhibited strong affinity for Lewis X and Lewis-like structures, specifically to Galβ1-3(Fucα1-3)GlcNAcβ1 and Galβ1- 3(Fucα1-4)GlcNAcβ1. It also engaged with other fucose-containing glycans, such as those 10255 / PC presenting the Fucα1-2Galβ1-4Glc epitope. The presence of terminal sialic acids (Neu5Ac) on these epitopes was observed to significantly diminish or eliminate binding interactions. VP304-CT demonstrated robust binding to a range of high-mannose N-glycans, specificallyfrom Man-6 to Man-9.VP304 exhibited a binding profile similar to VP304-CT (see Figure 24A-B). It displayed pronounced affinity for Lewis X and Lewis-like structures, notably Galβ1-3(Fucα1- 3)GlcNAcβ1 and Galβ1-3(Fucα1-4)GlcNAcβ1. Additionally, VP304 interacted with other fucose-containing glycans presenting the Fucα1-2Galβ1-4Glc epitope. Binding interactions were significantly reduced or absent in the presence of terminal sialic acids (Neu5Ac) on these epitopes. Furthermore, VP304 demonstrated strong binding to a high-mannose N- glycan. These glycans that were bound by VP304 are present on pathological tissues such asinfection and cancer and are not found on normal human tissues.Example 10. Neutralization of human cytomegalovirus (CMV) with VP304 The Tim-1 and DC-SIGN fragments contained in VP304 were shown to bind to the glycosylated human CMV surface protein gH pentamer (see VP303 binding in Figure 5). VP304 has an active huIgG1-Fc domain that can elicit ADCC, ADCP and complement activation. It is an ideal platform to not only neutralize pathogens, but also engage the immune system through its Fc domain. VP304 was tested for its ability to neutralize human CMV in vitro. In the assay, VP304 is mixed with human CMV which expresses a luciferase reporter gene allowing for luminescence detection, and then added to MRC-5 cells (human lung fibroblast) to measure infectivity. A Toledo-Luc containing luciferase expression cassette was used in this study as described previously (Dulal et al., 2009)6. The MRC-5 cells were seeded into 24-well plates. The Toledo-Luc hCMV was treated with indicated concentrations of VP304 for 1 hour at 37 degrees. After 1 hour of treatment, the virus-antibody mixture samples were added to MRC-5 cells at an MOI of 0.1 in triplicate wells.Toledo-Luc treated with the buffer vehicle was used as a control. The growth kinetics of Toledo-Luc was determined by a bioluminescence assay. The luciferase activity of theToledo-Luc virus was measured every 48 hours using an in vivo imaging system (IVIS-50) asdescribed previously (Dulal K., Zhang Z., Zhu H. Development of a gene capture method to 10255 / PC rescue a large deletion mutant of human cytomegalovirus. J. Virol. Methods.2009;157:180– 187). The time course for CMV infection and the neutralization effectiveness for VP304 is shown in Figure 25. Maximum infectivity of the MRC-5 cells was observed at Day 5. VP304 showed potent neutralization of infectivity, with an IC50 of ~10nM at Day 1 and an IC50 of <100 pM at Day 5. A positive control antibody PC0034 (Ai et al. Microbiol Spectr.2022 Dec 21;10(6):e0139322. doi: 10.1128 / spectrum.01393-22.) that is specific for CMV antigens was used for comparison. VP034 at 23 nM showed the same level of neutralization as PC0034 at130 nM concentration (see Figure 26).Example 11. Dose-dependent in vitro potency of VP308 in killing human Acute Myleoid Leukemia (AML) cell lines VP308 was tested for its ability to re-direct T cells to kill human AML tumor cell lines in vitro. In this assay, two human AML cell lines (THP-1 and SET-2, which had been stably transfected with luciferase reporter gene) were incubated with activated human T cells at a 2:1 effector- to-target ratio and VP308 at concentrations ranging from 0.6 pM to 4 nM. Tumor cell viability was then monitored with the addition of luciferin at 24 and 48h. The results are shown in Figure 27A-B. Decrease is luminescence signal indicates target cell death. For the THP-1 target cells, VP308 had an IC50 of 4.8 pM at 24h and an IC50 of 5.0 pM at 48h. For the SET-2 target cells, VP308 had an IC50 of 4.3 pM at 24h and an IC50 of 46 pM at 48h. This indicated highly potent activity for VP308 to redirect T cells to kill human AML tumors. Example 12. Safety and pharmacokinetic study of oral and intravenous dosing of VP304 and VP308 in immunocompetent mice To investigate the pharmacokinetics and safety of orally and intravenous administration of VP304 and VP308 in immunocompetent mice, a dosing study was done using 80 Swiss Webster mice (40 male, 40 female). The mice were divided into 8 groups (see Table 18) and treated with either VP304 or VP308 at 2 different dose levels and either via oral or intravenous administration. Following dose administration, all animals were observed daily 10255 / PC for 5 days. Approximately 150 µL of whole blood was collected at staggered time points and saved for pharmacokinetic analysis (analysis pending). No adverse events were observed during the observation phase, and there were no notable findings upon gross necropsy examination. Table 18. Groups of mice used for pharmacokinetic and safety study Group Number of Mice Dosing Route1 5 male / 5 female 0.12 mg / kg VP304 IV2 5 male / 5 female 0.12 mg / kg VP304 Oral3 5 male / 5 female 0.3 mg / kg VP304 IV4 5 male / 5 female 0.3 mg / kg VP304 Oral5 5 male / 5 female 0.4 mg / kg VP304 IV6 5 male / 5 female 0.4 mg / kg VP304 Oral7 5 male / 5 female 0.06 mg / kg VP304 IV8 5 male / 5 female 0.06 mg / kg VP304 OralExample 13. Re-engineering of VP304 and VP308 to improve manufacturability Expression and purification of VP304 from transient expression in ExpiCHO cells resulted in approximately 25-30 mg per L culture after protein A purification and subsequent polishing step involving cation exchange could recover 14-40% of the product at a purity of 79-85%, with higher purity obtainable (>95%) at the sacrifice of total yield. To improve the overall yield and purity, VP304 was re-engineered to have longer linkers between the Tim-1 (TM) or CTLD (CT) domains and the human IgG1 Fc domain, and an extra disulfide bridge was added between the two chains in the Fc (see Figure 28). The new construct was designated as VP304-CL (SEQ ID NO: 94 and SEQ ID NO: 95). Small scale expression (25 mL culture) was done and the product was purified by Protein A GraviTrap columns in the presence of calcium. The analytical SEC, SDS-PAGE analysis, and the yield comparison of VP304 andVP304-CL are shown in Table 19. VP304-CL showed a 5-fold higher yield than VP304, 10255 / PC resulting in 125.7 mg / L culture after protein A purification, compared to VP304 which has a yield of 24.5 mg / L culture. Similarly, VP308 was re-engineered to improve manufacturability. A new construct VP308- CL (see Figure 28) was designed to have longer linkers between the Tim-1 (TM) or CTLD (CT) domains and the human IgG1 Fc domain, and an extra disulfide bridge was added between the two chains in the Fc. In addition, silencing the Fc was done via LALA mutations (L234A,L235A) and K322A, rather than the aglycosylation mutation N297G found in VP308 (IMGTnumbering )). The new construct was designated as VP308-CL (SEQ ID NO: 96 and SEQ ID NO: 97). VP308-CL was transiently expressed in ExpiCHO cells and purified with a single step protein A GraviTrap column. VP308-CL had comparable yield to VP308, approximately 22 mg / L culture. Table 19: Purity and yield of VP304 and VP304-CL after single step protein A purification. Structu DescripTT# PurificaConc Amoun Yield Purity Yield re tion tion (mg / mL t (mg) (mg / L) (%) POI method ) (mg / L) VP304 TIM TT02 ProtA 0.10 0.49 24.5 52.2 12.8Grav VP304- NewTT35 ProtA 0.65 3.8 125.7 52.1 65.4CL linker Grav and DS Example 14. Design of alternate form of Tim-1 x CTLD x anti-CD3 trispecific molecule VP308 (Tim-1 x CTLD x anti-CD3 trispecific) had been shown to have highly potent activity in re-directing T cells to kill tumor cells in Example 11. An alternate form of this Tim-1 x CTLD x anti-CD3 trispecific format was designed where the anti-CD3 fragment was moved in closer proximity to the Tim-1 and CTLD domains (see Figure 29). This new version was named VP320 (SEQ ID NO: 96 and SEQ ID NO: 98) and is similar in format to VP308-CL, where there are 20 amino acid length Gly-Ser linkers upstream of the Fc domain, and contains the LALA (L234A, L235A) and K322A Fc-silencing mutations. The anti-CD3 scFv fragment was placed 10255 / PC after the CTLD and before the 20 amino acid long gly-ser linker and CH2 and CH3 domains of the Fc. A 15 amino acid gly-ser linker was placed between the CTLD and anti-CD3 scFv domains. The second chain containing the Tim-1 fragment fused to the silent CH2-CH3 Fc domain was identical to that found in VP308-CL. An alternative version of VP320 can be made by placing the anti-CD3 moiety between the Tim-1 domain and the Fc domain. The anti-CD3 moiety can also be replaced by a different immune cell engaging moiety, such as an anti-CD16 fragment to engage NK cells. Plasmids were generated encoding for V320 using PCDNA 3.4 vector (Thermo Fisher) and then used to transiently transfect ExpiCHO cells for 7 days. The supernatant was then used to purify VP320 using a 2 step purification using mAb Select SuRe protein A resin followed by cation exchange polishing step. The resulting product was highly pure with >95% purity by analytical SEC-HPLC.The in vitro activity of VP320 to re-direct T cells to kill human AML tumors was directlycompared to VP308 and VP308-CL. Human AML cell line SET-2 with a luciferase reporter gene was used as target cell. SET-2 cells were incubated with activated human T cells at a 2:1 effector-to-target ratio and either VP320, VP308 or VP308-CL at concentrations ranging from 0.1 pM to 1 nM. Tumor cell viability was then monitored with the addition of luciferin from 6h to 66h. Maximal target killing was observed at the 32h and 42h time point and are shown in Figure 30A-B. VP308 and VP308-CL had comparable activity with an IC50 of ~100 pM. VP320 had an IC50 of ~1 pM. It was unexpected that VP320 would have a ~100-fold higher potency in killing AML tumor cells than VP308 and VP308-CL. Example 15. In vivo efficacy study of VP320 in syngeneic mouse AML modelAn in vivo mouse efficacy study was conducted to determine if VP320 could treat AML in animmunocompetent syngeneic mouse model. Mouse tumors, like human tumors, contain PAMP and PS antigens. VP320 contains an anti-CD3 scFv based on clone OKT3 whichrecognized human CD3-epsilon and does not cross-react with mouse CD3. For this reason, atransgenic huCD3-epsilon mouse was chosen for this study (B-hCD3e mouse strain, 10255 / PC Biocytogen, Beijing, China). The B-hCD3e is a C57BL / 6 mouse strain where exons 2-6 ofmouse Cd3e gene that encode the extracellular domain were replaced by human CD3E exons2-7 in B-hCD3E mic (Reference: Zhang et al. Exp Anim. 2022 Nov 10;71(4):442-450. doi:10.1538 / expanim.22-0012.) B-hCD3e mice were implanted with 1 x 10^6 mouse AML tumors cells (C1498 cell line transfected with a luciferase reporter gene) and allowed to engraft for 1-2 weeks until bioluminescence imaging signal of 1 x 10^6 photons / sec was reached. Once the imaging threshold had been reached, mice were treated with either vehicle control (PBS, n=5), 1.6 mg / kg VP320 (n=3), or 4.8 mg / kg VP320 (n=4) at Day 0, Day 3 and Day 7. Data is shown inFigure 31A-G and Table 20. Mice were monitored for 15 days post treatment. Mice in theVP320 treatment arms had reduced tumor burdens compared to control group, with highest efficacy seen in the 1.6 mg / kg VP320 group. All mice in the control group died by Day 10, as expected, whereas the VP320-treated groups had longer survival. Table 20: AUC of tumor fold change for treatment cohorts. Control 1.6 mg / kg4.8 mg / kg VP320 VP320 average tumor AUC1815 43.01 1688(fold change x day) %reduction 97.6 7.0Example 16. Development of immunohistochemistry (IHC) method to profile human tumor and normal tissues An IHC method was developed to use VP320 to bind to Formalin-Fixed Paraffin-Embedded (FFPE) tissues. Slides were first deparaffinized in xylene and then hydrated through graded alcohols. Next, slides were subject to antigen retrieval in a Tris-EDTA buffer (pH 9). Slides were then blocked against both endogenous biotin and peroxidases. Following the blocking steps, slides were incubated with 5 microgram / mL VP320, which was then detected with an HRP-labeled secondary (anti-human-IgG-Fc clone JDC10, Southern Biotech) and visualized with a green chromogen. The slides were counterstained with hematoxylin, dehydrated in 10255 / PC graded alcohols, cleared in xylene, and mounted with permanent mounting media. All rinses were performed using either distilled water or TBST at room temperature. The IHC staining profile of VP320 on human lung cancer and triple negative breast cancer are shown in in Figure 32A-B. The IHC staining profile of VP320 on invasive ductal carcinoma and normal mammary gland tissue are shown in Figure 33A-B. Specific staining of the three tumor samples with VP320 was observed. No staining was observed in normal mammary gland tissue. Additional tumor sections with matched normal tissues from pancreas, lung, bladder, and breast were stained with VP320 (or secondary alone control) and are shown in Figure 34. Specific staining of tumors were observed.Example 17. Engineering of chimeric antigen receptor natural killer (CAR-NK) cells andchimeric antigen receptor (CAR-T) cells Two chimeric antigen receptors were designed (VC001 and VC003, see Figure 35) to create chimeric antigen receptor NK Cells (CAR-NK) or chimeric antigen receptor T Cells (CAR-T). The VC001 and VC003 can also be used to generate CAR modified macrophages, invariant Natural Killer T (iNKT) cells, γδT cells, neutrophils, and embryonic or pluripotent stem cells. VC001 is a two chain CAR construct where the first chain contains Tim-1 IgV domain, a Flag tag (to monitor expression), a CD28 hinge and transmembrane domain, a CD28 co- stimulatory domain, 4-1BB costimulatory domain, 2B4 co-stimulatory domain, and a CD3- zeta activation domain (SEQ ID NO: 99). The second chain of VC001 contains DC-SIGN CTLD domain, a TF tag (to monitor expression), a CD28 hinge and transmembrane domain, a CD28 co-stimulatory domain, 4-1BB costimulatory domain, 2B4 co-stimulatory domain, and a CD3- zeta activation domain (SEQ ID NO: 101). In VC001, both chains contain the CD3-zetaactivation domain. VC001 is similar to construct VC304, where VC001 contains costimulatorydomains of CD28, 4-1BB and 2B4. VC003 is a two chain CAR construct where the first chain contains Tim-1 IgV domain, a Flag tag (to monitor expression), a CD28 hinge and transmembrane domain, and a CD3-zeta activation domain (SEQ ID NO: 102). The second chain of VC003 contains DC-SIGN CTLD 10255 / PC domain, a TF tag (to monitor expression), a CD28 hinge and transmembrane domain, a CD28 co-stimulatory domain, 4-1BB costimulatory domain, and a 2B4 co-stimulatory domain (SEQ ID NO: 103). In VC003, the first chain contains the activation domain and no co-stimulatorydomains and the second chain contains the co-stimulatory domains and no activationdomain. This would require that both the Tim-1 and CTLD would need to bind theirrespective target to significantly activate the engineered immune cell. VC003 is similar toconstruct VC307, where VC003 contains costimulatory domains of CD28, 4-1BB and 2B4. To generate VC001, a single lentiviral expression vector was generated where a MNDU3promoter controlled expression of VC001 chain 1 (SEQ ID NO: 99), followed by a cleavablelinker / P2A element (SEQ ID NO:100) and VC001 chain 2 (SEQ ID NO: 101). The expression vector contained a second promoter (PGK) that expressed GFP for monitoring virus transduction efficiency. After the sequencing verification of the VC001 virus vector, lentivirus was generated, and the expression was verified and titered by FACS by transducing HEK293FT cells with different amounts of the virus. Titer of VC001 lentivirus was 2.8x107IFU / mL based on GFP expression. The VC001-encoded lentivirus was then used to transduceNK-92 cells (human NK cell line) (see Figure 36A-B) and human T cells (see Figure 37A-B).Based on GFP expression at 5 days post transduction, VC001 had about a 5% expressionabove background in NK-92 cells at a multiplicity of infection (MOI) of 1.7 compared to non-transduced NK-92 cells. Using T cells from a healthy donor, VC001 lentivirus had a nearly30% expression of VC001 in T cells using an MOI of 2.4 at Day 5 post transduction. TheVC001 transduced T cells were used in real time killing assays of human breast cancer cellline MDA-MB-231 and lung cancer cell line NCI-H460) using an xCELLigence Real-Time CellAnalysis system (Agilent) (see Figure 38A-B). The total T cell to tumor cell ratio (effector-to-target E:T ratio) was 10:1. Given the 30% transduction efficiency of VC001 expression theeffective E:T ratio of the VC001 T cells to tumor cells was 3:1. The percent cytotoxicity of thecancer target cells at the 4, 8, 24 and 48 hour time points are shown in Table 21. At all thetime points, the VC001 T cells had substantially higher killing of both tumor targets cells, with the highest tumor cytotoxicity observed in the first 4 hours of the assay, when compared to the non-transduced control T cells from the same donor. 10255 / PC Table 21. Real-time cytotoxicity assay of Non-transduced T cells versus VC001 T cells ofbreast cancer cell line MDA-MB-231 and lung cancer cell line NCI-H460MDA-MB-231 NCI-H460 Hour Non-Transduced T VC001 T Hour Non-Transduced T VC001 T Cells cells Cells cells 413.0% 55.0% 4 42.6% 80.1%8 34.7% 73.0% 8 56.8% 90.3%24 33.7% 71.0% 24 83.0% 115.6%48 39.1% 68.6% 48 69.9% 108.6%Additional constructs were designed where both the Tim-1 and CTLD are on the same chain(schematized as VC302 in Fig.20A), one containing the CD28, 41BB and 2B4 co-stimulatory domains (VC005, SEQ ID NO: 111) and one containing only the CD28, 41BB co-stimulatorydomains (VC007, SEQ ID NO: 112). Both VC005 and VC007 contain the CD3-zeta activationdomain. Table 22. Design of tandem Tim-1 x CTLD chimeric antigen receptors Construct SequenceVC005: MALPVTALLLPLALLLHAARP- CD8 leader – Tim-1 IgVSVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIVWTN domain – linker – CTLD-GTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCRVEHRGWF FLAGtag-CD28 hinge / TM- NDMKITVSLEIV-GGGGSGGGGSGGGGS- CD28costim-41BBcostim- ERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVI 2B4-CD3z KSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPSF KQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLAKFWICKKSAASC S-DYKDDDDK-KGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWV- RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS- KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL- WRRKRKEKQSETSPKEFLTIYEDVKDLKTRRNHEQEQTFPGGGSTIYS MIQSQSSAPTSQEPAYTLYSLIQPSRKSGSRKRNHSPSFNSTIYEVIGKS QPKAQNPARLSRKELENFDVYS- 10255 / PC RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMG GKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLY QGLSTATKDTYDALHMQALPPR (SEQ ID NO: 111)VC007: MALPVTALLLPLALLLHAARP- CD8 leader – Tim-1 IgVSVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIVWTN domain – linker – CTLD-GTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCRVEHRGWF FLAGtag-CD28 hinge / TM- NDMKITVSLEIV-GGGGSGGGGSGGGGS- CD28costim-41BBcostim- ERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVI CD3z KSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPSF KQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLAKFWICKKSAASC S-DYKDDDDK-KGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWV- RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS- KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL- RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMG GKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLY QGLSTATKDTYDALHMQALPPR (SEQ ID NO: 112)Example 18. Binding of pediatric leukemia patient tumor samples and leukemic stem cellsVP304, VP304-TM and VP304-CT were used to bind 8 pediatric AML and 2 pediatric ALL patientsample by flow cytometry using an anti-IgG-FITC secondary antibody for detection (see Figure39). The samples were additionally co-stained with CD45, CD34, CD38, and CD133 to see ifVP304 co-localizes to tumor cells with a CD45dimCD34+CD38−CD133+ phenotype, which hasbeen shown to correspond to leukemic stem cells (Heo et al. BMC Cancer. 2020 Apr6;20(1):285. doi: 10.1186 / s12885-020-06760-1). Example 19. Binding of pediatric leukemia patient tumor samples and leukemic stem cells VP304, VP304-TM and VP304-CT were used to bind 5 pediatric AML patient tumor samplesthat contained leukemic stem cells by flow cytometry. The samples were additionally co-stained with CD45, CD34, CD38, and CD133 to verify leukemic stem cell content. The CD45dimCD34+CD38−CD133+phenotype has been shown to correspond to leukemic stem cells. High CD45dimCD34+CD38−CD133+cell counts in AML patients is a significant risk factor for poor overall and event free survival. (Heo et al. BMC Cancer. 2020 Apr 6;20(1):285. doi: 10.1186 / s12885-020-06760-1). The binding data is shown in Figure 39, where all three test 10255 / PC articles (VP304, VP304-CT, and VP304-TM) were able to bind all 5 of the pediatric AML tumor samples. When gated for leukemic stem cells (CD45dimCD34+CD38−CD133+), all three test articles (VP304, VP304-CT, and VP304-TM) had higher binding to the leukemic stem cells, with VP304 having an approximately 3-fold higher signal to the CD45dimCD34+CD38−CD133+cell population. This indicates that TIM-1 x CTLD containing molecules have enriched binding to cancer stems cells. Example 20. CAR T cells can eliminate cancer cells Aberrant expression of high-mannose glycans (Man9) and phosphatidylserine (PS) lipids on tumor cells represents a promising immunotherapeutic target for cancer. Previously, we demonstrated that a Man9xPS targeting T cell engager molecule significantly improved tumor control and survival in acute myeloid leukemia (AML) mouse models. Building on these findings, we developed a Man9xPS CAR T cell therapy designed to enhance tumor targeting specificity and overcome the challenges seen with protein-antigen escape and mutational background. Methods: Man9xPS CAR T cells (comprising VC001 as disclosed in Example 17, and mVC302 as disclosed in Example 36) were engineered to target high-mannose glycans and PS lipids enriched on the outer leaflet of cancer cell membranes. Binding specificity was assessed using glycan array analysis, flow cytometry, and immunohistochemistry (IHC) of human tumor and normal tissue sections. Functional efficacy of Man9xPS CAR T cells was evaluated via in vitro cytotoxicity assays against several solid tumor cell lines, including breast cancer MDA-MB-231, lung cancer NCI-H460, and liver cancer Hep3B. Pancreatic cancer targeting was validated using human pancreatic cell lines PANC-1, Capan-2 and AsPC-1. In vivo therapeutic potential was assessed using bioluminescence in a syngeneic, orthotopic pancreatic cancer mouse model (PANC02- Luc), implanted in the pancreas tail of female C57BL / 6 mice.A CAR construct mVCAR300 (mVC302, as disclosed in Example 36) comprising the Tim-1 andCTLD are on the same chain prepared essentially as VC302 format disclosed in Example 17, 10255 / PC except using mouse transmembrane and intercellular domain with the polypeptide chain sequence disclosed in SEQ ID NO: 134.ELISA analysis was done with a Tim1 x DC-SIGN bispecific recombinant protein. Histologicalanalysis were also done with either the Tim1 x DC-SIGN bispecific or Tim1xDC-SIGNxanti-CD3trispecific molecule. Results: Man9xPS CAR T cells demonstrated high in vitro specificity for pancreatic tumors and pancreatic cancer stem cells, with no binding to normal pancreatic cells or stem cells. IHCconfirmed robust expression of these targets on pancreatic cancer tissues, with minimaldetection in healthy tissues. In vitro killing assays revealed potent cytotoxic activity of Man9xPS CAR T cells against several solid tumor cell lines, achieving significant target cell lysis at low effector-to-target ratios. Preliminary in vivo data from the pancreatic cancer syngeneicmodel showed promising tumor control, with detailed survival analyses currently underway.Conclusions:The example showed that Man9xPS CAR T cell therapy exhibited strong preclinical efficacy andspecificity in targeting tumors characterized by aberrant high-mannose glycans and PS lipids. These findings support the potential of Man9xPS CAR T cells as a novel immunotherapy forpancreatic cancer, a challenging disease with known antigen escape mechanisms and geneticheterogeneity. Example 21. Targets for Immunotherapy in Leukemias and Solid Tumors Acute myeloid leukemia (AML) and many solid tumors are difficult to treat. Tumor-associated protein targets that are the focus of cancer immunotherapy research are prone to on-target, off-tumor toxicity and antigen-negative relapse due to mutation or downregulation. Targetingcancer-specific markers less susceptible to resistance is key for safer therapies. This exampleexplores high mannose (Man 9) oligosaccharides and phosphatidylserine (PS) as non-protein targets. Man9 glycans are absent on healthy cells but are present in cancers like AML, breast, 10255 / PC colon, and lung. PS, exposed during malignant transformation, is found on colon, prostate, and brain tumors. Methods: We have engineered trispecific T cell engagers (Man9 / PS / CD3) to target Man9 and / or PS-positive cancers. We tested solid tumor cell lines (pancreatic, lung, colorectal) via flow cytometry and found that the dual affinity molecule (Man 9 x PS) had high binding tomany solid tumors (Table 23). We assessed their efficacy in vivo and specificity using glycanmicroarray, and immunohistochemistry to confirm tumor specificity and predict favorable safety profiles. Results: Flow cytometry showed that our therapeutic molecules specifically bind to AML cells and various solid tumors while sparing healthy tissues. Glycan microarrays confirmed selectivebinding to abnormal glycans on cancer cells. Immunohistochemistry of FFPE tissues indicatedtumor specificity and enrichment on cancer stem cells. In vitro studies (coculture of luciferase-transduced target cells with activated CD8+ T cells in the presence of absence of the T cell engager) demonstrated strong anti-leukemia activity against AML cell lines, with IC50 valuesof 5–10 pM. In vivo studies in human CD3 transgenic mice treated with intravenous doses ofVTRU200 (VP320, Man9 x PS x CD3) showed significant therapeutic responses, based on invivo bioluminescence imaging.Conclusions: Our data supported Man9 and PS as promising non-protein targets for pan-cancer immunotherapy. The dual targeting approach with T cell engagers reduced on-target,off-tumor toxicity and antigen-negative relapse, advancing a first-in-class Man9 x PS x CD3 trispecific T cell engager. Table 23:Cell type Man9 / PS positivity (%) Sample sizeMouse AML (cell line) 75-80 2Human AML (cell line) 54-100 9Human adult AML (primary) 35-98 8 10255 / PCHuman pediatric AML (primary) 31-87 7Human pediatric ALL (primary) 80-97 3Human MM (cell line) 88-99.9 2Human DLBCL (cell line) 56-93 3Human pancreatic cancer (cell line) 46-95 3Human colorectal cancer (cell line) 66-98 2Human lung cancer (cell line) 82 1Example 22. Co-staining with anti-CD133 to detect cancer stem cells by immunohistochemistry An immunohistochemistry method was developed to sequentially co-stain Formalin-Fixed Paraffin-Embedded (FFPE) human tissues with an anti-CD133 antibody with a red chromogenand VP320 with a green chromogen. Representative images of co-stained tissues from 2pancreatic tumors and a normal pancreas are shown in Figure 40. Co-localization was observed with VP320 and anti-CD133 antibody in the tumor samples and not normal tissue, indicating that Tim-1 x CTLD domains can target cancer stem cells in solid tumors. Example 23. In vivo anti-tumor efficacy of PS x Man9 x CD3 trispecific in a human AML cell line-derived xenograft mouse model Groups of immunodeficient NSG mice with MHC I / II double knock-out were implanted with human PBMC and human AML tumor cell line SET-2 with a luciferase gene reporter. After tumors were established, 7 mice per group were treated with vehicle control or VP320 at three dose levels (0.07, 0.7 or 2.1 mg / kg) twice a week for 6 weeks and monitored for weight, clinical signs, tumor burden by bioluminescence imaging, and survival. Blood and serum were collected at baseline and end of treatment for flow cytometry, cytokine analysis and complete blood count analyses. Tumor growth was monitored by bioluminescence images. The average radiance measurements are shown in Figure 41, and images at Day 55 after initiation of treatment is 10255 / PC shown in Figure 42. Tumor area-under-the-curve (AUC) measurements are shown in Figure 43, and survival in shown in Figure 44. Treatment of mice at 3 dose levels of VP320 (0.07, 0.7 and 2.1 mg / kg) were well tolerated in PBMC humanized NSG MHCI / II DKO mice, showing no significant changes in body weight or clinical signs. Tumor growth analysis showed that at 62 days post treatment initiation, tumor burden was reduced 87% in the low dose group, 78% in the medium dose group, and 82% in the high dose groups, compared to the control group. Suboptimal tumor implantation rates in the control group resulted in large standard deviations in tumor burden. Median survival was 90 days for the control group, 89 days for the low dose group, 119 days for the medium dose group and 138 days for the high dose group, demonstrating the efficacy of the compound. Example 24. Design of Tim-1 x CTLD x anti-CD3 Trispecfic molecules with additional properties Four additional Tim-1 x CTLD x anti-CD3 Trispecfic molecules based on the architecture ofVP320 were designed and produced (see Figure 45 and Table 24). VP321 has the samesequence as VP320 expect for the silencing mutations at the Fc. VP321 has L234A, L235A andS267K silencing mutations, whereas VP320 has L234A, L235A and K322A silencing mutations(EU numbering). The S267K silencing mutation has previously been described (Armour K.L., Clark M.R., Hadley A.G., Williamson L.M. Recombinant human IgG molecules lacking Fc- gamma receptor I binding and monocyte triggering activities. Eur. J. Immunol.1999;29:2613–2624) and in combination with L234A and L324A has superior silencing than L234A, L235A andK322A (https: / / pubmed.ncbi.nlm.nih.gov / 37753968 / , Pejchal et al. Antibodies (Basel), 2023Aug 22;12(3):54), doi: 10.3390 / antib12030054). VP322, VP323 and VP324 have the samesilencing as VP321 (L234A / L235A / S267K) but utilize a different anti-CD3 scFv based onhumanized SP4, which has been shown in the literature to bind to both human and monkey CD3. The anti-CD3 domain in VP308, VP320 and VP321 are based on humanized OKT3, which does not cross-react with monkey CD3. Sequence of humanized SP34 VH: EVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTVSS (SEQ ID NO:116) 10255 / PC Sequence of humanized SP34 VL: QTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLAPGTPARFSGSLL GGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGGTKLTVL (SEQ ID NO: 117): VP322 utilizes the same architecture as VP321, but utilizes the huSP34 scFv. VP323 is avariation of VP322 that contains a disulfide between the VH and VL domains of the huSP34scFv at the VH44-VL100 (Kabat numbering) position. VP324 is a variation of VP323 with shorter glycine-rich linkers. See Table 24. Table 24. Sequences of Tim-1 x CTLD x anti-CD3 Trispecfic molecules based on thearchitecture of VP320. Each construct contains 2 chains as listed below.Construct Name Amino Acid Sequence SVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIVWTNGTHVTYRKDTRY KLLGDLSRRDVSLTIENTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVGGGGSGGGGS GGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVKH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK (Tim1IgV – Fc, SEQ ID NO: 118)ERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVIKSAEEQNFLQL QSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPSFKQYWNRGEPNNVGEEDCAEFS VP321 GNGWNDDKCNLAKFWICKKSAASCSGGGGSGGGGSGGGGSQVQLVQSGGGVVQP GRSLRLSCKASGYTFTRYTMHWVRQAPGKCLEWIGYINPSRGYTNYNQKVKDRFTISR DNSKNTAFLQMDSLRPEDTGVYFCARYYDDHYSLDYWGQGTPVTVSSGGGGSGGGG SGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWY QQTPGKAPKRWIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNP FTFGCGTKLQITGGGGSGGGGSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPP KPKDTLMISRTPEVTCVVVDVKHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKN QVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGK (CTLD – huOKT3 scFv – Fc, SEQ ID NO:119) (Tim1IgV – Fc, SEQ ID NO: 118)VP322: ERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVIKSAEEQNFLQL contains QSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPSFKQYWNRGEPNNVGEEDCAEFS huSP34 scFv GNGWNDDKCNLAKFWICKKSAASCSGGGGSGGGGSGGGGSEVQLVESGGGLVQPG (underlined) GSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTIS RDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTVSSGGGG SGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQ KPGQAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRW 10255 / PC VFGGGTKLTVLGGGGSGGGGSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPK PKDTLMISRTPEVTCVVVDVKHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQ VSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (CTLD – huSP34 scFv – Fc, SEQ ID NO:121) (Tim1IgV – Fc, SEQ ID NO: 118)ERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVIKSAEEQNFLQL QSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPSFKQYWNRGEPNNVGEEDCAEFS VP323: GNGWNDDKCNLAKFWICKKSAASCSGGGGSGGGGSGGGGSEVQLVESGGGLVQPG contains GSLKLSCAASGFTFNKYAMNWVRQAPGKCLEWVARIRSKYNNYATYYADSVKDRFTIS huSP34 scFv RDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTVSSGGGG (underline) SGGGGSGGGGSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVT with extra SGNYPNWVQQKPGQAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEY disulfide YCVLWYSNRWVFGCGTKLTVLGGGGSGGGGSGGGGSGGGGSDKTHTCPPCPAPEA AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVKHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL PPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (CTLD – huSP34 scFv withdisulfide – Fc SEQ ID NO: 122)(Tim1IgV – Fc with shorter linker, SEQ ID NO: 118)VP321-TM: contains ERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVIKSAEEQNFLQL huSP34 scFv QSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPSFKQYWNRGEPNNVGEEDCAEFS with extra GNGWNDDKCNLAKFWICKKSAASCSGGGGSGGGGSEVQLVESGGGLVQPGGSLKLS disulfide and CAASGFTFNKYAMNWVRQAPGKCLEWVARIRSKYNNYATYYADSVKDRFTISRDDSK shorter NTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTVSSGGGGSGGG linkers GSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPGQ (underlined) APRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGC GTKLTVLGGGGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVKH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK (CTLD – huSP34 scFv with disulfide – Fc with shorter linkers, SEQ IDNO: 124) VP321 had a high yield from transient expression in CHO cells, with a yield of 90mg / L after protein A purification. Additional purification resulted in >95% purity and exceptional stability with no aggregation after 3 weeks at 4 deg C 10255 / PC The human / monkey reactive VP322, VP323 and VP324 had approximate yields of 12, 20 and 38 mg / L, respectively, after single step protein A or protein A / G purification. VP323 had thehighest full intact fraction compared to VP322 and VP324 and was chosen for additionalpurification to achieve >95% purity and further testing.Example 25. Characterization of Tim-1 x CTLD x anti-CD3 Trispecfic moleculesThe CD3 and T cell binding properties of the Tim-1 x CTLD x anti-CD3 molecules VP308, VP320, VP321, and VP323 were tested by various methods, including surface plasmon resonance (SPR), ELISA and FACS. CD3 binding was tested using recombinant biotinylated huCD3de andcynomolgus CD3de (cynoCD3) fragments. ELISA binding results of VP321 and VP323 torecombinant CD3de are shown in Figure 46A. VP323 showed higher binding to recombinanthuCD3de than VP321. VP323 showed nearly identical binding to both huCD3de andcynoCD3de. Binding to AML cell line THP-1 and human CD8 T cells by VP321 and VP323 are shown in Figure 46B. Binding was determined by FACS using an anti-human Fc secondary antibody with FITCfluorescent label. The data shows comparable binding to tumor and T cells by VP321 andVP323In vitro T cell-mediated killing potencies of VP321 and VP323 were tested using CD8 T cellsand 2 target cell lines: AML cell line THP-1 and MM cell line NCI-H929, using a 5:1 effector-to-target ratio (see Figure 46C). Both VP321 and VP323 had high potency, with VP321 havingsuperior in vitro potency against both THP-1 and NCI-H929.In vitro potencies of VP321 and VP323 were also tested using pan T cells and the pancreaticcell line AsPC-1, using a 3:1 effector-to-target ratio (see Figure 46D). Both VP321 and VP323had showed comparable potency, with VP323 showing a higher level of activity than VP321for T cell mediated killing of AsPC-1.A pilot in vivo efficacy study was conducted with VP321 in a pediatric AML patient derivedxenograft mouse model (see Figure 46E). CD34+ hu-SGM3 mice mice were implanted with 10255 / PCthe AML PDX with a luciferase reporter gene and treated with VP321 (twice weekly for 3weeks) at 0.07 mg / kg per dose (n=3 mice) and compared to vehicle control (n=5 mice). TheVP321 group showed higher tumor control compared to the control group.Example 26. Design of Tim-1 x anti-CD3 and CTLD x anti-CD3 Bispecific molecules To assess the relative contribution of targeting PS with the Tim-1 domain or a PAMP with the CTLD domain, a Tim-1 x anti-CD3 and CTLD x anti-CD3 bispecific molecules were designedusing the VP321 or VP323 architecture (see Figure 47 and Table 25).Table 25. Sequences of Tim-1 x anti-CD3 and CTLD x anti-CD3 Bispecific molecules Construct Name Amino Acid Sequence (Tim1-Fc, SEQ ID NO: 118,) QVQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGKCLEWIGYINPSRGYT NYNQKVKDRFTISRDNSKNTAFLQMDSLRPEDTGVYFCARYYDDHYSLDYWGQGTPVT VSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCS VP321-TM ASSSVSYMNWYQQTPGKAPKRWIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIAT YYCQQWSSNPFTFGCGTKLQITGGGGSGGGGSGGGGSGGGGSDKTHTCPPCPAPEAA GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVKHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPC RDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (huOKT3 scFv – Fc, SEQ ID NO:124) ERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVIKSAEEQNFLQLQ SSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPSFKQYWNRGEPNNVGEEDCAEFSGN GWNDDKCNLAKFWICKKSAASCSGGGGSGGGGSGGGGSGGGGSDKTHTCPPCPAPE AAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVKHEDPEVKFNWYVDGVEVHNAKTKP VP321-CT REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTL PPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (CTLD-Fc, SEQ ID NO: 125)(huOKT3 scFv – Fc, SEQ ID NO: 124)(Tim1-Fc, SEQ ID NO: 118) EVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKCLEWVARIRSKYNN YATYYADSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYW VP323-TM GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGG TVTLTCGSSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLAPGTPARFSGSLLGGKAAL TLSGVQPEDEAEYYCVLWYSNRWVFGCGTKLTVLGGGGSGGGGSGGGGSGGGGSDK THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVKHEDPEVKFNWYVDG 10255 / PC VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG QPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (huSP34 scFvwith disulfide – Fc, SEQ ID NO: 145)(CTLD-Fc, SEQ ID NO: 125) VP323-CT(huSP34 scFv with disulfide – Fc, SEQ ID NO: 145)Example 27. In vitro activity of Tim-1 x CTLD x anti-CD3 trispecific and Tim-1 x anti-CD3 / CTLD x anti-CD3 bispecific molecules The potency of VP321, compared to the bispecific VP321-TM and VP321-CT molecules were tested against AML cell line THP-1 (see Figure 48). All three molecules showed high potency with killing AML cell line THP-1, with picomolar EC50s. Example 28. Design of Fc-containing payload carrying agents with Tim-1 and CTLD domains Constructs were designed where Tim-1 and CTLD domains are fused to an Fc domain with silencing mutation (L234A / L235A / S267K) and where site-specific cysteines are incorporatedat position K274 (EU numbering) to allow for site-specific thiol conjugation (see Figure 49 andTables 26 and 27).Table 26. Sequence of Tim-1 x CTLD – Fc fusion with K274C thiol-conjugation sitesConstruct Name Amino Acid SequenceSVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIVWTNGTHVTYR KDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVG GGGSGGGGSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI SRTPEVTCVVVDVKHEDPEVCFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL VP601 TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTK (2 chain NQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDK heterodimer with knob-in-holeSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 127)mutations and ERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVIKSAEEQ disulfide) NFLQLQSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPSFKQYWNRGEPNN K274C mutation is VGEEDCAEFSGNGWNDDKCNLAKFWICKKSAASCSGGGGSGGGGSGGGGSG underlined GGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVKHED PEVCFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK (SEQ ID NO: 128) 10255 / PCTable 27. Sequences of Tim-1 – Fc fusion and CTLD – Fc fusion with K274C thiol-conjugationsites Construct Name Amino Acid SequenceSVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIVWTNGTHVTYR KDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVG VP602 GGGSGGGGSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMI (2 chain homodimer) SRTPEVTCVVVDVKHEDPEVCFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV K274C mutation is LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK underlined NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 129)ERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVIKSAEEQ NFLQLQSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPSFKQYWNRGEPNN VP603 VGEEDCAEFSGNGWNDDKCNLAKFWICKKSAASCSGGGGSGGGGSGGGGS (2 chain homodimer) GGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVKH K274C mutation is EDPEVCFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK underlined CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 130)VP601, VP602 and VP603 can be thiol-conjugated to any payload containing a maleimide group, including imaging agents, drugs, toxins, nanoparticles, chelators with radioisotopes, etc. VP601, VP602 and VP603 were expressed and purified from CHO cell cultures. The binding affinities of VP601 to the PAMPS Man9 and Lewis X and to PS were tested by ELISA and shown in Figure 50. Biotinylated Man9, PS and Lewis X were coated onto streptavidin coated plates. Binding was quantified using an anti-humanFc-HRP secondary antibody. VP601 was found to have a Kd of 26 nM to PS, 20nM to Man9 and 11nM to Lewis X. This confirms the glycan array data showing that the CTLD has high specificity to oligomannose and Lewis x fucosyl-containing trisaccharide glycan, as shown in Example 9.Example 29. Ex vivo imaging of CMV infected mouse tissue with VP601As a proof-of-concept that Tim1 x CTLD can be used to image infectious agents, VP601 wasused for ex vivo immunofluorescence (IF) imaging of organ tissue from mice infected withmurine CMV (see Figure 51). Murine CMV accumulates in mouse salivary gland. Salivary gland were harvested from control mice (no infection) and mCMV infected mice. CMV infection was verified by qPCR. The salivary were fresh frozen and embedded for sectioning and staining 10255 / PC with VP601, followed by staining with an anti-human Fc-FITC secondary (green) and a nuclear stain (blue). The tissue membranes were either left intact or permeabilized with Triton X-100.The images show that VP601 can image CMV infected cellular surfaces when the membranesare left intact and also image virus clusters within the tissues when the membranes are permeabilized. No VP601 binding was seen in the control mouse tissue. Example 30. Immunofluorescence imaging of human tumor and normal tissues with VP601 As a proof-of-concept that Tim1 x CTLD can be used to image tumors and not normal tissues, VP601 was used for ex vivo immunofluorescence imaging of FFPE human tumor and normaltissue sections. A similar method for immunofluorescence method as in Example 29 was used,except that xylene was used to remove the paraffin and no membrane permeabilization wasdone. Figure 52 shows the fluorescence microscopy images of breast cancer tissue, pancreaticcancer tissue and patient-matched normal pancreas, with both blue channel (nuclear stain) and the green channel (VP601), or just the green channel (VP601). VP601 shows high IF staining to the tumor tissues and not the patient-matched normal pancreas. The staining was also done on a full panel of 33 normal human tissues (see Figure 53), and no staining was observed with VP601. This demonstrates that targeting PS and Man9 with TM and CTLD domains does not bind normal human tissues and would therefore be highly useful in imaging and treating infectious agents and tumors. Example 31. Conjugation of VP601 with DFO and labeling with 89Zr for PET imagingVP601 was used for conjugation to desferrioxamine (DFO) and radiolabeled with zirconium-89 (89Zr) for PET imaging studies. VP601 was first treated with TCEP, buffer-exchanged to remove TCEP, conjugated with DFO-maleimide, and then buffer-exchanged to remove unreacted DFO. High conjugation efficiency was obtained with a high purity profile. The VP601-DFO conjugate was then radiolabeled with a [89Zr]Zr-oxalic acid solution / sodium carbonate solution at 0.5 MBq / µg of the VP601 DFO-conjugate. The labeling efficiency determined by iTLC was 88%. The profile of the radiolabeled product is shown in Figure 54, showing high purity. 10255 / PC Example 32. Functional activity of Fc-containing payload carrying agents with Tim-1 and CTLD domains The bispecific (TM x CTLD) protein VP601, the monospecific VP602 (TM only), and the monospecific VP603 (CTLD only) were conjugated at the K274C posi^on (EU numbering) with Fluorescein Isothiocyanate (FITC) byfirst trea^ng the molecule (VP601, VP602, or VP603) with Tris(2-carboxyethyl)phosphine (TCEP) and then reac^ng with FITC-maleimide. The resul^ng products were then used for immunofluorescence imaging of pediatric AML cell line THP-1 (Figure 55A), pancrea^c cancer cell line AsPC-1 (Figure 55B), and adult AML cell line SET-2 (Figure 55C) . FITC imaging was done using the green GFP channel on afluorescent microscope. THP-1 and SET-2 cells had been stably transfected with tdTomato and emit red under the Texas Red channel. Figure 61A shows that VP601-FITC and VP602-FITC can specifically recognize and image AML tumor cells. Figure 61B shows that VP601-FITC and VP602-FITC can specially recognize and image pancrea^c cancer cells. Figure 61C shows that VP601-FITC, VP602-FITC and VP603-FITC can recognize adult AML cancer cells, where the bispecific VP601 had stronger binding than the monospecific VP602-FITC or VP603-FITC. Example 33. Binding to tumor exosomes The VP601, VP602 and VP603 molecules were also tested for their ability to bind cell linederived tumor exosomes (see Figure 56). ELISA assays were done using exosome standardsfrom glioblastoma cell line U87-MG and colon cancer cell line HCT 116 (both from NovusBiologicals). All three test articles had robust binding to the exosomes, the bispecific VP601having superior binding to the monospecific VP602 and VP603. Example 34. Design of mini-protein payload carrying agents with Tim-1 and CTLD domainsMini-proteins (protein carriers) of the Tim-1 IgV domain, the CTLD of DC-SIGN and the fusionof the Tim-1 x CTLD domains were made without additional protein scaffolds, with C-terminal 10255 / PC His tags for purification and site-specific C-terminal Cys for thiol conjugation (see Figure 57 and Table 28).Table 28. Sequences of mini-protein payload carrying agents with Tim-1 and CTLD domainsConstruct Name SequenceSVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIVWTN VP701 GTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCRVEHRGWF NDMKITVSLEIVHHHHHHGGGGSC (SEQ ID NO: 131)ERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVI KSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPSF VP702 KQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLAKFWICKKSAASC SHHHHHHGGGGSC (SEQ ID NO: 132)SVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIVWTN GTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCRVEHRGWF NDMKITVSLEIVGGGGSGGGGSGGGGSERLCHPCPWEWTFFQGNC VP703 YFMSNSQRNWHDSITACKEVGAQLVVIKSAEEQNFLQLQSSRSNRFT WMGLSDLNQEGTWQWVDGSPLLPSFKQYWNRGEPNNVGEEDCA EFSGNGWNDDKCNLAKFWICKKSAASCSHHHHHHGGGGSC (SEQID NO: 133) Example 35. Conjugation of mini-protein payload carrying agents with nanoparticlesVP701, VP702, VP703, or an equimolar mixture of VP701 and VP702 were conjugated toConjugated Polymer Nanoparticles (CPN) containing maleimide functional groups, an ironoxide core and fluorophores that emit at 530nm (green) wavelength (CPN-530, from StreamBio, Cheshire, UK). The conjugated CPNs were then used for immunofluorescence imaging ofAML cell line THP-1 (Figure 58A) and pancreatic cancer cell line AsPC-1 (Figure 58B). Imagingwas done using the green GFP channel on a fluorescent microscope to detect the conjugatedand control nanoparticles. THP-1 cells had been stably tranfected with a tdTomato reporter gene, and imaging for THP-1 cells were done using a Texas red channel. A control sample ofunconjugated CPNs was also used for imaging. For both THP-1 and AsPC1, the monospecificVP701- and VP702-conjugated CPNs showed punctate binding to the tumor cell surfaces,with VP702 showing a tendency to cluster. The bispecific VP703 and the VP701xVP702 conjugated CPNs also showed specific binding to the tumor cell surfaces, compared to the control unconjugated CPNs. 10255 / PC Example 36. Murine chimeric antigen receptors containing Tim-1 and CTLD domains Chimeric antigen receptors utilizing the Tim-1 and CTLD domains fused to murine intracellular domains were made using retroviral transduction to generate murine CAR T cells for syngeneicstudies (see Figure 59 and Table 29).Table 29. Sequences of Murine chimeric antigen receptors containing Tim-1 and CTLD domains Constructs SequencemVC302: MASPLTRFLSLNLLLLGESIILGSGEASVKVGGEAGPSVTLPCHYSGAVT leader -- Tim1IgV x DC-SMCWNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVS SIGN-CTLD – LTIENTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVGGGGSGGGGSG Transmembrane – mCD28GGGSERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGA costim – mCD3zetaQLVVIKSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVDGSP activation domain – linker --LLPSFKQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLAKFWICKK EGFP SAASCSAAASTTTKPVLRTPSPVHPTGTSQPQRPEDCRPRGSVKGTGL DFACDIYIWAPLAGICVALLLSLIITLICYNSRRNRLLQSDYMNMTPRRP GLTRKPYQPYAPARDFAAYRPRAKFSRSAETAANLQDPNQLYNELNL GRREEYDVLEKKRARDPEMGGKQQRRRNPQEGVYNALQKDKMAEA YSEIGTKGERRRGKGHDGLYQGLSTATKDTYDALHMQTLAPRGGGG SGGGGSGGGGSVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGD ATYGKLTLKFICTTGKLPVPWPTLVTTLTYGVQCFSRYPDHMKQHDFF KSAMPEGYVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKE DGNILGHKLEYNYNSHNVYIMADKQKNGIKVNFKIRHNIEDGSVQLA DHYQQNTPIGDGPVLLPDNHYLSTQSKLSKDPNEKRDHMVLLEFVTA AGITLGMDELYK (SEQ ID NO: 134)mVC302-TM: MASPLTRFLSLNLLLLGESIILGSGEASVKVGGEAGPSVTLPCHYSGAVT leader -- Tim1IgV–SMCWNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVS Transmembrane – mCD28LTIENTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVAAASTTTKPVLR costim – mCD3zetaTPSPVHPTGTSQPQRPEDCRPRGSVKGTGLDFACDIYIWAPLAGICVA activation domain – linker --LLLSLIITLICYNSRRNRLLQSDYMNMTPRRPGLTRKPYQPYAPARDFA EGFP AYRPRAKFSRSAETAANLQDPNQLYNELNLGRREEYDVLEKKRARDP EMGGKQQRRRNPQEGVYNALQKDKMAEAYSEIGTKGERRRGKGHD GLYQGLSTATKDTYDALHMQTLAPRGGGGSGGGGSGGGGSVSKGE ELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLKFICTTGKLP VPWPTLVTTLTYGVQCFSRYPDHMKQHDFFKSAMPEGYVQERTIFFK DDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNILGHKLEYNYNSHN VYIMADKQKNGIKVNFKIRHNIEDGSVQLADHYQQNTPIGDGPVLLP DNHYLSTQSKLSKDPNEKRDHMVLLEFVTAAGITLGMDELYK (SEQID NO: 135) mVC302-CT MASPLTRFLSLNLLLLGESIILGSGEAERLCHPCPWEWTFFQGNCYFM leader -- DC-SIGN-CTLD –SNSQRNWHDSITACKEVGAQLVVIKSAEEQNFLQLQSSRSNRFTWM Transmembrane – mCD28GLSDLNQEGTWQWVDGSPLLPSFKQYWNRGEPNNVGEEDCAEFSG 10255 / PC costim – mCD3zetaNGWNDDKCNLAKFWICKKSAASCSAAASTTTKPVLRTPSPVHPTGTS activation domain – linker --QPQRPEDCRPRGSVKGTGLDFACDIYIWAPLAGICVALLLSLIITLICYN EGFP SRRNRLLQSDYMNMTPRRPGLTRKPYQPYAPARDFAAYRPRAKFSRS AETAANLQDPNQLYNELNLGRREEYDVLEKKRARDPEMGGKQQRRR NPQEGVYNALQKDKMAEAYSEIGTKGERRRGKGHDGLYQGLSTATK DTYDALHMQTLAPRGGGGSGGGGSGGGGSVSKGEELFTGVVPILVE LDGDVNGHKFSVSGEGEGDATYGKLTLKFICTTGKLPVPWPTLVTTLT YGVQCFSRYPDHMKQHDFFKSAMPEGYVQERTIFFKDDGNYKTRAE VKFEGDTLVNRIELKGIDFKEDGNILGHKLEYNYNSHNVYIMADKQKN GIKVNFKIRHNIEDGSVQLADHYQQNTPIGDGPVLLPDNHYLSTQSKL SKDPNEKRDHMVLLEFVTAAGITLGMDELYK (SEQ ID NO: 136)mVC302 transduced mouse T cells were used for in vitro killing assays of human liver cancercell line Hep3B (see Figure 60) and murine pancreatic cancer cell line Panc-02 (see Figure 61). For Hep3B, robust killing of approximately 73% was observed at 48h at a modest Effector-to- Target (ET) ratio of 8:1. The killing of Panc-02 cells was even more efficient, with 80% killingat 0.3 ET ratio, compared to 30% killing from untransduced (non-transduced) T cells (Figure61). The bispecific mVC302 (Tim x CTLD) CAR T cells were compared to the monospecific mVC302-TM (Tim-1 IgV domain) and mVC302-CT (CTLD domain) CAR T cells in killing assays with AMLcell line C1498 and multiple myeloma 5TGM1 (see Figure 62). The bispecific mVC302 had superior killing compared to the monospecific mVC302-TM and mVC302-CT, although the monospecific CAR Ts did have killing activity. In a small pilot study, 3 C57 / BL6 mice per group were implanted with 1 x 10^6 Panc-02 tumorcells with luciferase reporter subcutaneously and treated intravenously with vehicle control,untransduced mouse T cells, or 1 x 10^6 mVC302 mouse CAR T cells (see Figure 63). Imagingat 3 days post treatment showed a 53% reduction in tumor burden as compared to the non- transduced group (p<0.001).In a second pilot study, 3 C57 / BL6 mice were implanted with 1 x 10^6 Panc-02 tumor cellswith luciferase reporter orthotopically into the tail of the pancreas and allowed to implant for3 weeks. Two of the mice were then treated intravenously with 1 x 10^6 mVC302 mouse CART cells, and the other mouse was treated with untransduced T cells (see Figure 64). Thecontrol mouse treated with untransduced T cells died after 5 days with a high tumor burden.After 7 days post treatment, one of the mVC302 CAR T treated mice had no tumor and the 10255 / PC other mouse had a substantially smaller tumor than the control mouse. Both treated mice were alive following the planned 7 day follow up. Example 37. Single-chain human chimeric antigen receptors containing Tim-1 and CTLD domains Single chain human chimeric antigen receptors that can be used on both T cells and NK cells were designed with containing both Tim-1 x CTLD domains and either CD28 co-stim, CD28 x4-1BB costim or CD28 x 4-1BB x 2B4 costimulatory domains (see Figure 65 and Table 30).Constructs were generated and packaged into lentivirus for transductions. Table 30. Sequences of single-chain human chimeric antigen receptors containing Tim-1 and CTLD domains Constructs SequencehVC302a: MALPVTALLLPLALLLHAARPSVKVGGEAGPSVTLPCHYSGAVTSMC CD8 leader – TMlinkerCT –WNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIE CD28 NTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVGGGGSGGGGSGGG hinge / Transmembrane- GSERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLV CD28costim-CD3z VIKSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPS FKQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLAKFWICKKSAAS CSAAAKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFW VRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFS RSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQ RRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLST ATKDTYDALHMQALPPR (SEQ ID NO: 137)hVC302a-TM: MALPVTALLLPLALLLHAARPSVKVGGEAGPSVTLPCHYSGAVTSMC CD8 leader – TM – CD28WNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIE hinge / Transmembrane- NTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVAAAKGKHLCPSPLFP CD28costim-CD3z GPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNM TPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQL YNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKD KMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPP R (SEQ ID NO: 140) 10255 / PC hVC302a-CT: MALPVTALLLPLALLLHAARPERLCHPCPWEWTFFQGNCYFMSNSQCD8 leader – CT – CD28RNWHDSITACKEVGAQLVVIKSAEEQNFLQLQSSRSNRFTWMGLSD hinge / Transmembrane- LNQEGTWQWVDGSPLLPSFKQYWNRGEPNNVGEEDCAEFSGNGW CD28costim-CD3z NDDKCNLAKFWICKKSAASCSAAAKGKHLCPSPLFPGPSKPFWVLVV VGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHY QPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEY DVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGM KGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 141) hVC302b: MALPVTALLLPLALLLHAARPSVKVGGEAGPSVTLPCHYSGAVTSMCCD8 leader – TMlinkerCT –WNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIE CD28 NTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVGGGGSGGGGSGGG hinge / Transmembrane- GSERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLV CD28costim-41BBcostim- VIKSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPS CD3z FKQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLAKFWICKKSAAS CSAAAKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFW VRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSKRGR KKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADA PAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNP QEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDT YDALHMQALPPR (SEQ ID NO: 138)hVC302c: MALPVTALLLPLALLLHAARPSVKVGGEAGPSVTLPCHYSGAVTSMCCD8 leader – TMlinkerCT –WNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIE CD28 hinge / TM- NTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVGGGGSGGGGSGGG CD28costim-41BBcostim- GSERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLV 2B4-CD3z VIKSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPS FKQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLAKFWICKKSAAS CSAAAKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFW VRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSKRGR KKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELWRRKRKEKQS ETSPKEFLTIYEDVKDLKTRRNHEQEQTFPGGGSTIYSMIQSQSSAPTS QEPAYTLYSLIQPSRKSGSRKRNHSPSFNSTIYEVIGKSQPKAQNPARLS RKELENFDVYSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLD KRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGER RRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 139)hVC302d: MALPVTALLLPLALLLHAARPSVKVGGEAGPSVTLPCHYSGAVTSMCCD8 leader – TMlinkerCT –WNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIE CD28 NTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVGGGGSGGGGSGGG hinge / Transmembrane- GSERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLV 41BBcostim-CD3z VIKSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPS FKQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLAKFWICKKSAAS CSAAAKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFW VKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFS RSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQ 10255 / PC RRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLST ATKDTYDALHMQALPPR (SEQ ID NO: 142) hVC302d-TM: MALPVTALLLPLALLLHAARPSVKVGGEAGPSVTLPCHYSGAVTSMC CD8 leader – TM – CD28WNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIE hinge / Transmembrane- NTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVAAAKGKHLCPSPLFP 41BBcostim-CD3z GPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVKRGRKKLLYIFKQPFM RPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLY NELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDK MAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 143) hVC302d-CT: MALPVTALLLPLALLLHAARPERLCHPCPWEWTFFQGNCYFMSNSQ CD8 leader – CT – CD28RNWHDSITACKEVGAQLVVIKSAEEQNFLQLQSSRSNRFTWMGLSD hinge / Transmembrane- LNQEGTWQWVDGSPLLPSFKQYWNRGEPNNVGEEDCAEFSGNGW 41BBcostim-CD3z NDDKCNLAKFWICKKSAASCSAAAKGKHLCPSPLFPGPSKPFWVLVV VGGVLACYSLLVTVAFIIFWVKRGRKKLLYIFKQPFMRPVQTTQEEDG CSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEY DVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGM KGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO:144) Packaged lentivirus samples were used to transduce human T cells freshly isolated from buffy coat at an MOI of 80. The transduced T cells were then used for in vitro killing assays of AML tumor cell line THP-1 (see Figure 66). Compared to non-transduced T cell, all three constructs had potent killing of the AML tumor cells at effector-to-target ratios of less than 1. Example 38. Binding of TM x CTLD molecules to brain tumor and liver cancer targetsThe binding of VP601 to glioblastoma cell line U-87 MG was tested by flow cytometry andshown in Figure 67A. VP601 demonstrated low nanomolar binding to U-87 MG. VP601 andVP304 were tested for binding to liver cancer cell line HepG2 by flow cytometry, see Figure67B. Both molecules also showed strong low nanomolar binding to HepG2.

Claims

10255 / PC Claims1. A method of treating, imaging or diagnosing cancer in a subject, comprisingadministering a fusion protein comprising: a. a polypeptide capable of binding to phosphatidylserine (PS); and / orb. a polypeptide capable of binding a pathogen-associated molecular pattern(PAMP).

2. The method of claim 1, wherein the subject is a human or animal subject.

3. The method of claim 1 or 2, wherein the polypeptide capable of binding to PS isselected among the Tyro3, Ax1 and Mer of the TAM family, TIM-1, TIM-3, and TIM-4.

4. The method of any of the preceding claims, wherein the polypeptide capable ofbinding to PS is selected among polypeptides having at least 80% sequence identity, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to one of SEQ ID NO: 1, SEQ ID NO: 43 - 49, or SEQ IDNO: 80 - 81.

5. The method of any of the preceding claims, wherein the polypeptide capable ofbinding PS is selected among polypeptides comprising a sequence having at least 80%, 85%, 90% or 95% sequence identity to XXXVXGVXGXXVTLPCXYRVSTXXXITTMCWGRGCXXXXXCXXXIIWTNGXXVTXXKXXRYXLKG XLXXGDVSLTIXNXXXSDSGXYCCRVEXXGWFNDXKXTXSLXIX (SEQ ID NO: 73) wherein X can be any amino acid.10255 / PC6. The method of any of the preceding claims, wherein the polypeptide capable ofbinding PS is selected among polypeptides comprising a sequence of XXXVXGVXGXXVTLPCXYRVSTXXXITTMCWGRGCXXXXXCXXXIIWTNGXXVTXXKXXRYXLKG XLXXGDVSLTIXNXXXSDSGXYCCRVEXXGWFNDXKXTXSLXIX (SEQ ID NO: 73) wherein X can be any amino acid.

7. The method of claim 5 or 6, wherein:The amino acid in position 1 is selected among S, Y, H, and G; The amino acid in position 2 is selected among V, T, S, K, and L; The amino acid in position 3 is selected among K, N, E, Q, and L; The amino acid in position 5 is selected among G, D, T, N and K; The amino acid in position 8 is selected among A, E, T, and V; The amino acid in position 10 is selected among P, L, Q, E, and H; The amino acid in position 11 is selected among S, P, and N; The amino acid in position 17 is selected among H, R, T, L, A, and F; The amino acid in position 19 is R or absent; The amino acid in position 20 is V or absent; The amino acid in position 21 is S, K or absent; The amino acid in position 23 is selected among G, A, E, and Y; The amino acid in position 24 is S, K, Y, R or absent; The amino acid in position 25 is selected among A, S, E, G, and D; The amino acid in position 35 is selected among S, T, A, E, V, and Q; The amino acid in position 37 is selected among S and P; The amino acid in position 38 is selected among L, A, T, W, I, V, and S; The amino acid in position 39 is selected among F, W, and S; The amino acid in position 40 is selected among T, S, H, Q, K, and A; The amino acid in position 42 is selected among Q, P, S, R, and L; The amino acid in position 43 is selected among N, D, E, and Q; The amino acid in position 44 is selected among G, Y, D, E, V, P, and T;The amino acid in position 51 is selected among T, Y, S, R, and H; The amino acid in position 52 is selected among H, N, K, and R; The amino acid in position 55 is selected among Y, F, and E; The amino acid in position 56 is selected among R and Q; The amino acid in position 58 is selected among D, E, H, and S; The amino acid in position 59 is selected among T, P, R, L, and S; The amino acid in position 62 is selected among K, L, Q, V, and N; The amino acid in position 66 is selected among D, N, Y, K, and H; The amino acid in position 68 is selected among S, G, and L; The amino acid in position 69 is selected among R, H, E, and K; The amino acid in position 77 is selected among E, A, V, K, and L; The amino acid in position 79 is selected among T, V, A, and S; The amino acid in position 80 is selected among A, K ,D, Q, and V; The amino acid in position 81 is selected among V, L, P, Q, and E; The amino acid in position 86 is selected among V, I, L, Q, and T; The amino acid in position 93 is selected among H, L, K, and I; The amino acid in position 94 is selected among R, S, A, K, and P; The amino acid in position 100 is selected among M, L, I, E, and Q; The amino acid in position 102 is selected among I, V, L, and T; The amino acid in position 104 is selected among V, I, Y, Q, L, and F; The amino acid in position 107 is selected among E, K, S, V, and Q; and / or The amino acid in position 109 is selected among V, G, R, K, and E; wherein the amino acid positions are the amino acid positions of SEQ ID NO:

73.

8. The method of any of the preceding claims, wherein the polypeptide capable ofbinding to a PAMP is selected among lectins.

9. The method of claim 8, wherein the lectin is selected among DC-SIGN C-Type lectinsand L-SIGN C-type lectins.

10. The method of claim 9, wherein the lectin is a DC-SIGN C-type lectin and comprisesan amino acid sequence having at least 80% sequence identity, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to one of SEQ ID NO: 2 and SEQ ID NO: 50 - 56.

11. The method of any of the preceding claims, wherein the polypeptide capable ofbinding a PAMP is selected among polypeptides comprising a sequence having at least 80%, 85%, 90%, 95% sequence identity to XXLCXPCPWXWEXFQGXCYFFSXXQXXWXXSXXACXXXGAQLVXIXSXEEQXFLXXXXXRXNXXTWIGLS DXXXEGXWXWVDXSPLXLSFXQYWKXGEPNNXGXNEDCAEXXXDGQWNDXXCXXEXFWICXKXXXXC P (SEQ ID NO: 74) wherein X can be any amino acid.

12. The method of any of the preceding claims, wherein the polypeptide capable ofbinding a PAMP is selected among polypeptides comprising the sequence of XXLCXPCPWXWEXFQGXCYFFSXXQXXWXXSXXACXXXGAQLVXIXSXEEQXFLXXXXXRXNXXTWIGLS DXXXEGXWXWVDXSPLXLSFXQYWKXGEPNNXGXNEDCAEXXXDGQWNDXXCXXEXFWICXKXXXXC P (SEQ ID NO: 74) wherein X can be any amino acid.

13. The method of claim 12, wherein:The amino acid in position 1 is selected among E, A, D, and L; The amino acid in position 2 is selected among R, G, and F; The amino acid in position 5 is selected among H, R, and G; The amino acid in position 10 is selected among E, H, N, K, D, and Q; The amino acid in position 13 is selected among F, L, H, and Y; The amino acid in position 17 is selected among N, R, and S;10255 / PC The amino acid in position 23 is selected among N, Q, W, L, and V; The amino acid in position 24 is selected among S, T, and A; The amino acid in position 26 is selected among R, S, N, K, and M; The amino acid in position 27 is selected among N, D, T, and S; The amino acid in position 29 is selected among H, K, R, and N; The amino acid in position 30 is selected among D, S, E, and K; The amino acid in position 32 is selected among I, L, V, A, and K; The amino acid in position 33 is selected among T, S, and A; The amino acid in position 36 is selected among K, Q, L, H, and E; The amino acid in position 37 is selected among E, D, L, and N; The amino acid in position 38 is selected among V, I, L, and M; The amino acid in position 44 is selected among V and I; The amino acid in position 46 is selected among K, N, E, and D; The amino acid in position 48 is selected among A, T, D, and Y; The amino acid in position 52 is selected among N and K; The amino acid in position 55 is selected among Q, K, N, and M; The amino acid in position 56 is L, S, F or absent; The amino acid in position 57 is selected among Q, W, and R; The amino acid in position 58 is selected among S, Y, N, and T; The amino acid in position 59 is selected among S, V, P, T, and R; The amino acid in position 61 is S, Y, N, K or absent; The amino acid in position 63 is selected among R, K, Q, G, and E; The amino acid in position 64 is selected among F, A, P, R, and Y; The amino acid in position 72 is selected among L, D, H, M, and E; The amino acid in position 73 is selected among N, T, H, and S; The amino acid in position 74 is selected among Q, H, N, S, and K; The amino acid in position 77 is selected among T, S, and E; The amino acid in position 79 is selected among Q, R, K, and Y; The amino acid in position 83 is selected among G, N, and D; The amino acid in position 87 is selected among L, Q, T, and R; The amino acid in position 91 is K, M, T, or absent; The amino acid in position 92 is Q, K, or absent;10255 / PC The amino acid in position 93 is Y, F, or absent; The amino acid in position 96 is selected among R, K, and E; The amino acid in position 102 is selected among V, I, H, L, and R; The amino acid in position 104 is selected among E, D, and F; The amino acid in position 105 is N or absent; The amino acid in position 111 is selected among F, L, and V; The amino acid in position 112 is selected among S, H, Y, R, and W; The amino acid in position 113 is selected among G, N, S, D, and T; The amino acid in position 120 is selected among D, S, G, N, T, and V; The amino acid in position 121 is selected among K, R, and Y; The amino acid in position 123 is selected among N, T, V, and S; The amino acid in position 124 is selected among L, V, T, N, and Y; The amino acid in position 126 is selected among K, N, and C; The amino acid in position 131 is selected among K, E, and L; The amino acid in position 133 is selected among S, P, G, and L; The amino acid in position 134 is selected among A, S, T, and L; The amino acid in position 135 is selected among A, S, V, P, and T; The amino acid in position 136 is selected among S, P, N, and K; The amino acid in position 137 is C or absent; and / or The amino acid in position 138 is S, P, or absent; wherein the amino acid positions are the amino acid positions of SEQ ID NO:

74.

14. The method of claim 9, wherein the lectin is a L-SIGN C-type lectin and comprises anamino acid sequence having at least 80% sequence identity, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to one of SEQ ID NO: 57 - 64.

15. The method of any of the preceding claims, wherein the polypeptide capable ofbinding a PAMP is selected among polypeptides comprising a sequence having at10255 / PC least 80%, 85%, 90%, 95% sequence identity to XXLCRXCPWXWEFFQGXCYFFSXXQXXWXXSXXACXXXXAQLVIIXSXEEQXFLXXXXXRXNXXT WIGLSDXXXEGXWXWVDXSPLXXSFXXYWKXGEPNNXGFXEDCVEXXXDGQWNDXXCXXEN XWICKKPXXPCPXXE (SEQ ID NO: 75) wherein X can be any amino acid.

16. The method of any of the preceding claims, wherein the polypeptide capable ofbinding a PAMP is selected among polypeptides comprising the sequence of XXLCRXCPWXWEFFQGXCYFFSXXQXXWXXSXXACXXXXAQLVIIXSXEEQXFLXXXXXRXNXXT WIGLSDXXXEGXWXWVDXSPLXXSFXXYWKXGEPNNXGFXEDCVEXXXDGQWNDXXCXXEN XWICKKPXXPCPXXE (SEQ ID NO: 75) wherein X can be any amino acid.

17. The method of claim 16, whereinThe amino acid in position 1 is selected among E, A, F, and L; The amino acid in position 2 is selected among R, G, and F; The amino acid in position 6 is selected among H, P, L, and A; The amino acid in position 10 is selected among D, E, H, N, K, and Q; The amino acid in position 17 is selected among N, R, and S; The amino acid in position 23 is selected among N, Q, W, L, and K; The amino acid in position 24 is selected among S and T; The amino acid in position 26 is selected among R, S, N, and M; The amino acid in position 27 is selected among N, D, T, and S; The amino acid in position 29 is selected among H, K, R, and N; The amino acid in position 30 is selected among D, S, E, and K; The amino acid in position 32 is selected among V, I, L, and K; The amino acid in position 33 is selected among T, S, and A;10255 / PC The amino acid in position 36 is selected among Q, K, L, and E; The amino acid in position 37 is selected among E, D, L, and N; The amino acid in position 38 is selected among V, I, L, and M; The amino acid in position 39 is selected among R, G, K, and H; The amino acid in position 46 is selected among K, N, E, and D; The amino acid in position 48 is selected among A, T, D, and Y; The amino acid in position 52 is selected among N, K, and T; The amino acid in position 55 is selected among Q, K, N, and M; The amino acid in position 56 is L, S, F, or absent; The amino acid in position 57 is selected among Q, W, and R; The amino acid in position 58 is selected among T, S, Y, and N; The amino acid in position 59 is selected among S, V, P, T, and R; The amino acid in position 61 is S, Y, N, A, or absent; The amino acid in position 63 is selected among R, K, Q, G, and E; The amino acid in position 64 is selected among F, A, P, and R; The amino acid in position 72 is selected among L, D, H, and E; The amino acid in position 73 is selected among N, T, H, and K; The amino acid in position 74 is selected among Q, N, S, and K; The amino acid in position 77 is selected among T, M, S, and E; The amino acid in position 79 is selected among Q, R, L, and K; The amino acid in position 83 is selected among G, D, and N; The amino acid in position 87 is selected among S, Q, and R; The amino acid in position 88 is selected among P, T, L, and S; The amino acid in position 91 is Q, K, T, or absent; The amino acid in position 92 is R, Q, K, or absent; The amino acid in position 93 is Y, F, or absent; The amino acid in position 96 is selected among S, R, E, and K; The amino acid in position 102 is selected among S, I, H, and R; The amino acid in position 104 is F or absent; The amino acid in position 105 is selected among N, E, and D; The amino acid in position 111 is selected among F, L, and V; The amino acid in position 112 is selected among S, N, H, Y, A, and W;10255 / PC The amino acid in position 113 is selected among G, N, S, and T; The amino acid in position 116 is Q or absent; The amino acid in position 120 is selected among N, D, S, G, and V; The amino acid in position 121 is selected among R, K, and Y; The amino acid in position 123 is selected among D, S, T, V, and E; The amino acid in position 124 is selected among V, A, T, L, and Y; The amino acid in position 127 is selected among Y, F, A, and P; The amino acid in position 134 is selected among A, S, and L; The amino acid in position 135 is selected among A, S, V, T, and P; The amino acid in position 139 is R, M, V, G, E, or absent; The amino acid in position 140 is D, L, P, G, or absent; and / or The amino acid in position 141 is E or absent; wherein the amino acid positions are the amino acid positions of SEQ ID NO:75.

18. The method according to any of the preceding claims, wherein the fusion proteinfurther comprises a Fc part or a scaffold protein.

19. The method of claim 18, wherein the scaffold protein is selected among proteins,such as albumins, transferrins, lactoglobulins and / or fragments thereof.

20. The method of claim 18, wherein the Fc part is derived from an IgG, IgG1, IgG3, IgG4,IgA, IgD, IgM and / or IgE antibody.

21. The method of claim 20, wherein the Fc part is selected among polypeptidescomprising a sequence selected among the sequences SEQ ID NO: 16 - 22.10255 / PC22. The method of claim 20, wherein the Fc part with minimal to no significant antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, or complement-dependent cytotoxicity, which preferably includes mutations N297G, N297A, N297Q, L234A, L235A, L235E, K322A, P329G, S267K, or D265A.

23. The method according to any of the preceding claims, wherein the protein furthercomprises an additional element capable of binding immune cells or otherwise recruit and / or activate the immune system.

24. The method of claim 23, wherein the additional element capable of binding-cells orotherwise recruit / activate the immune system is a CD3 binding site or a CD16 binding site.

25. The method of claim 24, wherein the CD3 binding site is selected amongpolypeptides comprising a sequence of SEQ ID NO: 33 - 36, or the CD16 binding site isselected among polypeptides comprising a sequence selected among the sequences SEQ ID NO: 76 - 79.

26. The method according to any of the previous claims, wherein the fusion proteinfurther comprises a payload.

27. The method of claim 26, wherein the payload is selected among from the groupconsisting of nanoparticles, and at least one cytotoxic drug, radionuclide, fluorescent dye, or imaging agent.

28. The method according to any of the preceding claims, wherein the fusion protein isselected among fusion proteins:10255 / PCa. comprising the sequence of SEQ ID NO: 15 (denoted VP303);b. comprising the sequence of SEQ ID NO: 83 (denoted VP020);c. comprising the sequence of SEQ ID NO: 83 and SEQ ID NO: 84 (denotedVP025);d. comprising the sequence of SEQ ID NO: 23 (denoted VP304-TM);e. comprising the sequence of SEQ ID NO: 24 (denoted VP304-CT);f. containing a first chain comprising SEQ ID NO: 23 and a second chaincompositing SEQ ID NO: 24 (denoted VP304);g. containing a first chain comprising SEQ ID NO: 31 and a second chaincomprising SEQ ID NO: 32 (denoted VP308);h. containing a first chain comprising SEQ ID NO: 94 and a second chaincomprising SEQ ID NO: 95 (denoted VP304-CL);i. containing a first chain comprising SEQ ID NO: 96 and a second chaincomprising SEQ ID NO: 97 (denoted VP320);j. containing a first chain comprising SEQ ID NO: 25 and a second chaincomprising SEQ ID NO: 26 (denoted VP305);k. containing a first chain comprising SEQ ID NO: 27 and a second chaincomprising SEQ ID NO: 28 (denoted VP306);l. containing a first chain comprising SEQ ID NO: 29 and a second chaincomprising SEQ ID NO: 30 (denoted VP307);m. comprising the sequence of SEQ ID NO: 37 (denoted VP309);n. comprising the sequence of SEQ ID NO: 38 (denoted VP310);o. comprising the sequence of SEQ ID NO: 39 (denoted VP311);p. comprising the sequence of SEQ ID NO: 40 (denoted VP312);q. containing a first chain comprising SEQ ID NO: 41 and a second chaincomprising SEQ ID NO: 42 (denoted VP313);r. containing a first chain comprising SEQ ID NO: 31 and a second chaincomprising SEQ ID NO: 82 (denoted VP310-CD16);s. containing a first chain comprising SEQ ID NO: 118 and a second chaincomprising SEQ ID NO: 119 (denoted VP321);10255 / PC t. containing a first chain comprising SEQ ID NO: 118 and a second chaincomprising SEQ ID NO: 121 (denoted VP322);u. containing a first chain comprising SEQ ID NO: 118 and a second chaincomprising SEQ ID NO: 122 (denoted VP323);v. containing a first chain comprising SEQ ID NO: 118 and a second chaincomprising SEQ ID NO: 145 (denoted VP323-TM); w. containing a first chain comprising SEQ ID NO 125 and a second chaincomprising SEQ ID NO: 145 (denoted VP323-TM); x. containing a first chain comprising SEQ ID NO: 118 and a second chaincomprising SEQ ID NO: 124 (denoted VP321-TM);y. containing a first chain comprising SEQ ID NO: 125 and a second chaincomprising SEQ ID NO: 124 (denoted VP321-CT); z. containing a first chain comprising SEQ ID NO: 127 and a second chaincomprising SEQ ID NO: 128 (denoted VP601);aa. comprising the sequence of SEQ ID NO: 129 (denoted VP602);bb. comprising the sequence of SEQ ID NO: 130 (denoted VP603); and / orcc. comprising the sequence of SEQ ID NO: 133 (denoted VP703).

29. The method according to any of the claims 1 - 27, wherein the fusion protein is achimeric antigen receptor (CAR), comprising an extracellular portion and an intracellular portion, wherein the extracellular portion comprises a fusion protein capable of binding a. a polypeptide capable of binding to phosphatidylserine (PS), and / orb. a polypeptide capable of binding a pathogen-associated molecular pattern(PAMP).

30. The method according to claim 29, wherein the fusion protein in addition to theextracellular portion comprises one or more of a hinge and transmembrane region, a co-stimulatory domain and / or a CD3-zeta domain.10255 / PC31. The method of claim 29 or 30, wherein the CAR is a single chain CAR consisting of asingle polypeptide chain.

32. The method of claim 29 or 30, wherein the CAR is a heterodimeric chimeric antigenreceptor, comprising two or more different chimeric antigen receptors each comprising an extracellular portion capable of binding an antigen, an intracellular portion optionally comprising a domain capable of activating an immune effector cell and / or a co-stimulatory domain; a hinge and a transmembrane domain, wherein a. the transmembrane domain is able to heterodimerize; andb. at least one of the two or more chimeric antigen receptors comprises adomain capable of activating an immune effector cell, located in the intracellular portion.

33. The method according to claim 29- 32, wherein the fusion protein is selected among:a. the fusion proteins disclosed in Table 2;b. the fusion proteins disclosed in Table 3;c. the fusion proteins comprising a first polypeptide comprising the sequence ofSEQ ID NO: 99 and a second polypeptide comprising the sequence of SEQ ID NO: 101; d. the fusion proteins comprising a first polypeptide comprising the sequence ofSEQ ID NO: 102 and a second polypeptide comprising the sequence of SEQ ID NO: 103; e. the fusion proteins comprising a polypeptide comprising the sequence of SEQID NO: 111; f. the fusion proteins comprising a polypeptide comprising the sequence of SEQID NO: 112; g. the fusion proteins comprising a polypeptide comprising the sequence of SEQID NO: 113; h. the fusion proteins comprising a polypeptide comprising the sequence of SEQID NO: 134;10255 / PC i. the fusion proteins comprising a polypeptide comprising the sequence of SEQID NO: 135; j. the fusion proteins comprising a polypeptide comprising the sequence of SEQID NO: 136; k. the fusion proteins comprising a polypeptide comprising the sequence of SEQID NO: 137; l. the fusion proteins comprising a polypeptide comprising the sequence of SEQID NO: 138; and m. the fusion proteins comprising a polypeptide comprising the sequence of SEQID NO: 139.

34. The method according to any of the previous claims, wherein the method is for thetreatment of a cancer selected among any solid or non-solid cancer such as leukemia, AML (Acute Myeloid Leukemia), multiple myeloma, lymphoma, B-cell lymphoma, Pancreatic cancer, breast cancer, bladder cancer, colon cancer, lung cancer, braincancer, glioblastoma and liver cancer.

35. A fusion protein selected among fusion proteins:a. comprising the sequence of SEQ ID NO: 15 (denoted VP303);b. comprising the sequence of SEQ ID NO: 83 (denoted VP020);c. comprising the sequence of SEQ ID NO: 83 and SEQ ID NO: 84 (denotedVP025); d. comprising the sequence of SEQ ID NO: 23 (denoted VP304-TM);e. comprising the sequence of SEQ ID NO: 24 (denoted VP304-CT);f. containing a first chain comprising SEQ ID NO: 23 and a second chaincompositing SEQ ID NO: 24 (denoted VP304);g. containing a first chain comprising SEQ ID NO: 31 and a second chaincomprising SEQ ID NO: 32 (denoted VP308);10255 / PCh. containing a first chain comprising SEQ ID NO: 94 and a second chaincomprising SEQ ID NO: 95 (denoted VP304-CL);i. containing a first chain comprising SEQ ID NO: 96 and a second chaincomprising SEQ ID NO: 97 (denoted VP320);j. containing a first chain comprising SEQ ID NO: 25 and a second chaincomprising SEQ ID NO: 26 (denoted VP305);k. containing a first chain comprising SEQ ID NO: 27 and a second chaincomprising SEQ ID NO: 28 (denoted VP306);l. containing a first chain comprising SEQ ID NO: 29 and a second chaincomprising SEQ ID NO: 30 (denoted VP307);m. comprising the sequence of SEQ ID NO: 37 (denoted VP309);n. comprising the sequence of SEQ ID NO: 38 (denoted VP310);o. comprising the sequence of SEQ ID NO: 39 (denoted VP311);p. comprising the sequence of SEQ ID NO: 40 (denoted VP312);q. containing a first chain comprising SEQ ID NO: 41 and a second chaincomprising SEQ ID NO: 42 (denoted VP313);r. containing a first chain comprising SEQ ID NO: 31 and a second chaincomprising SEQ ID NO: 82 (denoted VP310-CD16);s. containing a first chain comprising SEQ ID NO: 118 and a second chaincomprising SEQ ID NO: 119 (denoted VP321);t. containing a first chain comprising SEQ ID NO: 118 and a second chaincomprising SEQ ID NO: 121 (denoted VP322);u. containing a first chain comprising SEQ ID NO: 118 and a second chaincomprising SEQ ID NO: 122 (denoted VP323);v. containing a first chain comprising SEQ ID NO: 118 and a second chaincomprising SEQ ID NO: 124 (denoted VP321-TM);w. containing a first chain comprising SEQ ID NO: 125 and a second chaincomprising SEQ ID NO: 124 (denoted VP321-CT);x. containing a first chain comprising SEQ ID NO: 118 and a second chaincomprising SEQ ID NO: 145 (denoted VP323-TM);y. containing a first chain comprising SEQ ID NO: 125 and a second chaincomprising SEQ ID NO: 145 (denoted VP323-CT);10255 / PC z. containing a first chain comprising SEQ ID NO: 127 and a second chaincomprising SEQ ID NO: 128 (denoted VP601);aa. comprising the sequence of SEQ ID NO: 129 (denoted VP602); andbb. comprising the sequence of SEQ ID NO: 130 (denoted VP603).

36. A pharmaceutical composition comprising the fusion protein of claim 35.

37. A chimeric antigen receptor (CAR) comprising an extracellular portion and anintracellular portion, where the extracellular portion comprises a fusion protein fusion protein capable of binding a. a polypeptide capable of binding to phosphatidylserine (PS), and / orb. a polypeptide capable of binding a pathogen-associated molecular pattern(PAMP).

38. The CAR of claim 37, where the CAR is engineered to express on a T cell, a naturalkiller (NK) cell, a cytotoxic T lymphocyte (CTL), a regulatory T cell, an embryonic or pluripotent stem cell, macrophage, neutrophils, natural killer T cell (NKT) or gamma delta T cell.

39. The CAR of claim 37 or 38, that in addition to the extracellular portion comprises oneor more of a hinge and transmembrane region, a co-stimulatory domain and / or a CD3-zeta domain.

40. The CAR according to any of claims 37 to 39, selected among:a. the fusion proteins disclosed in Table 2;b. the fusion proteins disclosed in Table 3;10255 / PC c. the fusion proteins comprising a first polypeptide comprising the sequence ofSEQ ID NO: 99 and a second polypeptide comprising the sequence of SEQ ID NO: 101; d. the fusion proteins comprising a first polypeptide comprising the sequence ofSEQ ID NO: 102 and a second polypeptide comprising the sequence of SEQ ID NO: 103; e. the fusion proteins comprising a polypeptide comprising the sequence of SEQID NO: 111; f. the fusion proteins comprising a polypeptide comprising the sequence of SEQID NO: 112; g. the fusion proteins comprising a polypeptide comprising the sequence of SEQID NO: 113; h. the fusion proteins comprising a polypeptide comprising the sequence of SEQID NO: 134; i. the fusion proteins comprising a polypeptide comprising the sequence of SEQID NO: 135; j. the fusion proteins comprising a polypeptide comprising the sequence of SEQID NO: 136; k. the fusion proteins comprising a polypeptide comprising the sequence of SEQID NO: 137; l. the fusion proteins comprising a polypeptide comprising the sequence of SEQID NO: 138; and m. the fusion proteins comprising a polypeptide comprising the sequence of SEQID NO: 139; n. the fusion protein comprising a polypeptide comprising the sequence of SEQID NO: 137; and o. the fusion protein comprising a polypeptide comprising the sequence of SEQID NO: 142.

41. A heterodimeric chimeric antigen receptor, comprising two or more differentchimeric antigen receptors each comprising an extracellular portion capable of10255 / PC binding an antigen, an intracellular portion optionally comprising a domain capable of activating an immune effector cell and / or a co-stimulatory domain; a hinge and a transmembrane domain, wherein a. the transmembrane domain is able to heterodimerize; andb. at least one of the two or more chimeric antigen receptors comprises adomain capable of activating an immune effector cell, located in the intracellular portion.

42. The heterodimeric chimeric antigen receptor of claim 41, wherein thetransmembrane domain is selected among amino acids 5 - 30 of SEQ ID NO: 92 oramino acids 6 - 28 of SEQ ID NO: 93.

43. The heterodimeric chimeric antigen receptor according to any of claims 41 - 42,comprising two different chimeric antigen receptors, wherein one of the two different chimeric antigen receptors is capable of binding PS and the other of the two different chimeric antigen receptors is capable of binding a PAMP.

44. The heterodimeric chimeric antigen receptor according to any of claims 41 - 43,selected among the heterodimeric chimeric antigen receptors disclosed in Table 3 or in Figure 21.

45. An immune effector cell comprising a CAR of any of the claims 37 - 40, or aheterodimeric chimeric antigen receptor of claims 41 - 44.

46. The immune effector cell of claim 45, wherein the CAR or the heterodimeric chimericantigen receptor is engineered on the surface of the immune effector cell.

47. The immune effector cell of claim 45 or 46, being a T cell.10255 / PC48. A nucleic acid encoding a CAR according to any of claims 37 - 40 or a heterodimericCAR according to any of claims 41 - 44.

49. A method for in vivo CAR engineering of immune cells, such as T or NK cells,comprising the steps of: a. providing liposomes, lipid nanoparticles or silica nanoparticles comprising anucleic acid that is either encapsulated in the internal phase of the particle or surface associated by covalent linkage, affinity interaction or electrostatic complexation; b. ensuring the surface of said liposomes, lipid nanoparticles or silicananoparticles comprises or are attached to anti-CD3 molecules or anti-CD16molecules to obtain a functionalized surface;wherein said obtained functionalized surface secures delivery of the nucleic acid to T cells if said surface comprises or are attached to anti-CD3 molecules or to NK cells if said surface comprises or are attached to anti-CD16 molecules.

50. The method of claim 49, wherein the nucleic acid comprises a nucleic acid accordingto claim 46.

51. The method according to claim 49 or 50, wherein the surface of said liposomes, lipidnanoparticles or silica nanoparticles comprises or are attached to anti-CD3 molecules having a sequence of SEQ ID NO.33, 34, 35, or 36 or comprises or are attached to anti-CD16 molecules having a sequence of SEQ ID NO.76, 77, 78 or 79.10255 / PC52. The method according to claim 51, wherein the surface of said liposomes, lipidnanoparticles or silica nanoparticles comprises or are attached to anti-CD3 moleculeshaving a sequence of SEQ ID NO.33, 34, 35, or 36, preferably SEQ ID NO.34.

53. A delivery system such as liposomes or nanoparticles carrying the nucleic acid ofclaim 48 that has been functionalized to target immune effector cells, such as T cell orNK cells, such that the PS and PAMP binding polypeptides are expressed on the surface of the immune effector cell.

54. The delivery system of claim 53, wherein the immune effector cell can include a T cell, aNatural Killer (NK) cell, a cytotoxic T lymphocyte (CTL), a regulatory T cell, an embryonic or a pluripotent stem cell, macrophage, neutrophils, natural killer T cell (NKT) or gamma delta T cell.

55. A method of treating cancer or an infectious disease in a human or animal subject,comprising administrating a population of immune effector cells according to any of claims 45 - 47 to the human or animal subject.

56. A protein carrier comprising the TIM-1 IgV domain and / or the CTLD of DC-SIGN, andone or more site-specific unpaired cysteine, preferably at the C-terminus or N-terminus for thiol conjugation.

57. The protein carrier of claim 56, comprising any amino acid sequence selected amongSEQ ID NO: 131, 132 and 133.

58. The protein carrier of claim 56 or 57, further comprising a nanoparticle or a payloadconjugated to one of the one or more site-specific unpaired cysteine, preferably at the C-terminus or N-terminus.10255 / PC59. The protein carrier of claim 58, wherein the nanoparticle is selected among silicananoparticles, lipid nanoparticles (LNP), liposomes, gold, iron oxide, and polymer nanoparticles, lipid-based nanoparticles, liposomes, solid lipid nanoparticles, polymeric nanoparticles, dendrimers, micelles, nanospheres, inorganic nanoparticles, gold nanoparticles, silica nanoparticles, magnetic nanoparticles, quantum dots, protein-based nanoparticles, albumin nanoparticles, or hybrid nanoparticles60. The protein carrier of claim 57 or 58, wherein the nanoparticles is conjugated to apayload.

61. The protein carrier of claim 58 - 60, wherein the payload is selected among: aradionuclide, a hapten that chelates a radionuclide, a small molecule and fluorescentagents.

62. Use of a protein carrier according to any of claims 56 - 61 for immunofluorescenceimaging of tumor tissues.

63. A fusion protein comprising an antibody Fc domain and:a. Site specific unpaired cysteine residueb. a polypeptide capable of binding to phosphatidylserine (PS); and / orc. a polypeptide capable of binding a pathogen-associated molecular pattern(PAMP).

64. The fusion protein of claim 63, comprising a cysteine residue at position K274 (EUnumbering).

65. A nanoparticle that is conjugated to a protein that contains:10255 / PC a. a polypeptide capable of binding to phosphatidylserine (PS); and / orb. a polypeptide capable of binding a pathogen-associated molecular pattern(PAMP).

66. The nanoparticle of claim 65, wherein the nanoparticle is selected among lipid-basednanoparticles, liposomes, solid lipid nanoparticles, polymeric nanoparticles,dendrimers, micelles, nanospheres, inorganic nanoparticles, gold nanoparticles, silica nanoparticles, magnetic nanoparticles, quantum dots, protein-based nanoparticles, albumin nanoparticles, or hybrid nanoparticles.

67. The nanoparticle of claim 65 or 66, where the protein contains a site-specific cysteinefor thiol conjugation68. The nanoparticle according to any of claim 65 - 67, wherein the PS-binding domainscomprises the IgV domain of TIM-1.

69. The nanoparticle according to any of claims 65 - 68, wherein the PAMP-bindingdomain comprises the TCLD of DC-SIGN.

70. A fusion protein comprising an antibody Fc domain and:a. An antibody fragment that binds to a receptor on immune effector cell,preferably CD3 on T cells or CD16 on NK cells; and b. a polypeptide capable of binding to phosphatidylserine (PS); and / orc. a polypeptide capable of binding a pathogen-associated molecular pattern(PAMP).

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