Targeting modules against cd19 and cd20 for use in a method for stimulating a reversed chimeric antigen receptor-mediated immune response in a mammal

Abstract

The present invention relates to a targeting module comprising at least one CD19-binding domain, at least one CD20-binding domain and a tag or tag-binding domain, a pharmaceutical composition and a kit comprising the targeting module and a vector or a cell comprising a nucleotide sequence encoding a reversible chimeric antigen receptor

Description

[0001] Targeting modules against CD19 and CD20 for use in a method for stimulating a reversed chimeric antigen receptor-mediated immune response in a mammalThe present invention relates to a targeting module comprising at least one CD19-binding domain,at least one CD20-binding domain and a tag or tag-binding domain, a pharmaceutical composition and a kit comprising the targeting module and a vector or a cell comprising a nucleotide sequence encoding a reversible chimeric antigen receptor. Chimeric antigen receptors (CARs) are artificial receptors consisting of a binding moiety, which provides the antigen-specificity, e.g. a single chain variable fragment (scFv) recognizing a surfaceantigen of a tumor cell, a transmembrane domain, and one or several signaling chains derivedfrom immune receptors, e.g. CD3ζ, that activates an immune cell (Cartellieri et al.2010).The first-generation CAR comprising one signaling chain was modified by adding a signaltransduction domain of e.g. CD28 or CD137 (4-1BB), which are co-stimulatory molecules of a Tcell, to increase the activation of immune cells (second generation CAR). A third generation CARwas developed by tandemly linking an additional complementary signal transduction domainderived from e.g. CD28, CD137 (4-1BB) or CD134 (OX40), both which are tumor necrosis factor(TNF) receptor superfamily members, to a second-generation CAR. However, not all signaltransduction domains derived from every T cell signal transducing protein sufficiently stimulate aT cell to damage and / or kill a target tumor cell. Therefore, finding intracellular signaling domains of signal transducing proteins that are effective when linked to a CAR is desirable. Immune cells, genetically modified to express CARs, can be used to bind cells or tissue structuresexpressing the appropriate target of the CAR binding moiety. Cross-linking leads to an inductionof signal pathways via the CAR signaling chains, which will change the biologic properties of the CAR-engrafted immune cell. In contrast, CAR activation in gene-modified regulatory T cells (Tregs) leads to an activation of Treg-specific immunomodulatory and suppressive mechanisms like interleukin (IL)-10 or tumor growth factor-beta (TGF-β) secretion. The adoptive transfer ofimmune cells engineered with chimeric antigen receptors (CARs) is currently considered a highlypromising therapeutic option for the treatment of otherwise incurable malignant, infectious or autoimmune diseases. However, the conventional CAR technology comes along with a number of critical issues, which need to be solved before this treatment modality can be widely applied for clinical treatments. First of all, several safety issues have to be addressed. So far, immune responses of T cells engineered with conventional CARs are difficult to control after infusion into the patient. Serious adverse event rates are high (Titov et al.2018). Especially unexpected target gene expression on normal tissue may provoke a rapid and rigorous immune reaction of engineered T cells against normal cells, which can cause severe side effects (Morgan et al.2010). Moreover, as CAR T cells are a new class of self-amplifying cell drugs, infused T cells can undergo a vigorous expansion in the presence of heavy tumor burden leading to tumor lysis syndrome, cytokine release syndrome and macrophage activation syndrome (Brudno and Kochenderfer 2016). Another drawback of conventional CAR technology is the restriction of engineered T cell retargeting to a single antigen. Such a monotherapeutic approach implies the risk for the development of tumor escape variants, which have lost the target antigen during treatment. The emergence of tumor escape variants under conventional CAR T cell therapy after several months was already observed in clinical trials (Sotillo et al.2015). Taken together, these obstacles restrict the application of CAR T cells to veryfew indications. In fact, examples of clinical effectiveness have mostly been seen with CD19- andBCMA-targeting CAR T cells until now. Modular switchable “universal” CAR T (UniCAR) approaches can overcome these limitations by separating antigen recognition and activating domain of a CAR into two separate operational units. T cells are engineered to express a CAR with a universal binding domain recognizing a tag (Cartellieri et al.2016). Antigen-specificity is provided by soluble adapter molecules, which consist of an antigen-binding domain fused to the tag recognized by the UniCAR. Cartellieri et al. describethe treatment of CD33- and / or CD123-positive acute myeloid leukemia cells in vitro and in vivo.Next to the UniCAR approach for recognizing various antigens (EP 2990416 A1) a reversed universal CAR (RevCAR) approach is known that promotes binding of an immune cell engineered to express a RevCAR comprising a tag to a target cell through an adaptor molecule comprising a tag-binding domain and a target cell binding domain (EP 3581200 A1). Moreover, switchable CAR T approaches like UniCAR or RevCAR provide the possibility to rest CAR T cells in-between cycles of activation and stimulation by pausing administration of thesoluble targeting module molecule. This is expected to prevent the exhaustion observed uponcontinuous stimulation of conventional CAR T cells thereby improving persistence (Weber et al. 2021).  Kittel-Boselli et al. describe targeting acute myeloid leukemia, in particular patient-derived AMLcells expressing CD33 and CD123, using the RevCAR platform, wherein the RevCARs consist of the extracellular peptide epitope E5B9 or E7B6 and CD28 (28) hinge domain (HiD), CD28 transmembrane domain (TMD), the intracellular CD28 costimulatory (CSD) and CDS zeta (3z)activating signaling domain (ASD) (Kittel-Boselli et al. 2021). The targeting modules areconstructed with the variable heavy (VH) and light chain (VL) domains derived from the monoclonal antibodies (mAbs) CD33, CD123, 5B9, or 7B6 connected via glycine (G)-serine (S) linkers.WO 2016 / 154621 A1 describes switchable chimeric receptors comprising a non-antibodyextracellular domain that interacts with a chimeric receptor binding partner presented on a switch. Furthermore, the chimeric receptor comprises a transmembrane domain and an intracellularsignaling domain. The switch comprises the chimeric receptor binding partner, preferably anantibody or antibody fragment, and a targeting moiety. Preferably the chimeric receptor bindingpeptide comprises a peptide epitope tag. Preferably the chimeric receptor binding partner and thenon-antibody extracellular domain are selected from the group consisting of isopeptag and pilin, spytag and spycatcher, SNARE and SNAP25, synaptobrevin and syntaxin, Hu-tag and RNAse I, K4 peptide and E4 peptide or a modified K4 peptide and a modified E4 peptide, afirst mouse coronin 1A alpha helix and a second mouse coronin 1A alpha helix, an anchor domain of an A- kinase anchor protein and a regulatory subunit of cAMP-dependent protein kinase A (AD) and adimerization and docking domain of cAMP-dependent protein kinase (DDD), barnase and barstar,coronin and ccCor1 peptide. The targeting moiety may target an antigen selected from CD19,Her2, CLL-1, CD33, EGFRvIII, CD20, CD22, BCMA or a fragment thereof.Darowski et al. describe flexible chimeric antigen receptor adaptor molecules (CAR-adaptors) forthe recruitment of chimeric antigen receptor T cells with tags like 5B9, GCN4, FITC, leucine zipper sequences, or biotinylated IgG, and targets like CD33, CD123, CD19, CD20, CD22, HER2, EGFR, CCR4, G2D, MCSP, ErbB2 (Darowski et al.2019). Feldmann et al. disclose RevCAR T cells efficiently kill tumor cells, flexibly redirected againstmultiple targets by exchanging the targeting modules, in particular targeting modules againstPSMA and PSCA (Feldmann et al. 2020).Spehr et al. disclose switchable allogeneic chimeric antigen receptor T cells for targeting CD19and CD20 in B cell malignancies, in particular a reverse universal chimeric antigen receptorplatform (RevCAR)-T cell comprising a short, non-immunogenic peptide motif derived from thehuman nuclear La / SSB autoantigen, and a soluble adaptor (targeting module, TM) specific forCD19 and CD20 (Spehr et al.2023). WO 2020 / 018922 A1 describes heavy chain-only antibody binding to CD19 comprising a heavy chain variable region, methods of making such antibodies, compositions, including pharmaceutical compositions, comprising such antibodies, and their use to treat B cell disorders that are characterized by the expression of CD19. WO 2023 / 196996 A2 discloses a cell comprising a signaling component comprising a firstmultimerization domain comprising an FRB polypeptide or variant thereof or a FKBP polypeptideor variant thereof, a first polypeptide linker, and a CD3ε polypeptide or variant thereof; and atargeting component comprising an anti-CLL1 scFv or single domain antibody (sdAb), an anti-CD33 scFv or single domain antibody (sdAb), a second polypeptide linker, a second multimerization domain comprising an FRB polypeptide or variant thereof or a FKBP polypeptide or variant thereof, a CD4 hinge polypeptide, a CD4 transmembrane polypeptide, and a truncated CD4 intracellular polypeptide.The object of the present invention is to provide an alternative targeting module for use in aswitchable CAR system and / or a targeting module with prolonged half-life.The object has been solved by a targeting module comprising at least one CD19-binding domain,at least one CD20-binding domain and a tag-binding domain or a tag, a pharmaceuticalcomposition and a kit according to the independent claims. Advantageous embodiments of the invention are indicated in the dependent claims. A first aspect of the invention provides a targeting module comprising i) at least one CD19-binding domain comprising one of the sequences selectedfrom SEQ ID No. 1 to SEQ ID No. 3 or a sequence identity of at least 95 %with one of the sequences selected from SEQ ID No. 1 to SEQ ID No. 3,ii) at least one CD20-binding domain comprising SEQ ID No.4, andiii) a tag-binding domain or a tag.Advantageously, the trispecific targeting module according to the invention targets both CD19and CD20 simultaneously. Advantageously, the targeting module according to the invention hasprolonged half-life. Advantageously, the targeting module according to the invention administeredwith a switchable chimeric antigen receptor could delay tumor growth, wherein the anti-tumorresponse of the switchable chimeric antigen receptor is only induced in the presence of thetargeting module. The effect can be interrupted by withholding the administration of the targetingmodule to rest the switchable CAR-T cells and prevent their exhaustion. The switchable CAR-Tcells can be reactivated and reexpanded by additional targeting module doses. The targeting module according to the invention used in combination with a switchable chimeric antigen receptor is safer and more versatile than a classical CAR construct directed against a target. The versatility of the switchable CAR platform embodies a significant advantage for treating tumors with a highly heterogeneous antigenic profile. This therapy can be quickly adapted to the evolving antigenic profile to avoid a treatment-induced selection of tumor cells lacking thetargeted antigen and the consequent tumor relapse. Moreover, only one switchable CAR-T cellproduct is required for different indications and targets. As used herein, the term “targeting module” refers to a molecule, preferably a polypeptide orprotein, with at least three different domains, wherein each domain is specific for a target or auniform group of targets, wherein at least two domains are specific for a target cell, in particularthe CD19-binding domain and CD20-binding domain; and one domain is specific for a switchablechimeric antigen receptor, in particular the tag-binding domain or tag.As used herein, the term “domain” refers to a part of a protein sequence, which can exist and function independently from the rest of the protein. As used herein, the term “specific” refers to the ability of an antibody or antibody fragment or a protein, peptide or low molecular weight organic ligand to recognize and bind with a binding partner (e.g. a tumor antigen) protein present in a sample, but not substantially recognize or bind other molecules in the sample. As used herein, the term “binds” or “binding” refers to a non-covalent binding, in particular ionic bonds, hydrogen bonds, Van der Waals forces and / or hydrophobic interactions. In embodiments, the targeting module is isolated. In embodiments, the targeting module according to the invention is expressed as a recombinant protein. In further embodiments, the targeting module is chemically synthesized. In embodiments, the targeting module is in monomeric, dimeric or polymeric form, preferably in monomeric form. According to the invention, the targeting module comprises at least one CD19-binding domain. As used herein “CD19” (Cluster of Differentiation19) refers to a surface antigen expressed by B lymphocytes. According to the invention, the targeting module comprises at least one CD19-binding domaincomprising one of the sequences selected from SEQ ID No. 1 to SEQ ID No. 3 or a sequenceidentity of at least 95 % with one of the sequences selected from SEQ ID No. 1 to SEQ ID No. 3.As used herein, the term “% sequence identity” refers to the number of identical amino acidresidues in relation to the length of the amino acid sequence. In embodiments, the CD19-bindingdomain comprises an amino acid sequence with at least 99% sequence identity with one of thesequences selected from SEQ ID No.1 to SEQ ID No.3.In embodiments, the CD19-binding domain comprises an amino acid sequence with at least 95%sequence homology with one of the sequences selected from SEQ ID No. 1 to SEQ ID No. 3,preferably at least 99% sequence homology with one of the sequences selected fromSEQ ID No. 1 to SEQ ID No. 3. As used herein, the term “% sequence homology” refers to thenumber of homologue amino acid residues in relation to the length of the amino acid sequence, wherein homologue amino acids are identical amino acids or amino acids comprising modifications selected from the group comprising D amino acids, pseudo peptide bonds, aminoalcohols, amino acids with modified side chains, in particular cysteine and selenocystein, and / or circular proteins. Advantageously, these homologues reveal increased stability. In embodiments, the CD19-binding domain comprises an amino acid sequence with at least 95%sequence similarity with one of the sequences selected from SEQ ID No. 1 to SEQ ID No. 3,preferably at least 99% sequence similarity with one of the sequences selected from SEQ ID No.1 to SEQ ID No.3. As used herein, the term “similarity” refers to the sequence homology, whereinconservative substitutions of amino acid residues having similar physicochemical properties overthe length of the amino acid sequence are comprised. The % sequence similarity is determinedwith any reasonable similarity-scoring matrix known by the person skilled in the art, preferably with a similarity-scoring matrix selected from BLOSUM50, BLOSUM62, PMBEC or VTML10 to VTML80. In embodiments, the at least one CD19-binding domain comprises CDR sequences accordingSEQ ID No. 8 to SEQ ID No. 13. As used herein, the term “CDR (Complementarity-determiningregions)” refers to parts of the variable chains in antibodies or antibody fragments, where the antibodies or antibody fragments bind to their specific antigen. An antibody comprises three CDRs (CDR1, CDR2 and CDR3), arranged non-consecutively, on the amino acid sequence of each variable domain and thus, six CDRs on the two variable domains (VHand VL), which can comeinto contact with the antigen. A single-domain antibody (sdAb) comprises three CDRs (CDR1,CDR2 and CDR3), arranged non-consecutively, on the amino acid sequence of its variable domain, which can come into contact with the antigen. According to the invention, the targeting module comprises at least one CD20-binding domain. As used herein “CD20” (Cluster of Differentiation20) refers to a glycosylated phosphoprotein expressed on the membrane surface of B cells. According to the invention, the targeting module comprises at least one CD20-binding domaincomprising SEQ ID No. 4, wherein X5, X14, X43, X44, X45, X62, X65, X75, X76, X79, X87, X88 and X116are independently from each other selected from a proteinogenic alpha-amino acid residue.In some embodiments, X5 to X116 are selected as follows:X5 is selected from Glutamine or Valine;X14 is selected from hydrophobic residues, such as Isoleucine, Leucine, Valine, Alanine, Methionine, Phenylalanine, Proline and Tryptophan; preferably Alanine or Proline;X43 is selected from Lysine or Glutamine;X44 is selected from Glutamate or Glycine; X45 is selected from Arginine or Leucine;X62 is selected from Alanine or Aspartate;X65 is selected from polar and basic residues, such as Lysine, Arginine and Histidine, preferably Arginine or Lysine;X75 is selected from Alanine or Serine;X76 is selected from Glutamate or Lysine;X79 is selected from hydrophobic residues, such as Isoleucine, Leucine, Valine, Alanine, Methionine, Phenylalanine, Proline and Tryptophan; preferably Valine or Leucine; X87 is selected from polar and basic residues, such as Lysine, Arginine and Histidine, preferably Arginine or Lysine; X88 is selected from hydrophobic residues, such as Isoleucine, Leucine, Valine, Alanine, Methionine, Phenylalanine, Proline and Tryptophan; preferably Alanine or Proline; andX116 is selected from Glutamine or Leucine.In embodiments, the targeting module comprises at least one CD20-binding domain comprisingone of the sequences selected from SEQ ID No.5 to SEQ ID No.7 or with a sequence identity ofat least 95 % with one of the sequences selected from SEQ ID No. 5 to SEQ ID No. 7. Inembodiments, the CD20-binding domain comprises an amino acid sequence with at least 99%sequence identity with one of the sequences selected from SEQ ID No.5 to SEQ ID No. 7.In embodiments, the CD20-binding domain comprises an amino acid sequence with at least 95%sequence homology with one of the sequences selected from SEQ ID No. 5 to SEQ ID No. 7,preferably at least 99% sequence homology with one of the sequences selected from SEQ ID No.5 to SEQ ID No. 7.In embodiments, the CD20-binding domain comprises an amino acid sequence with at least 95%sequence similarity with one of the sequences selected from SEQ ID No. 5 to SEQ ID No. 7,preferably at least 99% sequence similarity with one of the sequences selected from SEQ IDNo. 5 to SEQ ID No. 7.In embodiments, the at least one CD20-binding domain comprises CDR sequences according SEQ ID No.14 to SEQ ID No.16 or SEQ ID No.14, SEQ ID No.16 and SEQ ID No.17. In embodiments, the CD19-binding domain and / or the CD20-binding domain independentlyselected from antibody and antigen-binding fragment.As used herein, the term “antibody” refers to a protein, which binds antigens via the antigen- binding fragment variable region (Fab). This is composed of one constant and one variable domain of each of the heavy (VH) and the light chain (VL). As used herein, the term “antibodyfragment” or “antigen-binding fragment” refers to a protein comprising at least the VL or VH of anantibody. In embodiments, antibody fragments are selected from single-chain variable fragments (scFv), single-chain antibodies, Fc fragment, F(ab')2 fragments, Fab fragments, and fragments produced by a Fab expression library or single-domain antibodies (nanobodies). As used herein, the term “single-chain variable fragment (scFv)” refers to an artificial antibody fragment comprising a variable domain of a light chain and a variable domain of a heavy chain of an antibody covalently linked. In embodiments, the VL and VH of an antibody are covalently linked by a short peptide of 10 to 25 amino acids. In further embodiments, the short peptide links the N- terminus of the VH with the C-terminus of the VL, or vice versa. As used herein, the term “Fab fragments” refers to an antibody fragment comprising one constant and one variable domain of each of the heavy and the light chain.As used herein, the term “single-domain antibody (sdAb)” or “nanobody” is an antibody fragmentconsisting of a single monomeric variable antibody domain, in particular a VHH fragment.In embodiments, the antibody is obtained from an animal species, preferably from a mammal such as human, simian, mouse, rat, rabbit, lama, alpaca, camel, shark, guinea pig, horse, cow, sheep, goat, pig, dog or cat. Preferably, the antibody or antibody fragment is a human, humanized or deimmunized antibody. Humanized antibodies can be prepared in various ways, for example, by resurfacing and CDR grafting. In case of resurfacing, a combination of molecular modeling, statistical analyses, and mutagenesis is used to modify all non-CDR regions on the surface of the antibody to become similar to the surface of antibodies of the target organism. In CDR grafting, the CDR regions according to the invention are introduced into known human framework regions, which are similar in sequence to the original ones. Deimmunized antibodies can be obtained by specifically mutating residues that confer immunogenicity hotspots as predicted based on in silico peptide-MHC affinity prediction. In embodiments, the antibody or antibody fragment is a polyclonal, a monoclonal or a chimeric antibody, wherein an antigen-binding region of a non-human antibody is transferred into the framework of a human antibody by recombinant DNA techniques including in silico design. In embodiments, antibodies to a selected tag or antigen may be produced by immunization of various hosts including, but not limited to, goats, rabbits, rats, mice, humans, through injection with cells expressing a particular protein, DNA or RNA encoding for the protein, the protein itself or any portion, fragment or oligopeptide that retain immunogenic properties of the protein. In embodiments, the CD19-binding domain and / or the CD20-binding domain are antigen-binding fragments. In embodiments, the CD19-binding domain and / or the CD20-binding domain are independently selected from single-chain variable fragments (scFv), single-chain antibodies, Fc fragment, F(ab')2 fragments, Fab fragments, and fragments produced by a Fab expression library or single- domain antibodies (nanobodies).In embodiments, both the CD19-binding domain and the CD20-binding domain are VHHfragments. In embodiments, the CD19-binding domain is a VHH. In embodiments, the CD20-binding domain is an scFv fragment.In embodiments, the CD19-binding domain is an scFv. In embodiments, the CD20-bindingdomain is a VHH fragment.In embodiments, the variable region(s) of the at least one CD19-binding domain and / or at leastone CD20-binding domain comprise(s) a humanized amino acid sequence.In embodiments, the targeting module comprisesi) at least one CD19-binding domain comprising one of the sequences selectedfrom SEQ ID No. 1 to SEQ ID No. 3 or a sequence identity of at least 95 %with one of the sequences selected from SEQ ID No. 1 to SEQ ID No. 3,ii) at least one CD20-binding domain comprising SEQ ID No.4, andiii) a tag.As used herein, the term “tag” refers to a marker, in particular a peptide sequence or an organicmolecule, attached to peptides or proteins to enable them to bind to specific atoms, ions ormolecules, in particular the tag-binding domain.In embodiments, the tag is selected from organic molecules including fluorescence labels, e.g.,FITC (Fluorescein isothiocyanate), and biotin. In embodiments, the tag is a peptide epitope tag. In further embodiments, the tag comprises 10 to 20 amino acids. In embodiments, the peptide epitope tag is a myc-tag, a His-tag, a peptide sequence from yeasttranscription factor GCN4, preferably according to SEQ ID No. 18, SEQ ID No. 19 or mutantsthereof; a leucine zipper sequence, preferably SYNZIP 1 to SYNZIP 48, BATF, FOS, ATF4, ATF3,BACH1, JUND, NFE2L3, HEPTAD (Reinke et al.2010), a sequence according to SEQ ID No.20 or SEQ ID No.21 or mutants thereof; or a peptide sequence from a human nuclear protein. In embodiments, the peptide epitope tag is a myc-tag, a His-tag, a peptide sequence from yeasttranscription factor GCN4 according to SEQ ID No.18, SEQ ID No.19, a leucine zipper sequenceselected from SYNZIP 1 to SYNZIP 48, BATF, FOS, ATF4, ATF3, BACH1, JUND, NFE2L3,HEPTAD (Reinke et al. 2010), a sequence according to SEQ ID No. 20 or SEQ ID No. 21 or apeptide sequence from a human nuclear protein.In embodiments, the tag is a peptide sequence from the human La protein, in particular accordingto SEQ ID No. 22, SEQ ID No.23, SEQ ID No. 24 or mutants thereof.In embodiments, the tag is the human La epitope E5B9 according to SEQ ID No. 22 or E7B6according to SEQ ID No.23 or SEQ ID No. 24, preferably the human La epitope E5B9 accordingto SEQ ID No. 23 or E7B6 according to SEQ ID No.24.As used herein, the term “nuclear protein” refers to a protein found in the cell nucleus. Advantageously, tags, which are peptide sequences from nuclear antigens, cannot be accessed and bound by the corresponding tag-binding domain in the context of the native protein under physiological conditions. Further advantageously, the tag is not immunogenic. This leads to minimization of the risk of uncontrolled on-target off-site toxicities by CAR-expressing immune cells like the release of toxic levels of cytokines, referred to variously as cytokine storms or cytokine release syndrome (CRS). In embodiments, the His-tag is an amino acid sequence consisting of histidine residues, preferably in the range of six to fourteen histidine residues.In embodiments, the targeting module comprisesi) at least one CD19-binding domain comprising one of the sequences selectedfrom SEQ ID No. 1 to SEQ ID No. 3 or a sequence identity of at least 95 %with one of the sequences selected from SEQ ID No. 1 to SEQ ID No. 3,ii) at least one CD20-binding domain comprising SEQ ID No.4, andiii) a tag-binding domain.In embodiments, the tag-binding domain is an antibody or antigen-binding fragment.In embodiments, the tag-binding domain is an antibody or an antigen-binding fragment binding toa myc-tag, a His-tag, a peptide sequence from yeast transcription factor GCN4, preferablyaccording to SEQ ID No. 18, SEQ ID No. 19 or mutants thereof; a leucine zipper sequence,preferably SYNZIP 1 to SYNZIP 48, BATF, FOS, ATF4, ATF3, BACH1, JUND, NFE2L3, HEPTAD(Reinke et al. 2010), a sequence according to SEQ ID No. 20 or SEQ ID No. 21 or mutantsthereof; or a peptide sequence from a human nuclear protein. In embodiments, the tag-bindingdomain is an antibody or an antigen-binding fragment binding to a myc-tag, a His-tag, a peptidesequence from yeast transcription factor GCN4 according to SEQ ID No. 18, SEQ ID No. 19, a leucine zipper sequence selected from SYNZIP 1 to SYNZIP 48, BATF, FOS, ATF4, ATF3,BACH1, JUND, NFE2L3, HEPTAD (Reinke et al.2010), a sequence according to SEQ ID No.20or SEQ ID No.21 or a peptide sequence from a human nuclear protein.In embodiments, the tag-binding domain is an antigen-binding fragment. In embodiments, the tag-binding domain is an scFv or a Fab fragment.In embodiments, the tag-binding domain is an scFv binding a La epitope. In embodiments, thetag-binding domain is an scFv binding La epitope 5B9 or 7B6 according to SEQ ID No.22 or SEQID No.24. In embodiments, VLand VHare connected via a glycine-serine linker with the structure (GxSy) with x and y selected from 1 to 10, preferably 3 to 5. Mostly preferred are 1 to 10 repeats of the sequence G4S1(SEQ ID No. 25). In embodiments, linkers are used that are constituted of a peptide sequence that can increase the protease resistance of the antibody derivatives. As usedherein, the term “linker” (also spacer) refers to a molecule or molecule part separating at leasttwo elements under consideration, in particular selected from functional groups, tags, bindingdomains or binding domain subunits, such as a VL and a VH domain.In embodiments, the linker comprises 20 to 30 amino acids, preferably 25 amino acids.In embodiments, the linker is an amino acid sequence according SEQ ID No. 26 or SEQ ID No.27. In embodiments, the tag-binding domain binding a human La epitope E5B9 comprises CDR sequences according to SEQ ID No.28, SEQ ID No.29, SEQ ID No.30, SEQ ID No.31, amino acid sequence WAS (Trp-Ala-Ser) and SEQ ID No.32.In embodiments, the tag-binding domain is an antibody or an antigen-binding fragment comprisinga VL according to the following sequence: DIVMTQSPDSLAVSLGERATINCX24SSQSLLNSRTX35KNYLAWYQQKPGQPPKLLIYWASTR X61SGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCKQSYNLX101TFGGGTKVElK (SEQ ID No.33), wherein X24, X35, X61 and X101 are independently from each other selected from aproteinogenic alpha-amino acid residue; or an amino acid sequence having at least 90 %sequence identity, preferably at least 95 % sequence identity; to sequence SEQ ID No. 34 orSEQ ID No.36.In some embodiments, X24 to X101 are selected as follows:X24is selected from polar and / or positive charged residues, such as Serine, Threonine, Asparagine, Glutamine, Histidine, Lysine and Arginine; preferably Lysine or Arginine; X35is preferably selected from Lysine and Proline; X61is selected from polar and charged residues, such as Asparagine, Aspartic Acid, Glutamine, Glutamic acid, Histidine, Lysine and Arginine, preferably Glutamic acid and Lysine; X101is selected from hydrophobic residues, such as Isoleucine, Leucine, Valine, Alanine, Methionine, Phenylalanine, Proline and Tryptophan; preferably Leucine or Proline.In embodiments, the tag-binding domain is an antibody or an antigen-binding fragment comprisinga VH with an amino acid sequence having at least 90 % sequence identity, preferably at least95 % sequence identity; to sequence SEQ ID No.35 or SEQ ID No. 37.In embodiments, the tag-binding domain comprises a sequence having each at least 90 %sequence identity, preferably at least 95 % sequence identity; to the sequences according to SEQID No.34 (VL) and SEQ ID No.35 (VH).In embodiments, the tag-binding domain is an anti-La 5B9 scFv according to SEQ ID No.34 (VL)and SEQ ID No. 35 (VH).In embodiments, the tag-binding domain comprises a sequence having each at least 90 %sequence identity, preferably at least 95 % sequence identity; to the sequences according to SEQID No.36 (VL) and SEQ ID No.37 (VH).In embodiments, the tag-binding domain is an anti-La 7B6 scFv according to SEQ ID No.36 (VL)and SEQ ID No. 37 (VH).In embodiments, the tag-binding domain comprises a VL-linker-VH structure, wherein the VL regionof the tag-binding domain comprises a sequence with at least 95 % identity, preferably 99 %identity, with the sequence according to SEQ ID No. 34 and / or the VH region of the tag-bindingdomain comprises a sequence with at least 95 % identity, preferably 99 % identity, with thesequence according to SEQ ID No. 35. As used herein, the term “VL-linker-VH structure” refers toa structure, wherein the C-terminus of the VL region is connected with a linker, which is connectedto the N-terminus of the VH region. In embodiments, the different domains of the targeting module are linked with each other by a linker. The linker comprises a short sequence of preferably 10 to 20 amino acid residues. In embodiments, the targeting module comprises a flexible peptide sequence that is selected such that the domains have a three-dimensional folding that allows them to exhibit the specificity for effector cell and target cell binding. Preferred linkers are glycine-serine linkers with the structure (GxSy) with x and y selected from 1 to 10, preferably 1 to 5. Mostly preferred are 1 to 10 repeats of the sequence G4S1(SEQ ID No.25). Moreover, linkers are preferred that are constituted of a peptide sequence that can increase the protease resistance of the antibody derivatives.In embodiments, the linker is SEQ ID No. 26 or SEQ ID No.27.In embodiments, the tag-binding domain is a Fab fragment binding a La epitope. In embodiments,the tag-binding domain is a Fab fragment binding La epitope 5B9 comprising an amino acidsequence according to SEQ ID No.38 and SEQ ID No.39.In embodiments, the targeting module comprises a further domain selected from the group comprising co-stimulatory ligands, radionuclides, cell death-inducing chemical compounds and half-life increasing domains, preferably IgG1 Fc, IgG2 Fc, IgG3 Fc, IgG4 Fc, HSA, FcRn-binding peptides or mutants thereof. As used herein, the term “mutants” refers to proteins having at least90 % sequence identity to the half-life increasing domain, preferably at least 95 % sequenceidentity. Advantageously, the mutant is capable of having one or more activities of the named peptides or proteins; in particular, the mutant increases the half-life like the half-life increasing domain.In embodiments, the tag-binding domain comprises at least one half-life increasing domain. Inembodiments, the tag-binding domain comprises at least one half-life increasing domain selectedfrom an amino acid sequence according to SEQ ID No.40 or SEQ ID No.41.In embodiments, the tag-binding domain comprises at least one leader peptide. As used herein,the term “leader peptide” (also signal peptide) refers to a short amino acid sequence at the N-terminus of proteins meant for secretion or membrane localization. In embodiments, the tag-binding domain comprises at least one leader peptide selected from an amino acid sequenceaccording to SEQ ID No.42 or SEQ ID No.43. In embodiments, the length of the targeting module is in the range of 200 to 1600 amino acids, preferably 600 to 1600 amino acids. In embodiments, the targeting module comprises three chains, wherein the length of the chains is independently from each other in the range of 200 to 550 amino acids.In embodiments, the targeting module comprises at least three chains comprising sequencesfrom the group comprising SEQ ID No. 44 to SEQ ID No.76.In embodiments, the targeting module comprises at least three chains comprising -one amino acid sequence selected from the group comprising SEQ ID No. 39, SEQID No. 46, SEQ ID No. 47, SEQ ID No. 72, SEQ ID No. 73, SEQ ID No. 74, SEQ IDNo. 75, and SEQ ID No.76, and- one amino acid sequence selected from the group comprising SEQ ID No. 44 andSEQ ID No. 45, and- one amino acid sequence selected from the group comprising SEQ ID No. 48, SEQID No. 49, SEQ ID No. 50, SEQ ID No. 51, SEQ ID No. 52, SEQ ID No. 53, SEQ IDNo. 54, SEQ ID No. 55, SEQ ID No. 56, SEQ ID No. 57, SEQ ID No. 58, SEQ ID No.59, SEQ ID No. 60, SEQ ID No. 61, SEQ ID No. 62, SEQ ID No. 63, SEQ ID No. 64,SEQ ID No.65, SEQ ID No.66, SEQ ID No.67, SEQ ID No.68, SEQ ID No.69, SEQID No.70, and SEQ ID No. 71.In embodiments, the targeting module comprises -SEQ ID No. 46, SEQ ID No.44 and SEQ ID No.48, or- SEQ ID No. 47, SEQ ID No.45 and SEQ ID No.49, or- SEQ ID No. 46, SEQ ID No.44 and SEQ ID No.50, or- SEQ ID No. 47, SEQ ID No.45 and SEQ ID No.51, or- SEQ ID No. 46, SEQ ID No.44 and SEQ ID No.52, or- SEQ ID No. 47, SEQ ID No.45 and SEQ ID No.53, or- SEQ ID No. 46, SEQ ID No.44 and SEQ ID No.54, or- SEQ ID No. 47, SEQ ID No.45 and SEQ ID No.55, or- SEQ ID No. 46, SEQ ID No.44 and SEQ ID No.56, or- SEQ ID No. 47, SEQ ID No.45 and SEQ ID No.57, or- SEQ ID No. 46, SEQ ID No.44 and SEQ ID No.58, or- SEQ ID No. 47, SEQ ID No.45 and SEQ ID No.59, or- SEQ ID No. 39, SEQ ID No.44 and SEQ ID No.60, or- SEQ ID No. 76, SEQ ID No.45 and SEQ ID No.61, or- SEQ ID No. 39, SEQ ID No.44 and SEQ ID No.62, or- SEQ ID No. 76, SEQ ID No.45 and SEQ ID No.63, or- SEQ ID No. 39, SEQ ID No.44 and SEQ ID No.64, or- SEQ ID No. 76, SEQ ID No.45 and SEQ ID No.65, or- SEQ ID No. 39, SEQ ID No.44 and SEQ ID No.66, or- SEQ ID No. 76, SEQ ID No.45 and SEQ ID No.67, or- SEQ ID No. 39, SEQ ID No.44 and SEQ ID No.68, or- SEQ ID No. 76, SEQ ID No.45 and SEQ ID No.69, or- SEQ ID No. 39, SEQ ID No.44 and SEQ ID No.70, or- SEQ ID No. 76, SEQ ID No.45 and SEQ ID No.71, or- SEQ ID No. 72, SEQ ID No.44 and SEQ ID No.54, or- SEQ ID No. 73, SEQ ID No.45 and SEQ ID No.55, or- SEQ ID No. 74, SEQ ID No.44 and SEQ ID No.54, or- SEQ ID No. 75, SEQ ID No.45 and SEQ ID No.55, or- SEQ ID No. 72, SEQ ID No.44 and SEQ ID No.56, or- SEQ ID No. 73, SEQ ID No.45 and SEQ ID No.57, or- SEQ ID No. 74, SEQ ID No.44 and SEQ ID No.56, or- SEQ ID No. 75, SEQ ID No.45 and SEQ ID No.57, or- SEQ ID No. 72, SEQ ID No.44 and SEQ ID No.58, or- SEQ ID No. 73, SEQ ID No.45 and SEQ ID No.59, or- SEQ ID No. 74, SEQ ID No.44 and SEQ ID No.58, or- SEQ ID No. 75, SEQ ID No.45 and SEQ ID No.59, or- SEQ ID No. 72, SEQ ID No.44 and SEQ ID No.48, or- SEQ ID No. 73, SEQ ID No.45 and SEQ ID No.49, or- SEQ ID No. 74, SEQ ID No.44 and SEQ ID No.48, or- SEQ ID No. 75, SEQ ID No.45 and SEQ ID No.49, or- SEQ ID No. 72, SEQ ID No.44 and SEQ ID No.50, or- SEQ ID No. 73, SEQ ID No.45 and SEQ ID No.51, or- SEQ ID No. 74, SEQ ID No.44 and SEQ ID No.50, or- SEQ ID No. 75, SEQ ID No.45 and SEQ ID No.51, or- SEQ ID No. 72, SEQ ID No.44 and SEQ ID No.52, or- SEQ ID No. 73, SEQ ID No.45 and SEQ ID No.53, or- SEQ ID No. 74, SEQ ID No.44 and SEQ ID No.52, or- SEQ ID No. 75, SEQ ID No.45 and SEQ ID No.53.In a further aspect, the invention is a nucleic acid, a vector or a cell comprising a nucleotidesequence encoding a targeting module according to the invention.In embodiments, the nucleic acid, vector or cell comprises at least three nucleic acid sequencesencoding one of the sequences according to SEQ ID No.44 to SEQ ID No.76.In embodiments, the nucleic acid, vector or cell comprises at least three nucleic acid sequencesencoding -one amino acid sequence selected from the group comprising SEQ ID No. 39, SEQID No.46, SEQ ID No.47, SEQ ID No.72, SEQ ID No.73, SEQ ID No.74, SEQ ID No.75, and SEQ ID No.76, and -one amino acid sequence selected from the group comprising SEQ ID No. 44 andSEQ ID No. 45, and- one amino acid sequence selected from the group comprising SEQ ID No. 48, SEQID No. 49, SEQ ID No. 50, SEQ ID No. 51, SEQ ID No. 52, SEQ ID No. 53, SEQ IDNo. 54, SEQ ID No. 55, SEQ ID No. 56, SEQ ID No. 57, SEQ ID No. 58, SEQ ID No.59, SEQ ID No. 60, SEQ ID No. 61, SEQ ID No. 62, SEQ ID No. 63, SEQ ID No. 64,SEQ ID No.65, SEQ ID No.66, SEQ ID No.67, SEQ ID No.68, SEQ ID No.69, SEQID No.70, and SEQ ID No. 71.In embodiments, the nucleic acid, vector or cell comprises at least three nucleic acid sequencesencoding SEQ ID No.46, SEQ ID No.44 and SEQ ID No.48, or- SEQ ID No. 47, SEQ ID No.45 and SEQ ID No.49, or- SEQ ID No. 46, SEQ ID No.44 and SEQ ID No.50, or- SEQ ID No. 47, SEQ ID No.45 and SEQ ID No.51, or- SEQ ID No. 46, SEQ ID No.44 and SEQ ID No.52, or- SEQ ID No. 47, SEQ ID No.45 and SEQ ID No.53, or- SEQ ID No. 46, SEQ ID No.44 and SEQ ID No.54, or- SEQ ID No. 47, SEQ ID No.45 and SEQ ID No.55, or- SEQ ID No. 46, SEQ ID No.44 and SEQ ID No.56, or- SEQ ID No. 47, SEQ ID No.45 and SEQ ID No.57, or- SEQ ID No. 46, SEQ ID No.44 and SEQ ID No.58, or- SEQ ID No. 47, SEQ ID No.45 and SEQ ID No.59, or- SEQ ID No. 39, SEQ ID No.44 and SEQ ID No.60, or- SEQ ID No. 76, SEQ ID No.45 and SEQ ID No.61, or- SEQ ID No. 39, SEQ ID No.44 and SEQ ID No.62, or- SEQ ID No. 76, SEQ ID No.45 and SEQ ID No.63, or- SEQ ID No. 39, SEQ ID No.44 and SEQ ID No.64, or- SEQ ID No. 76, SEQ ID No.45 and SEQ ID No.65, or- SEQ ID No. 39, SEQ ID No.44 and SEQ ID No.66, or- SEQ ID No. 76, SEQ ID No.45 and SEQ ID No.67, or- SEQ ID No. 39, SEQ ID No.44 and SEQ ID No.68, or- SEQ ID No. 76, SEQ ID No.45 and SEQ ID No.69, or- SEQ ID No. 39, SEQ ID No.44 and SEQ ID No.70, or- SEQ ID No. 76, SEQ ID No.45 and SEQ ID No.71, or- SEQ ID No. 72, SEQ ID No.44 and SEQ ID No.54, or- SEQ ID No. 73, SEQ ID No.45 and SEQ ID No.55, or- SEQ ID No. 74, SEQ ID No.44 and SEQ ID No.54, or- SEQ ID No. 75, SEQ ID No.45 and SEQ ID No.55, or- SEQ ID No. 72, SEQ ID No.44 and SEQ ID No.56, or- SEQ ID No. 73, SEQ ID No.45 and SEQ ID No.57, or- SEQ ID No. 74, SEQ ID No.44 and SEQ ID No.56, or- SEQ ID No. 75, SEQ ID No.45 and SEQ ID No.57, or- SEQ ID No. 72, SEQ ID No.44 and SEQ ID No.58, or- SEQ ID No. 73, SEQ ID No.45 and SEQ ID No.59, or- SEQ ID No. 74, SEQ ID No.44 and SEQ ID No.58, or- SEQ ID No. 75, SEQ ID No.45 and SEQ ID No.59, or- SEQ ID No. 72, SEQ ID No.44 and SEQ ID No.48, or- SEQ ID No. 73, SEQ ID No.45 and SEQ ID No.49, or- SEQ ID No. 74, SEQ ID No.44 and SEQ ID No.48, or- SEQ ID No. 75, SEQ ID No.45 and SEQ ID No.49, or- SEQ ID No. 72, SEQ ID No.44 and SEQ ID No.50, or- SEQ ID No. 73, SEQ ID No.45 and SEQ ID No.51, or- SEQ ID No. 74, SEQ ID No.44 and SEQ ID No.50, or- SEQ ID No. 75, SEQ ID No.45 and SEQ ID No.51, or- SEQ ID No. 72, SEQ ID No.44 and SEQ ID No.52, or- SEQ ID No. 73, SEQ ID No.45 and SEQ ID No.53, or- SEQ ID No. 74, SEQ ID No.44 and SEQ ID No.52, or- SEQ ID No. 75, SEQ ID No.45 and SEQ ID No.53.According to the invention, the nucleic acid, vector and / or cell are isolated. In embodiments, the nucleic acid is a cDNA. As used herein, the term “cDNA” (complementary DNA) refers to double-stranded DNA synthesized from a single-stranded RNA, e.g. mRNA, in a reaction catalyzed by the enzyme reverse transcriptase. In embodiments, cDNA is of synthetic origin. In further embodiments, cDNA is derived from mRNA, therefore containing only exons but no introns, as opposed to genomic DNA. The vector is preferably a plasmid, an artificial chromosome, linearized DNA or RNA, a virus particle or another vector that contains an expression cassette that is incorporated stably into the genome of a host cell or host organism. In embodiments, the cell is selected from immune cells, preferably with cytolytic, phagocytic or immunosuppressive activity, such as T cells, Natural Killer (NK) cells and macrophages. In preferred embodiments, the cell is selected from T cells, including alpha / beta and gamma / delta T cells or subpopulations of T cells like stem-cell memory T cells or central memory T cells, cytotoxic T cells or NK cells. Another aspect of the invention is the use of the targeting module in the treatment of cancer, infectious disease or autoimmune disease,wherein the targeting module is administered in combination with a cell comprising a nucleotidesequence encoding a switchable chimeric antigen receptor, wherein the switchable chimericantigen receptor comprises -a tag-binding domain or a tag,- an extracellular hinge and a transmembrane domain and- a signal transduction domain,wherein the tag-binding domain of the targeting module binds to the tag of the switchable chimeric antigen receptor or the tag of the targeting module binds to the tag-binding domain of the switchable chimeric antigen receptor. The term “autoimmune disorder” refers to an abnormal immune response of the body against substances and tissues normally present in the body (autoimmunity).As used herein, the term “switchable chimeric antigen receptor” refers to an artificial chimericfusion protein, in particular a receptor comprising a tag-binding domain or a tag, an extracellular hinge and a transmembrane domain and a signal transduction domain. The domains can be derived from different sources and therefore, the receptor is called chimeric. Advantageously, thereceptor can bind with the tag-binding domain or tag to different targeting modules. Advantageously, the cell comprising a nucleotide sequence encoding a switchable CAR expresses the switchable CAR, which has binding specificity for the tag or tag-binding domain ofthe targeting module, which in turn binds to CD19 and CD20 on a target cell.As used herein, the term “administered in combination” refers to a treatment, wherein the targeting module is administered prior to, simultaneously with and / or after the administration of the cellcomprising a nucleotide sequence encoding a switchable chimeric antigen receptor (CAR).In embodiments, the targeting module is administered on its own, preferably one hour to 2 days, more preferably 4 to 24 hours, prior to the administration of the cell comprising a nucleotide sequence encoding a switchable CAR. Advantageously, the administration of the targeting module prior to the administration of the cell comprising a nucleotide sequence encoding a switchable CAR stimulates the switchable CAR and increases the expansion of the switchable CAR carrying effector cells and their accumulation at the target site. In embodiments, the targeting module is administered simultaneously with the cell comprising a nucleotide sequence encoding a switchable CAR.In embodiments, the targeting module is administered until, preferably in the range of 3 days to30 days, after the administration of the cell comprising a nucleotide sequence encoding aswitchable CAR. In embodiments, additional such doses of the targeting module may be administered following resting periods to reactivate the switchable CAR-carrying effector cells.In embodiments, the targeting module is used in the treatment of cancer. In embodiments, thetargeting module is used in the treatment of tumors of the hematopoietic and lymphoid tissues. Inembodiments, the targeting module is used in the treatment of blood cancer. In embodiments, thetargeting module is used in the treatment of b cell lymphomas.In embodiments, the targeting module is administered in combination with a cell comprising anucleotide sequence encoding a switchable chimeric antigen receptor and at least one further targeting module,wherein the at least one further targeting module comprises at least one target cell-bindingdomain and a tag-binding domain or a tag, wherein the at least one target cell-binding domain is an antibody, antibody fragment, a protein,a peptide or a low molecular weight organic ligand that binds to a surface antigen selected fromthe group comprising CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD15, CD22, CD23, CD25, CD30, CD33, CD38, CD44, CD44v6, CD52, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD90, CD99, CD123, CD133, CD135, CD150, CD181, CD182, CD184, CD223, CD229, CD269, CD273, CD274, CD276, CD279, CD319, CD366, CD371, cytokine receptors, CXCR4, c-Met, mesothelin, a member of the epidermal growth factor receptor family or a mutant thereof, a member of the tumor necrosis factor receptor superfamily, a claudin, an ephrin, an ephrin receptor, a fucosyltransferase, a prostate specific antigen, an embryonic antigen, a member of the vascularendothelia growth factor family, epithelial cell adhesion molecule, alpha-fetoprotein, a member of the intercellular adhesion molecule family, a C-type lectin, an integrin, a member of the mucin protein family, a follicle-stimulating hormone receptor, a high molecular weight-melanoma associated antigen, a folate binding protein, a folate receptor, a somatostatin receptor, a ligand of the NKG2D receptor, a member of the epithelia glycoprotein family, a diasialoganglioside, a glypican, a G protein-coupled receptor, a human papillomavirus protein, cancer / testis antigen, fibroblast activation protein, a member of the carbonic anhydrase family, a member of the carbohydrate antigen family, a Notch ligand, melanoma-associated chondroitin sulfate proteoglycan, glycoprotein A33, guanylate cyclase 2C and tumor-specific glycan, wherein the targeting module and the at least one further targeting module comprise different target cell-binding domains, and identical tag-binding domains or tags.In embodiments, the at least one target cell-binding domain is an antibody, antibody fragment, aprotein, a peptide or a low molecular weight organic ligand that binds to a surface antigen selectedfrom the group comprising CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD15, CD22, CD23, CD25, CD30, CD33, CD38, CD44, CD44v6, CD52, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD90, CD99, CD123, CD133, CD135, CD150, CD181, CD182, CD184, CD223, CD229, CD269, CD273, CD274, CD276, CD279, CD319, CD366, CD371, cytokine receptors, CXCR4, c-Met, mesothelin, a member of the epidermal growth factor receptor family, a member of the tumor necrosis factor receptor superfamily, a claudin, an ephrin, an ephrin receptor, a fucosyl transferase, a prostate specific antigen, an embryonic antigen, a member of the vascular endothelia growth factor family, epithelial cell adhesion molecule, alpha-fetoprotein, a member of the intercellular adhesion molecule family, a C-type lectin, an integrin, a member of the mucin protein family, a follicle-stimulating hormone receptor, a high molecular weight-melanoma associated antigen, a folate binding protein, a folate receptor, a somatostatin receptor, a ligand of the NKG2D receptor, a member of the epithelia glycoprotein family, a diasialoganglioside, a glypican, a G protein-coupled receptor, a human papillomavirus protein, cancer / testis antigen, fibroblast activation protein, a member of the carbonic anhydrase family, a member of the carbohydrate antigen family, a Notch ligand, melanoma-associated chondroitin sulfate proteoglycan, glycoprotein A33, guanylate cyclase 2C and tumor-specific glycan. As used herein, the term “target cell-binding domain” refers to a peptide, protein, or low molecular weight organic ligand, which specifically binds a protein or protein complex (antigen) on thesurface of a target cell, in particular a cancer cell, T cell, infected cell, pathogens or parasites.As used herein, the terms “peptide”, “polypeptide” and “protein” are used interchangeably and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprise a protein’s or peptide’s sequence. As used herein, the term “low molecular weight organic ligand” refers to an organic molecule with a molecular weight of maximal 10 kilodaltons, preferably of maximal 3 kilodaltons, which specifically binds a protein or protein complex (antigen) on the surface of a target cell, preferably a cancer cell, T cell, infected cell or pathogens or parasites. The term “target cell-binding domain” also comprises soluble T cell receptors, which are composed of the alpha and beta or the gamma and delta chains of a T cell receptor (TCR), fragments or mutants thereof. Such TCR-derived binding moieties recognize and bind to peptides presented by human leukocyte antigen class (HLA) I and II protein complexes. Examples are, but are not limited to, TCRs specific for peptides derived from proteins like EGFR family, survivin, sry- like high motility group box (SOX) protein family, melanoma-associated antigens (e.g. autoimmunogenic cancer / testis antigen NY-ESO-1, members of the melanoma antigen family AMAGEA, the preferentially expressed antigen in melanoma PRAME), and leukemia-associated antigens (e.g. Wilms tumor gene 1 WT1). In embodiments, the target cell-binding domain is a soluble T cell receptor consisting of the alpha and beta or the gamma and delta chain of a T cell receptor (TCR).In embodiments, the targeting module according to the invention is used in combination with thevector or cell comprising a nucleotide sequence encoding a switchable chimeric antigen receptor for the manufacture of a medicament for the treatment of cancer, infectious disease or autoimmune disease.In embodiments, the targeting module according to the invention is used in a method for treatmentcancer, infectious disease or autoimmune disease in a subject in need thereof,wherein the targeting module is administered in combination with a cell comprising a nucleotidesequence encoding a switchable chimeric antigen receptor, wherein the switchable chimeric antigen receptor comprises -a tag-binding domain or a tag,- an extracellular hinge and a transmembrane domain and- a signal transduction domain,wherein the tag-binding domain of the targeting module binds to the tag of the switchable chimeric antigen receptor or the tag of the targeting module binds to the tag-binding domain of the switchable chimeric antigen receptor. Another aspect of the invention is a pharmaceutical composition comprising the targeting module and a pharmaceutically acceptable thinner or carrier. In embodiments, the pharmaceutical composition is administered parenterally, particularly intravenously. In embodiments, the pharmaceutical composition is present in a form suitable forintravenous administration. In embodiments, the pharmaceutical composition is a solution,emulsion or suspension. In embodiments, the pharmaceutical composition is an injectable buffered solution comprising a concentration in the range of 1 ng / ml to 500 mg / ml of the targeting module. In embodiments, thepharmaceutical composition comprises a concentration in the range of 50 µg / ml to 5 mg / ml of thetargeting module. The pharmaceutical composition comprises a pharmaceutically acceptable thinner (dilution agent) or carrier. In embodiments, the carrier is selected from water, an aqueous buffer solution, 0.9 % saline solution, 5 % glucose, 5 % xylitol, 0.3 % glycine solution, ringer solutions or amino acid solutions. In embodiments, the aqueous buffer solution is selected from an aqueous histidine,sodium succinate, sodium citrate, sodium acetate, sodium phosphate or potassium phosphate-buffered solution with a pH value in the range of pH 5.0 to pH 7.0. In embodiments, the aqueousbuffer solution has a buffer concentration in the range of 1 mmol / l (mM) to 500 mM. In embodiments, the aqueous buffer solution has a buffer concentration in the range of 5 mM to20 mM. In embodiments, the aqueous buffer solution has a buffer concentration in the range of 5mM to 10 mM. In embodiments, the carrier comprises sodium chloride. In embodiments, the carrier comprises sodium chloride with a concentration in the range of 1 mM to 300 mM. In embodiments, the carrier comprises sodium chloride with a concentration of about 150 mM. In embodiments, the pharmaceutical composition comprises a stabilizer. In embodiments, the pharmaceutical composition comprises a stabilizer with a concentration in the range of 1 mM to 900 mM. In embodiments, the pharmaceutical composition comprises a stabilizer with a concentration in the range of 50 mM and 600 mM. In embodiments, the stabilizer is sucrose, trehalose or L-methionine. In embodiments, the pharmaceutical composition comprises pharmaceutically acceptable excipients. The term “pharmaceutically acceptable excipients” refers to compounds, whichprovide approximately physiological conditions and / or increase the stability, such as agents foradjusting the pH value and buffering agents, agents for adjusting the toxicity and the like. In embodiments, pharmaceutically acceptable excipients are selected from sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and polysorbate-80, preferably polysorbate-80 in the range of 0.0001 % (w / v) to 1 % (w / v). In embodiments, the pharmaceutically acceptable excipient is in the range of 0.001 % (w / v) to 0.1 % (w / v). In embodiments, the pharmaceutical composition comprises the targeting module in a dosage quantity in the range of 25 µg / day to 100 mg / day. In embodiments, the pharmaceutical composition comprises the targeting module in a dosage quantity in the range of 0.1 mg / day to 20 mg / day. In embodiments, the pharmaceutical composition is sterile. In embodiments, the pharmaceutical composition sterilized by conventional well-known techniques including, but not limited to, sterile filtration. In embodiments, the pharmaceutical composition is used for administration to a subject. In embodiments, the pharmaceutical composition is lyophilized prior to storage or stored as solution at ambient temperature or below, including, but not limited to, frozen storage. In embodiments, the pharmaceutical composition is reconstituted and / or diluted in an infusion and stabilizer solution prior to administration to a subject. The solutions used for reconstitution or infusion / stabilization may contain any of the components mentioned for the pharmaceutical composition or similar components. In embodiments, the pharmaceutical composition comprises a cell comprising a nucleotide sequence encoding a switchable chimeric antigen receptor, wherein the switchable chimeric antigen receptor comprises - a tag-binding domain or a tag, -an extracellular hinge and a transmembrane domain and- a signal transduction domain,wherein the tag-binding domain of the targeting module binds to the tag of the switchable chimeric antigen receptor or the tag of the targeting module binds to the tag-binding domain of the switchable chimeric antigen receptor.In embodiments, the pharmaceutical composition comprises at least one further targeting module,wherein the at least one further targeting module comprises at least one target cell-binding domain and a tag-binding domain or a tag, wherein the at least one target cell-binding domain is an antibody, antibody fragment, a protein,a peptide or a low molecular weight organic ligand that binds to surface antigens selected fromthe group comprising CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD15, CD22, CD23, CD25, CD30, CD33, CD38, CD44, CD44v6, CD52, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD90, CD99, CD123, CD133, CD135, CD150, CD181, CD182, CD184, CD223, CD229, CD269, CD273,CD274, CD276, CD279, CD319, CD366, CD371, cytokine receptors, CXCR4, c-Met, mesothelin,a member of the epidermal growth factor receptor family or a mutant thereof, a member of the tumor necrosis factor receptor superfamily, a claudin, an ephrin, an ephrin receptor, a fucosyl transferase, a prostate specific antigen, an embryonic antigen, a member of the vascular endothelia growth factor family, epithelial cell adhesion molecule, alpha-fetoprotein, a member of the intercellular adhesion molecule family, a C-type lectin, an integrin, a member of the mucin protein family, a follicle-stimulating hormone receptor, a high molecular weight-melanoma associated antigen, a folate binding protein, a folate receptor, a somatostatin receptor, a ligand of the NKG2D receptor, a member of the epithelia glycoprotein family, a diasialoganglioside, a glypican, a G protein-coupled receptor, a human papillomavirus protein, cancer / testis antigen, fibroblast activation protein, a member of the carbonic anhydrase family, a member of the carbohydrate antigen family, a Notch ligand, melanoma-associated chondroitin sulfate proteoglycan, glycoprotein A33, guanylate cyclase 2C and tumor-specific glycan, wherein the targeting module and the at least one further targeting module comprise different target cell-binding domains, and identical tag-binding domains or tags. In embodiments, the at least one target cell-binding domain is an antibody, antibody fragment, aprotein, a peptide or a low molecular weight organic ligand that binds to surface antigens selectedfrom the group comprising CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD15, CD22, CD23, CD25, CD30, CD33, CD38, CD44, CD44v6, CD52, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD90, CD99, CD123, CD133, CD135, CD150, CD181, CD182, CD184, CD223, CD229, CD269, CD273, CD274, CD276, CD279, CD319, CD366, CD371, cytokine receptors, CXCR4, c-Met, mesothelin, a member of the epidermal growth factor receptor family, a member of the tumor necrosis factor receptor superfamily, a claudin, an ephrin, an ephrin receptor, a fucosyl transferase, a prostate specific antigen, an embryonic antigen, a member of the vascular endothelia growth factor family, epithelial cell adhesion molecule, alpha-fetoprotein, a member of the intercellular adhesion molecule family, a C-type lectin, an integrin, a member of the mucin protein family, a follicle-stimulating hormone receptor, a high molecular weight-melanoma associated antigen, a folate binding protein, a folate receptor, a somatostatin receptor, a ligand of the NKG2D receptor, a member of the epithelia glycoprotein family, a diasialoganglioside, a glypican, a G protein-coupled receptor, a human papillomavirus protein, cancer / testis antigen, fibroblast activation protein, a member of the carbonic anhydrase family, a member of the carbohydrate antigen family, a Notch ligand, melanoma-associated chondroitin sulfate proteoglycan, glycoprotein A33, guanylate cyclase 2C and tumor-specific glycanIn embodiments, the pharmaceutical composition is used in a method for treatment of cancer,infectious disease or autoimmune disease.Another aspect of the invention is kit comprisinga) a targeting module comprisingi) at least one CD19-binding domain comprising one of the sequences selectedfrom SEQ ID No.1 to SEQ ID No.3 or a sequence identity of at least 95 % withone of the sequences selected from SEQ ID No. 1 to SEQ ID No.3,ii) at least one CD20-binding domain comprising one of the sequences selectedfrom SEQ ID No.4 to SEQ ID No.6 or with a sequence identity of at least 95 %with one of the sequences selected from SEQ ID No. 4 to SEQ ID No. 6, andiii) a tag-binding domain or a tag, andb) a vector or a cell comprising a nucleotide sequence encoding a switchable chimericantigen receptor, wherein the switchable chimeric antigen receptor comprises -a tag-binding domain or tag,- an extracellular hinge and a transmembrane domain and- a signal transduction domain,wherein the tag-binding domain of the targeting module binds to the tag of the switchable chimericantigen receptor or the tag of the targeting module binds to the tag-binding domain of theswitchable chimeric antigen receptor. In embodiments, the switchable CAR is a reversible universal chimeric antigen receptor(RevCAR). In embodiments, the kit comprises a vector or a cell comprising a nucleotide sequenceencoding a RevCAR, comprising a tag, an extracellular hinge and a transmembrane domain and a signal transduction domain, wherein the tag-binding domain of the targeting module binds to the tag of the RevCAR. In embodiments, the tag-binding domain or tag is present at the amino-terminal end of the polypeptide that comprises the switchable CAR. Advantageously, locating the tag-binding domain or the tag at the amino terminus permits unhampered access to the targeting module that is bound to the target cell. In embodiments, the RevCAR comprises a tag present at the amino-terminal end of the polypeptide that comprises the switchable CAR. As used herein, the term “extracellular hinge and a transmembrane domain” refers to a flexible peptide sequence connected to the tag-binding domain or tag, which anchors the switchable CAR into the cell membrane of the cell and protrudes from the surface of the cell for optimal binding to its particular targeting module. In embodiments, the extracellular hinge and a transmembrane domain is selected from the group comprising a hinge and transmembrane domain of human CD8α, CD28, ICOS (CD278), parts of a NK cell receptor, parts of the constant region of an antibody or mutants and combinationsthereof. In embodiments, the extracellular hinge and a transmembrane domain is selected fromthe group comprising a hinge and transmembrane domain of human CD8α, CD28, ICOS (CD278), parts of a NK cell receptor, parts of the constant region of an antibody and combinationsthereof. As used herein, the term “combinations thereof” refers to combinations of the differenthinge and transmembrane domains. In embodiments, the extracellular hinge domain is selected from the group comprising a hingedomain of human CD8α according to SEQ ID No. 138 or SEQ ID No. 139, CD28 according toSEQ ID No.140 or SEQ ID No.141, IgG1 according to SEQ ID No.143, IgG2 according to SEQID No. 144 and IgG4 according to SEQ ID No. 142 or mutants thereof. In embodiments, theextracellular hinge domain is selected from the group comprising a hinge domain of human CD8αaccording to SEQ ID No.138 or SEQ ID No.139, CD28 according to SEQ ID No. 140 or SEQ IDNo. 141, IgG1 according to SEQ ID No. 143, IgG2 according to SEQ ID No. 144 and IgG4 according to SEQ ID No.142.In embodiments, the transmembrane domain is selected from the group comprising atransmembrane domain of human CD8α according to SEQ ID No. 145, CD28 according to SEQID No. 146, ICOS (CD278) according to SEQ ID No. 147 and CD4 according to SEQ ID No. 148or mutants thereof. In embodiments, the transmembrane domain is selected from the groupcomprising a transmembrane domain of human CD8α according to SEQ ID No. 145, CD28according to SEQ ID No.146, ICOS (CD278) according to SEQ ID No.147 and CD4 according to SEQ ID No.148. Pinthus et al. and Cartellieri et al. describe the use of hinge and transmembrane domains of the human CD28 molecule in CARs (Pinthus et al.2003, Cartellieri et al.2016).Milone et al. describes the use of hinge and transmembrane domains of human CD8α moleculein CARs (Milone et al.2009). Zhang et al. describe the use of hinge and transmembrane domains of NKG2D in CARs (Zhang et al.2005).Frigault et al. describes the use of hinge and transmembrane domains of parts of the constantregion of immunoglobulin G1 (IgG) and the use of hinge domains of the constant region of IgG4 (Frigault et al.2015). Examples of combinations of the extracellular hinge and transmembrane domain are, but are not limited to, CD28 extracellular hinge and transmembrane domain, CD8alpha extracellular hinge and transmembrane domain, IgG1 or IgG4 constant regions combined with CD28 or CD137 transmembrane domain. In embodiments, the extracellular hinge and a transmembrane domain is selected from the group comprising a hinge and transmembrane domain of human CD8α, CD28, ICOS (CD278) and combinations thereof. As used herein, the term “signal transduction domain” refers to a peptide sequence whichtransmits a signal into the cell by cross-linkage of the cell expressing the switchable CAR (effector cell) to a human cell surface protein or protein complex (target cell). Cross-linkage between effector and target cell is mediated by the targeting module.In embodiments, the signal transduction domain comprises at least two signal transductiondomains independently selected from a cytoplasmic region of a CD3 chain, CD28, CD137 (4- 1BB), CD134 (OX40), CD278 (ICOS), DAP10, CD27, programmed cell death-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), DAP12, CD122 (interleukin-2 receptor β), CD132 (interleukin- 2 receptor γ), CD127 (interleukin-7 receptor α), CD360 (interleukin-21 receptor), an activating Fc receptor and mutants thereof.As used herein, the term “mutants” refers to proteins having at least 90 % sequence identity tothe signal transduction domains, preferably at least 95 % sequence identity. Advantageously, the mutant transmits a signal into the cell by cross-linkage of the cell expressing the switchable CAR (effector cell) to a human cell surface protein or protein complex (target cell) in the same way as the named signal transduction domains. In embodiments, mutants are truncated versions. As used herein, the term “truncated versions” refers to shortened proteins having at least 90 % sequence identity to the signal transduction domains, preferably at least 95 % sequence identity, more preferably having a chain length of at least 90 % and a sequence identity of 100 %, most preferably a chain length of at least 95 % and a sequence identity of 100 %. Advantageously, the truncated version has an activity of at least80 %, preferably of at least 90 %, more preferably of at least 95 %; of the named signaltransduction domains.In embodiments, the signal transduction domain comprises at least two signal transductiondomains independently selected from a cytoplasmic region of a CD3 chain according to SEQ IDNo. 149, CD28 according to SEQ ID No. 151 or SEQ ID No. 152, CD137 (4-1BB) according toSEQ ID No.154, CD134 (OX40) according to SEQ ID No.153, CD278 (ICOS) according to SEQID No. 155, DAP10 according to SEQ ID No. 156, CD27 according to SEQ ID No. 150,programmed cell death-1 (PD-1) according to SEQ ID No.158, cytotoxic T-lymphocyte antigen 4(CTLA-4) according to SEQ ID No. 159, DAP12 according to SEQ ID No. 157 and CD122(interleukin-2 receptor β) or mutants thereof. In embodiments, the signal transduction domaincomprises at least two signal transduction domains independently selected from a cytoplasmicregion of a CD3 chain according to SEQ ID No.149, CD28 according to SEQ ID No.151 or SEQID No. 152, CD137 (4-1BB) according to SEQ ID No. 154, CD134 (OX40) according to SEQ IDNo. 153, CD278 (ICOS) according to SEQ ID No. 155, DAP10 according to SEQ ID No. 156,CD27 according to SEQ ID No. 150, programmed cell death-1 (PD-1) according to SEQ ID No.158, cytotoxic T-lymphocyte antigen 4 (CTLA-4) according to SEQ ID No.159, DAP12 accordingto SEQ ID No. 157 and CD122 (interleukin-2 receptor β).Hombach et al. describes the use of cytoplasmic regions of CD28 as signal transduction domainin CARs (Hombach et al. 2001). Guedan et al. describes the use of a mutant of cytoplasmic regions of CD28 as signal transduction domain (Guedan et al.2020).Finney et al. describes the use of cytoplasmic regions of CD137 (4-1BB) and of CD134 (OX40)as signal transduction domain (Finney et al.2004). Guedan et al. describes the use of cytoplasmic regions of CD278 (ICOS) as signal transduction domain (Guedan et al.2018). Zhang et al. describes the use of DAP10 as signal transduction domain (Zhang et al.2005). Fedorov et al. describes the use of programmed cell death 1 (PD-1) and of cytotoxic T-lymphocyte antigen 4 (CTLA-4) as signal transduction domain in CARs (Fedorov et al.2013). Gong et al. describes the use of cytoplasmic regions of CD3 chains, in particular the CD3ζ chain, as signal transduction domain in CARs (Gong et al.1999). Töpfer et al. describes the use of DAP12 as signal transduction domain in CARs (Töpfer et al. 2015). Kagoya et al. describes the use of signaling chains or motifs derived from interleukin receptors as signal transduction domain in CARs (Kagoya et al.2018). Lamers et al. describes the use of activating Fc receptors, in particular the Fc epsilon receptor γ chain, as signal transduction domain (Lamers et al.2004).In embodiments, the signal transduction domain comprises at least two signal transductiondomains independently selected from a cytoplasmic region of a CD3 chain, CD28, CD137 (4- 1BB), CD134 (OX40), CD278 (ICOS), DAP10, CD27, programmed cell death-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), DAP12, CD122 (interleukin-2 receptor β), CD132 (interleukin-2 receptor γ), CD127 (interleukin-7 receptor α), CD360 (interleukin-21 receptor) and an activatingFc receptor. In embodiments, the signal transduction domain comprises at least two signaltransduction domains independently selected from a cytoplasmic region of a CD3 chain, CD28, CD137 (4-1BB), CD134 (OX40), CD278 (ICOS), DAP10, CD27, programmed cell death-1 (PD- 1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), DAP12, CD122 (interleukin-2 receptor β), CD132(interleukin-2 receptor γ), CD127 (interleukin-7 receptor α) and CD360 (interleukin-21 receptor).In embodiments, the switchable chimeric antigen receptor comprises two, three or four signaltransduction domains independently selected from a cytoplasmic region of a CD3 chain, CD28, CD137 (4-1BB), CD134 (OX40), CD278 (ICOS), DAP10, CD27, programmed cell death-1 (PD- 1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), DAP12, CD122 (interleukin-2 receptor β), CD132 (interleukin-2 receptor γ), CD127 (interleukin-7 receptor α), CD360 (interleukin-21 receptor) and an activating Fc receptor. In further embodiments, the switchable CAR comprises a fourth domain, wherein the fourth domain is a short peptide linker in the extracellular portion of the receptor that may serve to detect the chimeric antigen receptor on the cell surface or stimulate the chimeric antigen receptor T cell. Advantageously, the switchable CAR engrafted cells with the fourth domain can be specifically stimulated to proliferate preferentially and persist longer compared to non-engrafted cells eitherin vitro or in vivo. Further advantageously, the fourth domain may be also used to purify switchableCAR engrafted cells from mixed cell populations or to dampen switchable CAR engrafted cell-mediated immune response and to eliminate switchable CAR engrafted cells in vivo. Inembodiments, the fourth domain comprises at least one linear epitope, preferably E7B6 accordingto SEQ ID No. 23 or SEQ ID No. 24.In embodiments, the fourth domain is located in between the tag-binding domain or the tag and the extracellular hinge domain or an integral part of the extracellular hinge domain. In further embodiments, the switchable CAR comprises a signal peptide. Advantageously, the signal peptide allows for expression on the cell surface of an effector cell. In embodiments, the signal peptide is located at the N-terminus of the switchable CAR nucleotide sequence in front of the tag-binding domain or the tag. In embodiments, the signal peptide targets proteins to the secretory pathway either co-translationally or post-translationally. In embodiments, the signalpeptide is a human signal peptide selected from CD8α, CSF2Rα, CD28, IL-2, lysozyme C, aheavy chain of an antibody, a light chain of an antibody or a part of a light chain of an antibody.In embodiments, the switchable chimeric antigen receptor comprises an amino acid sequenceaccording to SEQ ID No. 77 to SEQ ID No. 107.In embodiments, the nucleotide sequence encoding a switchable chimeric antigen receptorcomprises a nucleotide sequence according to SEQ ID No.108 to SEQ ID No. 137.According to the invention, the vector and / or cell are isolated. In embodiments, the vector is a plasmid, an artificial chromosome, linearized DNA or RNA, a virus particle or another vector that contains an expression cassette that is incorporated stably into the genome of a host cell or host organism. In embodiments, the cell is selected from immune cells, preferably with cytolytic, phagocytic or immunosuppressive activity, such as T cells, Natural Killer (NK) cells and macrophages. Inembodiments, the cell is selected from T cells, including alpha / beta and gamma / delta T cells orsubpopulations of T cells like stem-cell memory T cells or central memory T cells, cytotoxic T cells or NK cells. In embodiments, the vector or cell further comprises an inducible expression system. In some embodiments, the inducible expression system is based on a prokaryotic operon, including, but not limited to, the lac operon, transposon Tn10 or tetracycline operon. In other embodiments, the inducible expression system is based on components of a eukaryotic signaling pathway, including, but not limited to, expression systems based on a steroid receptor, an estrogen receptor, progesterone or metallothionein. In embodiments, the inducible expression system induces the transcription of the nucleotide sequence encoding a switchable CAR and / or a nucleotide sequence encoding a targeting module according to the invention, preferably the inducible expression system induces the transcription of the nucleotide sequence encoding a targeting module according to the invention.In embodiments, the kit further comprises at least one further targeting module,wherein the at least one further targeting module comprises at least one target cell-binding domain and a tag-binding domain or a tag, wherein the at least one target cell-binding domain is an antibody, antibody fragment, a protein,a peptide or a low molecular weight organic ligand that binds to surface antigens selected fromthe group comprising CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD15, CD22, CD23, CD25, CD30, CD33, CD38, CD44, CD44v6, CD52, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD90, CD99, CD123, CD133, CD135, CD150, CD181, CD182, CD184, CD223, CD229, CD269, CD273, CD274, CD276, CD279, CD319, CD366, CD371, cytokine receptors, CXCR4, c-Met, mesothelin, a member of the epidermal growth factor receptor family or a mutant thereof, a member of the tumor necrosis factor receptor superfamily, a claudin, ephrin, an ephrin receptor, a fucosyltransferase, a prostate specific antigen, an embryonic antigen, a member of the vascularendothelia growth factor family, epithelial cell adhesion molecule, alpha-fetoprotein, a member of the intercellular adhesion molecule family, a C-type lectin, an integrin, a member of the mucin protein family, a follicle-stimulating hormone receptor, a high molecular weight-melanoma associated antigen, a folate binding protein, a folate receptor, a somatostatin receptor, a ligand of the NKG2D receptor, a member of the epithelia glycoprotein family, a diasialoganglioside, a glypican, a G protein-coupled receptor, a human papillomavirus protein, cancer / testis antigen, fibroblast activation protein, member of the carbonic anhydrase family, member of the carbohydrate antigen family, Notch ligand, melanoma-associated chondroitin sulfate proteoglycan, glycoprotein A33, guanylate cyclase 2C and tumor-specific glycan, wherein the targeting module and the at least one further targeting module comprise different target cell-binding domains, and identical tag-binding domains or tags. In embodiments, the at least one target cell-binding domain is an antibody, antibody fragment, aprotein, a peptide or a low molecular weight organic ligand that binds to surface antigens selectedfrom the group comprising CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD15, CD22, CD23, CD25, CD30, CD33, CD38, CD44, CD44v6, CD52, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD90, CD99, CD123, CD133, CD135, CD150, CD181, CD182, CD184, CD223, CD229, CD269, CD273, CD274, CD276, CD279, CD319, CD366, CD371, cytokine receptors, CXCR4, c-Met, mesothelin, a member of the epidermal growth factor receptor family, a member of the tumor necrosis factor receptor superfamily, a claudin, ephrin, an ephrin receptor, a fucosyl transferase, a prostate specific antigen, an embryonic antigen, a member of the vascular endothelia growth factor family, epithelial cell adhesion molecule, alpha-fetoprotein, a member of the intercellular adhesion molecule family, a C-type lectin, an integrin, a member of the mucin protein family, a follicle-stimulating hormone receptor, a high molecular weight-melanoma associated antigen, a folate binding protein, a folate receptor, a somatostatin receptor, a ligand of the NKG2D receptor, a member of the epithelia glycoprotein family, a diasialoganglioside, a glypican, a G protein- coupled receptor, a human papillomavirus protein, cancer / testis antigen, fibroblast activation protein, member of the carbonic anhydrase family, member of the carbohydrate antigen family, Notch ligand, melanoma-associated chondroitin sulfate proteoglycan, glycoprotein A33, guanylate cyclase 2C and tumor-specific glycanIn embodiments, the kit comprises one to three targeting modules, preferably one targetingmodule according to the invention and one or two further targeting modules. In embodiments, the targeting module and / or the cell comprising a nucleotide sequence encoding a switchable chimeric antigen receptor are in the form of a pharmaceutical composition.In embodiments, the kit is used in the treatment of cancer, infectious disease or autoimmunedisease.In embodiments, the kit is used for the manufacture of a medicament for the treatment of cancer,infectious disease or autoimmune disease.In embodiments, the kit is used in a method for treatment of cancer, infectious disease orautoimmune disease.In embodiments, the method for treatment of cancer, infectious disease or autoimmune diseasecomprises the administration of a targeting module, a cell or a vector, a pharmaceutical composition or a kit according to the invention to a subject in need thereof, preferably a mammal,more preferable a human, having cancer, an infectious or an autoimmune disease. Fortherapeutic applications, a sterile pharmaceutical composition according to the invention or asterile kit according to the invention, comprising a pharmacologically effective quantity of targetingmodule according to the invention and a vector or a cell comprising a nucleotide sequence encoding a switchable chimeric antigen receptor, is administered to a subject in order to treat the aforementioned illnesses. In some embodiments, the method for treatment of cancer, infectious or autoimmune disease, comprises the following steps: a) administering to a mammal an effective amount of a targeting module according tothe invention and b) administering to the mammal an effective amount of a vector or a cell comprising anucleotide sequence encoding a switchable chimeric antigen receptor, wherein the switchable chimeric antigen receptor comprises -a tag-binding domain or tag,- an extracellular hinge and a transmembrane domain and- a signal transduction domain, wherein the tag-binding domain of the targeting module binds to the tag of the switchable chimeric antigen receptor or the tag of the targeting module binds to the tag-binding domain of the switchable chimeric antigen receptor, wherein the targeting module is administered to a mammal prior to, concurrent with or after the administration of the vector or cell.The invention is not limited to the specifically described combinations of features but may also bedefined by any other combination of specific features of all the individual features disclosed as a whole, provided that the individual features are not mutually exclusive, or a specific combination of individual features is not explicitly excluded.The following detailed description of exemplary embodiments of the invention is presented toenable any person skilled in the art to make and use the disclosed subject matter in the context of one or more implementations. Various modifications to the disclosed implementations will be readily apparent to those skilled in the art, and the general principles defined herein may be applied to other implementations and applications without departing from scope of the disclosure. Thus, the present disclosure is not intended to be limited to the described or illustrated implementations but is to be accorded the widest scope consistent with the principles and features disclosed herein.Fig. 1 shows a schematic illustration of the mode of action of engineered immune cell incombination with a CD19- and CD20-specific targeting module (TM) together forming the activedrug. A switchable CAR expressing immune cell carries the tag-binding domain or tag on the cellsurface. When ligands (targeting module) binding to the tag-binding domain or tag are not presentwithin the human body immune cells remain in an off-mode (left). Antigen-specificity of switchableCAR immune cell is provided via the soluble targeting module (TM) with exclusive specificity forthe target antigens CD19 and CD20, consisting of at least two target cell-binding domains (CD19-binding domain and CD20-binding domain) and a tag or tag-binding domain specific for the tag-binding domain or tag of the switchable CAR. Cross-linking of switchable CAR-immune cell andthe target antigen-expressing tumor cell by TMs activates switchable CAR-immune cell effectorfunctions and subsequently killing of the tumor cells (right).Fig. 2 shows a cellular binding assay of different targeting modules according to the inventionon CD19-positive OCI-AML3-CD19 cells: normalized gMFIs of OCI-AML3-CD19 cells binding toA) CD19 VHH-based CD19-CD20-targeting modules according to the invention and B) CD19scFv-based CD19-CD20-targeting modules according to the invention. Error bars represent thestandard error of the mean from biological triplicates.Fig. 3 shows a cellular binding assay of different targeting modules according to the inventionon CD20-positive OCI-AML3-CD20 cells: normalized gMFIs of OCI-AML3-CD20 cells binding toA) CD19 VHH-based CD19-CD20-targeting modules according to the invention and B) CD19scFv-based CD19-CD20-targeting modules according to the invention. Error bars represent thestandard error of the mean from biological triplicates.Fig. 4 shows a cellular binding assay of different targeting modules according to the inventionon CD19 / CD20-positive NALM-6-CD20 cells: normalized gMFIs of NALM-6-CD20 cells bindingto A) CD19 VHH-based CD19-CD20-targeting modules according to the invention and B) CD19scFv-based CD19-CD20-targeting modules according to the invention. Error bars represent thestandard error of the mean from biological triplicates.Fig. 5 shows a cytotoxicity assay with targeting module (R-TM) titration: Co-culture of RevCAR-T cells and CD19-positive OCI-AML3-CD19 target cells at effector cell (E):target cell (T) ratio of1:2 with A) CD19 VHH-based CD19-CD20-targeting modules serial dilutions and B) CD19 scFv-based CD19-CD20-targeting modules serial dilutions. Target cell counts were determined viaFACS at 48 hours after adding targeting module in reference to OCI-AML3-CD19 cell counts intarget cell-only conditions (no targeting module (R-TM), no RevCAR-T cells (RC01)). Each datapoint represents the mean of three biological replicates (different T cell donors). Error bars represent the standard error of the mean.Fig. 6 shows a cytotoxicity assay with targeting module (R-TM) titration: Co-culture of RevCAR-T cells and CD20-positive OCI-AML3-CD20 target cells at E:T ratio of 1:2 with A) CD19 VHH-based CD19-CD20-targeting modules serial dilutions and B) CD19 scFv-based CD19-CD20-targeting modules serial dilutions. Target cell counts were determined via FACS at 48 hours afteradding targeting module in reference to OCI-AML3-CD19 cell counts in target cell-only conditions(no R-TM, no RC01). Each data point represents the mean of three biological replicates (differentT cell donors). Error bars represent the standard error of the mean.Fig. 7 shows a cytotoxicity assay with targeting module (R-TM) titration: Co-culture of RevCAR-T cells and CD19 / CD20-positive positive NALM-6-CD20 target cells at E:T ratio of 1:2 with A)CD19 VHH-based CD19-CD20-targeting modules serial dilutions and B) CD19 scFv-basedCD19-CD20-targeting modules serial dilutions. Target cell counts were determined via FACS at48 hours after adding targeting module in reference to OCI-AML3-CD19 cell counts in target cell-only conditions (no R-TM, no RC01). Each data point represents the mean of three biologicalreplicates (different T cell donors). Error bars represent the standard error of the mean.Fig. 8 shows pharmacokinetic of the targeting module according to the invention (R-TM19 / 20)and bioavailability in Nalm6-CD20 engrafted NSG mice. Left: Concentration decay over time oftargeting module after a single bolus intravenous injection of 1 µg / g in tumor-bearing NSG miceas determined by ELISA. Right: Nalm6-CD20 cell decoration with targeting module detected with anti-Fc mab by flow cytometry in bone marrow samples. Mice were pre-engrafted with 5·105Nalm6-CD20 cells 7 days prior to bolus injection of targeting module.Fig. 9 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst Nalm6-CD20. Co-culture assay of allo-RevCAR T cell products with target cell line Nalm6-CD20 in presence of varying concentrations of targeting module according to the invention (R-TM19 / 20). Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated withpropidium iodide and specific lysis is calculated (relative to control without targeting module).Mean of three replicates is plotted and fitted with a 4-parameter logistic regression. Calculated EC50 values represent the sensitivity of allo-RevCAR T cell products to the targeting module used.Fig. 10 shows in vitro potency assay results for switchable CAR (allo-RevCAR) T cells againstNalm6-CD20. Co-culture assay of allo-RevCAR T cell products with target cell line Nalm6-CD20in presence of varying concentrations of targeting module according to the invention (R-TM19 / 20).Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated with propidiumiodide and specific lysis is calculated (relative to control without targeting module). Mean of threereplicates is plotted and fitted with a 4-parameter logistic regression. Calculated EC50 values represent the sensitivity of allo-RevCAR T cell products to the targeting module used. Fig.11 shows results of a serial killing assay results of allogeneic switchable CAR (allo-RevCAR) T cells against Nalm6-CD20 cells. Co-culture assay of allo-RevCAR T cell products with targetcell line Nalm6-CD20 in presence of 1 nM targeting module according to the invention (R-TM19 / 20). Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated withpropidium iodide and specific lysis is calculated (relative to control without targeting module).Mean of three replicates is plotted and fitted with a 4-parameter logistic regression. Calculated EC50 values represent the capacity of RevCAR T cell products to kill multiple target cells. Fig.12 shows results of a long-term restimulation assay results of allogeneic switchable CAR(allo-RevCAR) T cells against Nalm6 cells. Co-culture assay of allo-RevCAR T cell products withtarget cell line Nalm6 (mcherry positive) in presence of 0.2 nM targeting module according to theinvention (R-TM19 / 20). Every 3 to 4 days 2·104 fresh target cells are added. Mcherry positivetarget cell counts are determined by fluorescence microscopy (Incucyte S3) twice a day over threeweeks. Mean and standard deviation of four replicates is plotted.Fig.13 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst Nalm6-CD20. Co-culture assay of allo-RevCAR T cell products with target cell line Nalm6-CD20 in presence of varying concentrations of targeting module according to the invention (R- TM19 / 20). Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated withpropidium iodide and specific lysis is calculated (relative to control without R-TM). Mean of threereplicates is plotted and fitted with a 4-parameter logistic regression. Calculated EC50 valuesrepresent the sensitivity of RevCAR T cell products to the targeting module used.Fig.14 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst Nalm6-CD20. Co-culture assay of allo-RevCAR T cell products with target cell line Nalm6-CD20 in presence of varying concentrations of targeting module according to the invention (R-TM19 / 20). Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated withpropidium iodide and specific lysis is calculated (relative to control without targeting module).Mean of three replicates is plotted and fitted with a 4-parameter logistic regression. CalculatedEC50 values represent the sensitivity of RevCAR T cell products to the targeting module used.Fig. 15 shows serial killing assay results of allogeneic switchable CAR (allo-RevCAR) T cellsagainst Nalm6-CD20 cells. Co-culture assay of allo-RevCAR T products with target cell lineNalm6-CD20 in presence of 1nM targeting module according to the invention (R-TM19 / 20).Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated with propidiumiodide and specific lysis is calculated (relative to control without targeting module). Mean of threereplicates is plotted and fitted with a 4-parameter logistic regression. Calculated EC50 valuesrepresent the capacity of RevCAR T cell products to kill multiple target cells.Fig. 16 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst Oci-AML-CD19 and Oci-AML-CD20 cells. Co-culture assay of allo-RevCAR T cellproducts with target cell line Oci-AML-CD19 and Oci-AML-CD20 in presence of varyingconcentrations of targeting module according to the invention (R-TM19 / 20). Target cells werestained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated with propidium iodide and specificlysis is calculated (relative to control without targeting module). Mean of three replicates is plottedand fitted with a 4-parameter logistic regression. Calculated EC50 values represent the sensitivity of RevCAR T cell products to the targeting module used.Fig. 17 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst Raji lymphoma cells. Co-culture assay of allo-RevCAR T cell products with target cell lineRaji in presence of varying concentrations of targeting module according to the invention (R-TM19 / 20). Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated withpropidium iodide and specific lysis is calculated (relative to control without targeting module). Mean of three replicates is plotted and fitted with a 4-parameter logistic regression. Calculated EC50 values represent the sensitivity of RevCAR T cell products to the targeting module used.Fig. 18 shows in long-term restimulation assay results of allogeneic switchable CAR (allo-RevCAR) T cells against Nalm6 and Nalm6-CD20 cells. Co-culture assay of allo-RevCAR T cellproducts with target cell line Nalm6 (mcherry positive) and Nalm6-CD20 (mcherry positive) inpresence of 0.2 nM targeting module according to the invention (R-TM19 / 20). Every 3 to 4 days2·104fresh target cells are added. Mcherry positive target cell counts are determined byfluorescence microscopy (Incucyte S3) twice a day over three weeks. Mean and standarddeviation of three replicates is plotted.Fig. 19 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst Nalm6-CD20 cells. Co-culture assay of allo-RevCAR T cell products with target cell lineNalm6-CD20 in presence of varying concentrations of targeting module according to the invention(R-TM19 / 20). Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated withpropidium iodide and specific lysis is calculated (relative to control without targeting module).Mean of three replicates is plotted and fitted with a 4-parameter logistic regression. CalculatedEC50 values represent the sensitivity of RevCAR T cell products to the targeting module used.Fig.20 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst Raji lymphoma cells. Co-culture assay of allo-RevCAR T cell products with target cell lineRaji in presence of varying concentrations of targeting module according to the invention (R-TM19 / 20). Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated withpropidium iodide and specific lysis is calculated (relative to control without targeting module).Mean of three replicates is plotted and fitted with a 4-parameter logistic regression. CalculatedEC50 values represent the sensitivity of RevCAR T cell products to the targeting module used.Fig. 21 shows serial killing assay of allogeneic switchable CAR (allo-RevCAR) T cells againstRaji lymphoma cells. Co-culture assay of allo-RevCAR T cell products with target cell line Raji inpresence of 0.1 nM targeting module according to the invention (R-TM19 / 20). Target cells werestained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated with propidium iodide and specificlysis is calculated (relative to control without targeting module). Mean of three replicates is plottedand fitted with a 4-parameter logistic regression. Calculated EC50 values represent the capacity of RevCAR T cell products to kill multiple target cells.Fig. 22 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) Tagainst Nalm6-CD20 cells. Co-culture assay of allo-RevCAR T cell products with target cell lineNalm6-CD20 in presence of varying concentrations of targeting module according to the invention (R-TM19 / 20). Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated withpropidium iodide and specific lysis is calculated (relative to control without targeting module).Mean of three replicates is plotted and fitted with a 4-parameter logistic regression. CalculatedEC50 values represent the sensitivity of RevCAR T cell products to the targeting module used.Fig.23 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst Raji lymphoma cells. Co-culture assay of allo-RevCAR T cell products with target cell lineRaji in presence of varying concentrations of targeting module according to the invention (R-TM19 / 20). Target cells were stained beforehand with the proliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry, dead cells are discriminated withpropidium iodide and specific lysis is calculated (relative to control without targeting module).Mean of three replicates is plotted and fitted with a 4-parameter logistic regression. CalculatedEC50 values represent the sensitivity of RevCAR T cell products to the targeting module used.Fig.24 shows in vitro potency assay results for allogeneic switchable CAR (allo-RevCAR) T cellsagainst Raji CD19Ko lymphoma cells. Co-culture assay of allo-RevCAR T cell products with targetcell line Raji CD19Ko (negative for CD19) in presence of varying concentrations of targetingmodule according to the invention (R-TM19 / 20). Target cells were stained beforehand with theproliferation dye efluor 450. After 48 hrs, viable target cell count is determined by flow cytometry,dead cells are discriminated with propidium iodide and specific lysis is calculated (relative tocontrol without targeting module). Mean of three replicates is plotted and fitted with a 4-parameter logistic regression. Calculated EC50 values represent the sensitivity of RevCAR T cell productsto the targeting module used.Fig. 25A and 25B show in vivo efficacy results of allogeneic switchable CAR (allo-RevCAR) Tcells against a B-ALL Nalm6-CD20 tumor. Evaluation of tumor control and tumor regressioncapacity of allo-RevCAR T cells in Nalm6-CD20-Fluc xenograft mice. Mice received 5·105Nalm6- CD20-Fluc cells 7 days prior to transplantation of 15·106allogeneic T cells (total). Therapy wasinitiated one day before mice received T cells with a bolus injection of 0.2 µg / g or 0.02 µg / gtargeting module according to the invention (R-TM19 / 20) intravenously, respectively. Mice whichreceived allo-RevCAR T cells and targeting module were rechallenged with tumor cells at day 17(1·106cells), day 28 (2·106cells) and day 37 (5·106cells). Normalized radiance for bioluminescentimaging (BLI) is ranging from 5·104 to 1·107 [p / sec / cm²sr].Fig.26 shows in vivo efficacy results of allogeneic switchable CAR (allo-RevCAR) T cells againsthigh burden B-ALL Nalm6-CD20 tumor in late-stage mice. Evaluation of tumor control and tumorregression capacity of allo-RC62T and RC63T cells in late-stage high tumor burden Nalm6-CD20- Fluc xenograft model. Mice received 5·105Nalm6-CD20-Fluc cells 7 days prior to transplantation of 15·106allo-RevCAR T cells (total). Therapy was initiated at day 21 after tumor application withintravenous bolus injections of targeting module according to the invention (R-TM19 / 20) in dosesof 1.0 µg / g (day 21, day 28 and day 35) and 0.2 µg / g (day 44). Normalized radiance for BLI isranging from 5·104to 1·107[p / sec / cm²sr].Fig. 27 shows cytokine release of human allogeneic switchable CAR (allo-RevCAR) T cells inmice. Quantification of human cytokines (GM-CSF, IFN-γ, IL-2, TNF-α and Perforin) fromperipheral blood of Nalm6-CD20 xenograft mice three days after allo-RevCAR T celltransplantation and initiation of therapy with targeting module according to the invention (R-TM19 / 20). (MACSPlex Cytotoxic T / NK Cell kit,from Miltenyi, Germany).Fig.28 shows tumor and T cell chimerism determined at individual end points via flow cytometry.Mice received 5·105Nalm6-CD20-Fluc cells 7 days prior to transplantation of 15·106allogeneic switchable CAR (allo-RevCAR) T cells (total). Therapy was initiated one day before mice receivedallo-RevCAR T cells with a bolus injection of 0.2 µg / g or 0.02µg / g targeting module according tothe invention (R-TM19 / 20) intravenously, respectively. Mice which received allo-RevCAR T cellsand targeting module were rechallenged with tumor cells at day 17 (1·106cells), day 28 (2·106cells) and day 37 (5·106cells).Fig. 29 shows tumor and T cell chimerism determined at individual end points via flow cytometryin high tumor burden mice. Mice received 5·105 Nalm6-CD20-Fluc cells 7 days prior totransplantation of 15·106allogeneic switchable CAR (allo-RevCAR) T cells (total). Therapy wasinitiated at day 21 after tumor application with intravenous bolus injections of targeting moduleaccording to the invention (R-TM19 / 20) in doses of 1.0 µg / g (day 21, day 28 and day 35) and0.2 µg / g (day 44).Fig. 30 shows in vivo efficacy of allogeneic switchable CAR (allo-RevCAR) T cells against Rajilymphoma. Evaluation of tumor control and tumor regression capacity of allo-RevCAR T cellsagainst Raji-Fluc in NSG mice. NSG mice received 5·105 Raji-Fluc cells intravenously 7 days priorto transplantation of 15·106 or 5·106 allo-RevCAR T cells (total). Therapy was initiated 3 daysprior to T cell transplantation with 0.2 µg / g or 0.02 µg / g targeting module according to theinvention (R-TM19 / 20) intravenously and biweekly repeated. Mice which received allo-RevCART cells and targeting module were rechallenged once with 2·106Raji-Fluc tumor cells at day 15 and 2·106Raji CD19KO tumor cells at days 22. For groups of allo-RC62T cells and allo-RC63T cells which initially received no targeting module, therapy started at day 17 with 0.02 µg / gtargeting module intravenously and was repeated weekly, here no tumor rechallenge was applied.Fig. 31 shows in vivo efficacy of allogeneic switchable CAR (allo-RevCAR) T cells against B-celllymphoma. Evaluation of tumor control and tumor regression capacity of allo-RevCAR T cellsagainst Raji-Fluc in NSG mice. NSG mice were engrafted with 5·105Raji-Fluc cells intravenously11 days prior to receiving 3·106 CAR T cells intravenously. One day before allo-RevCAR T cellsgot transplanted, therapy with 0.05 µg / g targeting module according to the invention (R-TM19 / 20)intravenously started and was repeated weekly. All targeting module treated animals gotrechallenged with 2·106CD19neg Raji cells at day 39. Normalized radiance for BLI is ranging from 5·104to 1·107[p / sec / cm² / sr]. Design of targeting modules according to the invention The targeting module is a soluble, recombinant fusion protein comprising two antibody-derived binding domains and a tag. One selectively binds to the target antigen CD19 and one to the targetantigen CD20, the other recognizes the tag-binding domain presented on the RevCAR expressingcells (epitope E5B9 from the human La protein). Thus, the TM functions as a bridging modulebetween RevCAR-T and a CD19 and CD20-expressing target cancer cell (Fig.1).Tab.1 Design of different targeting modules according to the invention (SEQ ID No. 44 to SEQID No.76) Targeting module Design1. chain 2. chain 3. chainR-TM-19 / 20_2 SEQ ID No. 47 SEQ ID No. 45 SEQ ID No. 51R-TM-19 / 20_3 SEQ ID No. 47 SEQ ID No. 45 SEQ ID No. 53R-TM-19 / 20_5 SEQ ID No. 47 SEQ ID No. 45 SEQ ID No. 57R-TM-19 / 20_8 SEQ ID No. 76 SEQ ID No. 45 SEQ ID No. 63R-TM-19 / 20_11 SEQ ID No. 76 SEQ ID No. 45 SEQ ID No. 69R-TM-19 / 20_15 SEQ ID No. 73 SEQ ID No. 45 SEQ ID No. 57R-TM-19 / 20_21 SEQ ID No. 73 SEQ ID No. 45 SEQ ID No. 51R-TM-19 / 20_23 SEQ ID No. 73 SEQ ID No. 45 SEQ ID No. 53Preparation of the targeting moduleExpression was mediated from an ExpiCHO cell line in ExpiCHO expression medium in 2000 mlshake flasks containing 400 ml medium. The product was then harvested after 7 days of culture and clarified by centrifugation and filtration. Harvested media was further purified with CH1-XL resin using the manufacturer’s protocol. The purified protein was buffer exchanged to PBS pH 7.0 containing 300 mM sucrose. The final product was characterized with respect to identity and purity. Characterization of the targeting moduleThermal stability of the targeting modules was assessed by nano-format of differential scanningfluorimetry (nanoDSF), backreflection, dynamic light scattering (DLS), static light scattering (SLS),size exclusion high performance liquid chromatography (SE-HPLC) and SDS-PAGE. Bindingproperties were assessed by surface plasmon resonance and / or cellular binding assay. Potencyof the targeting modules was investigated by in vitro killing assays with target cells expressingCD19 and / or CD20.Figures 2 to 4 show the cellular binding potential assessed using the CD19 and / or CD20 positivetarget cell lines Oci-AML3 and NALM-6. Different concentrations of targeting modules accordingto the invention were incubated with cells, washed and quantified. A dose-response curve wasobtained when the geometric mean fluorescence (MFI) was plotted against the TM concentration. The data for the cellular binding of CD19 and CD20-binding TMs on the CD19 and / or CD20 positive target cell lines Oci-AML3 and NALM-6 were fitted using a four-parameter model with a variable slope for sigmoidal curves. The 50% effective concentration (EC50) obtained from this model can be interpreted as a representative value of the TM affinity for the cells overexpressing the target receptor (see Tab.2).Tab.2 Targeting module affinity the cells overexpressing the target receptor: concentration ofhalf-maximal binding (EC50) determined by cellular binding assays.Targeting module CD19 bindingCD20 binding CD19 / CD20 binding EC50[nM] EC50[nM] EC50[nM] R-TM19 / 20_02 18.4 43.6 18.5R-TM19 / 20_03 19.0 29.2 not determinedR-TM19 / 20_05 14.7 24.1 16.4R-TM19 / 20_08 14.8 37.0 18.7R-TM19 / 20_11 5.2 62.0 24.3R-TM19 / 20_15 3.7 45.5 26.6R-TM19 / 20_21 2.2 53.8 20.6R-TM19 / 20_23 3.4 23.0 14.2RevCAR T cellsFor the genetical engineering to express RevCARs, a polynucleotide vector encoding theRevCAR and all necessary elements to ensure its expression in the genetically engineeredimmune cell is transferred into the immune cell. In particular, the RevCAR comprises a humansignal peptide, tag, ECD (extracellular domain), TMD (transmembrane domain), ICD (intracellulardomain). The transfer of the vector can be performed by electroporation or transfection of nucleic acids orthe help of viral vector systems like adeno-, adeno-associated, retro-, foamy- or lentiviral viralgene transfer. The lentiviral gene transfer is applied for stable expression of RevCARs in immune cells by first constructing a lentiviral vector encoding for a selected RevCAR. The lentiviral vector is pLVX- EF1alpha UniCAR 28 / ζ (Clontech, Takara Bio Group), in which the lentiviral parts of the vectorare derived from the human immunodeficiency virus (HIV) and the MSC / IRES / ZxGreenI portionwas replaced by the RevCAR construct. The lentiviral particles are produced by transient transfection of human embryonal kidney (HEK) 293T (ACC 635) cells with the RevCAR encoding lentiviral vector plasmid and co-transfection with a group specific antigen (gag) and Polymerase (pol) encoding plasmid (psPAX2) plus a plasmid encoding for an envelope (pMD2.G). After transfection, the packaging plasmid expresses Gag and Pol protein of HIV-1. The plasmid MD2.G encodes the glycoprotein of the vesicular stomatitis virus (VSV-G). VSV-G protein is used to lentiviral vectors to transduce a broad rangeof mammalian cells. Various envelopes from different virus species can be utilized for thispurpose. Lentiviral vectors can successfully pseudo type with the envelope glycoproteins (Env)of amphotropic murine leukemia virus (MLV) or the G protein of vesicular stomatitis virus (VSV-G), a modified envelope of the prototypic foamy virus (PFV) or chimeric envelope glycoprotein variants derived from gibbon ape leukemia virus (GaLV) and MLV.Supernatants from transfected HEK293T cells are harvested 24 h to 96 h after transfection andvirus particles are concentrated from the supernatant by ultracentrifugation or other methods. Forlentiviral transduction of immune cells, peripheral blood mononuclear cells (PBMC) or isolated Tcells are activated with mab specific for the CD3 complex, e.g. clone OKT3 or UCHT1, eithergiven in solution or coated to plastic cell culture dishes or magnetic beads or a biodegradablepolymer matrix. Activation of PBMC or isolated T cells is further enhanced by stimulatingcostimulatory pathways with mabs or ligands specific for CD27, CD28, CD134 or CD137 eitheralone or in combinations coated to plastic cell culture dishes or magnetic beads or abiodegradable polymer matrix and the supply with exogenous recombinant cytokines likeinterleukin (IL)-2, IL-7, IL-12, IL-15 and IL-21. Concentrated or non-concentrated virus particlesare added to PBMC or T cell cultures 24 h to 96 h after initial administration of activating CD3specific antibodies and / or antibodies specific for costimulatory receptors CD27, CD28, CD134 orCD137 and / or recombinant cytokines as single or multiple doses. T cell electroporation, transduction and expansion may be performed in open cell culture systems by manual handling or in closed partially or fully automated systems. Stable transduction of T cells may be determined by flow cytometry after staining with tag-containing molecules for surface expression of RevCARs or mabs directed against a fourthdomain of RevCARs from day 3 onwards after the final administration of virus supernatant.RevCAR transduced T cells can be propagated in vitro by culturing them under the supply ofrecombinant cytokines and activating anti-CD3 mabs.In case the RevCAR harbors a tag the optional fourth domain, a peptide sequence forming alinear epitope for a mab, immune cells genetically modified to express RevCARs can bespecifically propagated in vitro by coating a mab or antibody fragments thereof binding to the tagor the fourth RevCAR domain to the surface of culture dishes or to beads of any kind or abiodegradable polymer matrix, which are added to the cell culture at a defined ratio. The binding of surface-coated mabs to the RevCAR peptide domain induces cross-linkage of cell-surface expressed RevCARs and formation of an immune synapse, which leads to the activation of signal pathways specifically triggered by the signal domain of the RevCAR. Depending on the signal pathways induced, this may lead to enhance proliferation and sustained resistance against activation-induced cell death of the RevCAR-carrying immune cells and therefore enrichment of RevCAR genetically modified immune cells in a mixed population. The tag or the optional fourth domain, a peptide sequence forming a linear epitope for a mab, can be further utilized to enrich and purify RevCAR-expressing immune cells from mixed populations.Enrichment and purification are performed with the help of a mab or antibody fragment thereofbinding to the fourth RevCAR domain to either mark RevCAR-expressing cells for cell sorting or to transiently link the RevCAR expressing immune cell to small particles, which can be utilized for cell isolation. In one aspect, RevCAR-engrafted immune cells are incubated with the mab recognizing the fourth domain. Next, magnetic beads are added, which are conjugated withantibodies or fragments thereof directed against the species- and isotype-specific heavy and lightchains of the mab binding to the optional fourth domain. Thus, RevCAR-expressing immune cells and magnetic beads are linked and are trapped and separated from other immune cells in a magnetic field. Cytotoxicity assay The potency of CD19 and CD20-binding TMs to induce a tumor cell elimination by RevCAR-Tcells was tested using a suspension cell-based co-cultivation assay with the acute myeloidleukemia cell line Oci-AML3 (Fig. 5 and 6) and acute lymphoblastic leukemia cell line NALM-6(Fig. 7) in the presence of variable concentrations of the targeting module. Switchable CAR-Tcells were incubated with the target cells at a E:T ratio of 1:2 in the presence of various TMconcentrations for 48 h. As CD19- and / or CD20-positive target cells the human cell line Oci-AML3(Fig. 5 and 6) or NALM-6 (Fig. 7), respectively, was used which was stained with efluor priorsetup. Target cells were quantified by flow cytometry and lysis was calculated normalizing the cell count of each sample to a control sample where only tumor cells were plated. Data were fitted with a four-parameter model with a variable slope for sigmoidal curves. The calculated EC50value can be interpreted as a representative value for the TM potency against these tumor cells.Tab.3 Cell lysis: concentration of half-maximal killing (EC50).Targeting module CD19 killingCD20 killingCD19 / CD20 killingEC50 [pM] EC50 [pM] EC50 [pM] R-TM19 / 20_02 3.8 7.2 2.4R-TM19 / 20_03 7.9 4.3 not determinedR-TM19 / 20_05 6.2 9.8 3.1R-TM19 / 20_08 7.1 14.2 3.8R-TM19 / 20_11 3.8 17.9 2.5R-TM19 / 20_15 1.2 10.7 1.5R-TM19 / 20_21 1.4 12.6 0.5R-TM19 / 20_23 1.0 2.1 0.5

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[0003] List of reference signs 1targeting module2 switchable chimeric antigen receptor3effector cell4 target cell

Claims

Claims1. A targeting module comprisingi) at least one CD19-binding domain comprising one of the sequences selectedfrom SEQ ID No. 1 to SEQ ID No. 3 or a sequence identity of at least 95 %with one of the sequences selected from SEQ ID No. 1 to SEQ ID No. 3,ii) at least one CD20-binding domain comprising SEQ ID No.4, andiii) a tag-binding domain or a tag.

2. The targeting module according to claim 1, wherein the tag is a peptide epitope tag.

3. The targeting module according to claim 2, wherein the peptide epitope tag is a myc-tag, aHis-tag, a short linear peptide sequence from yeast transcription factor GCN4, a leucine zipper sequence or a short linear peptide sequence from a human nuclear protein, preferably from the human La protein.

4. The targeting module according to one of the claims 1 to 3, wherein at least one CD20-binding domain comprises one of the sequences selected from SEQ ID No.5 to SEQ ID No.7 or with a sequence identity of at least 95 % with one of the sequences selected from SEQID No.5 to SEQ ID No.7.

5. The targeting module according to one of the claims 1 to 4, wherein the length is in the rangeof 200 to 1600 amino acids.

6. The targeting module according to one of the claims 1 to 5 comprising at least three chainscomprising -one amino acid sequence selected from the group comprising SEQ ID No. 39, SEQID No.46, SEQ ID No.47, SEQ ID No.72, SEQ ID No.73, SEQ ID No.74, SEQ ID No.75, and SEQ ID No.76, and -one amino acid sequence selected from the group comprising SEQ ID No. 44 andSEQ ID No. 45, and- one amino acid sequence selected from the group comprising SEQ ID No. 48, SEQID No.49, SEQ ID No.50, SEQ ID No.51, SEQ ID No.52, SEQ ID No.53, SEQ ID No.54, SEQ ID No.55, SEQ ID No.56, SEQ ID No.57, SEQ ID No.58, SEQ ID No. 59, SEQ ID No.60, SEQ ID No.61, SEQ ID No.62, SEQ ID No.63, SEQ ID No.64,SEQ ID No.65, SEQ ID No.66, SEQ ID No.67, SEQ ID No.68, SEQ ID No.69, SEQ ID No.70, and SEQ ID No.71.

7. A targeting module according to one of the claims 1 to 6 for use in the treatment of cancer,infectious disease or autoimmune disease, wherein the targeting module is administered in combination with a cell comprising anucleotide sequence encoding a switchable chimeric antigen receptor, wherein the switchable chimeric antigen receptor comprises -a tag-binding domain or a tag,- an extracellular hinge and a transmembrane domain and- a signal transduction domain,wherein the tag-binding domain of the targeting module binds to the tag of the switchable chimeric antigen receptor or the tag of the targeting module binds to the tag-binding domain of the switchable chimeric antigen receptor.

8. The targeting module for use in the treatment of cancer, infectious disease or autoimmunedisease according to claim 7, wherein the targeting module is administered in combination with a cell comprising anucleotide sequence encoding a switchable chimeric antigen receptor and at least one further targeting module, wherein the at least one further targeting module comprises at least one target cell-bindingdomain and a tag-binding domain or a tag, wherein the at least one target cell-binding domain is an antibody, antibody fragment, a protein, a peptide or a low molecular weight organic ligand that binds to a surface antigen selected from the group comprising CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD15, CD22, CD23, CD25, CD30, CD33, CD38, CD44, CD44v6, CD52, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD90, CD99, CD123, CD133, CD135, CD150, CD181, CD182, CD184, CD223, CD229, CD269, CD273, CD274, CD276, CD279, CD319, CD366, CD371, cytokine receptors, CXCR4, c-Met, mesothelin, a member of the epidermal growth factor receptor family or a mutant thereof, a member of the tumor necrosis factor receptor superfamily, a claudin, an ephrin, an ephrin receptor, a fucosyl transferase, a prostate specific antigen, an embryonic antigen, a member of the vascular endothelia growth factor family, epithelial cell adhesion molecule, alpha-fetoprotein, a member of the intercellular adhesion molecule family, a C-type lectin, an integrin, a member of the mucin protein family, a follicle-stimulating hormone receptor, a high molecular weight-melanoma associated antigen, a folate binding protein, a folate receptor, a somatostatin receptor, a ligand of the NKG2D receptor, a memberof the epithelia glycoprotein family, a diasialoganglioside, a glypican, a G protein-coupledreceptor, a human papillomavirus protein, cancer / testis antigen, fibroblast activation protein, a member of the carbonic anhydrase family, a member of the carbohydrate antigen family, a Notch ligand, melanoma-associated chondroitin sulfate proteoglycan, glycoprotein A33, guanylate cyclase 2C and tumor-specific glycan, wherein the targeting module and the at least one further targeting module comprise different target cell-binding domains, and identical tag-binding domains or tags.

9. A pharmaceutical composition comprising the targeting module according to one of the claims1 to 6 and a pharmaceutically acceptable thinner or carrier.

10. The pharmaceutical composition according to claim 9 comprising at least one furthertargeting module, wherein the at least one further targeting module comprises at least one target cell-binding domain and a tag-binding domain or a tag, wherein the at least one target cell-binding domain is an antibody, antibody fragment, a protein, a peptide or a low molecular weight organic ligand that binds to surface antigens selected from the group comprising CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD15, CD22, CD23, CD25, CD30, CD33, CD38, CD44, CD44v6, CD52, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD90, CD99, CD123, CD133, CD135, CD150, CD181, CD182, CD184, CD223, CD229, CD269, CD273, CD274, CD276, CD279, CD319, CD366, CD371, cytokinereceptors, CXCR4, c-Met, mesothelin, a member of the epidermal growth factor receptorfamily or a mutant thereof, a member of the tumor necrosis factor receptor superfamily, a claudin, an ephrin, an ephrin receptor, a fucosyl transferase, a prostate specific antigen, an embryonic antigen, a member of the vascular endothelia growth factor family, epithelial cell adhesion molecule, alpha-fetoprotein, a member of the intercellular adhesion molecule family, a C-type lectin, an integrin, a member of the mucin protein family, a follicle-stimulating hormone receptor, a high molecular weight-melanoma associated antigen, a folate binding protein, a folate receptor, a somatostatin receptor, a ligand of the NKG2D receptor, a member of the epithelia glycoprotein family, a diasialoganglioside, a glypican, a G protein-coupled receptor, a human papillomavirus protein, cancer / testis antigen, fibroblast activation protein, a member of the carbonic anhydrase family, a member of the carbohydrate antigen family, a Notch ligand, melanoma-associated chondroitin sulfate proteoglycan, glycoprotein A33, guanylate cyclase 2C and tumor-specific glycan, wherein the targeting module and the at least one further targeting module comprise different target cell-binding domains, and identical tag-binding domains or tags.

11. A kit comprisinga) a targeting module comprisingi) at least one CD19-binding domain comprising one of the sequencesselected from SEQ ID No.1 to SEQ ID No.3 or a sequence identity ofat least 95 % with one of the sequences selected from SEQ ID No. 1to SEQ ID No. 3,ii) at least one CD20-binding domain comprising SEQ ID No.4, andiii) a tag-binding domain or a tag, andb) a vector or a cell comprising a nucleotide sequence encoding a switchable chimericantigen receptor, wherein the switchable chimeric antigen receptor comprises -a tag-binding domain or tag,- an extracellular hinge and a transmembrane domain and- a signal transduction domain,wherein the tag-binding domain of the targeting module binds to the tag of the switchable chimeric antigen receptor or the tag of the targeting module binds to the tag-binding domain of the switchable chimeric antigen receptor.

12. The kit according to claim 11, wherein the tag is a myc-tag, a His-tag, a short linear peptidesequence from yeast transcription factor GCN4, a leucine zipper sequence or a short linearpeptide sequence from a human nuclear protein, preferably from the human La protein.

13. The kit according to claim 11 or 12, wherein the tag-binding domain is an antibody or anantibody fragment binding to a myc-tag, a His-tag, a short linear peptide sequence from yeast transcription factor GCN4, a leucine zipper sequence or a short linear peptide sequence froma human nuclear protein, preferably from a human La protein.

14. The kit according to one of the claims 11 to 13, wherein the at least one CD20-binding domaincomprises one of the sequences selected from SEQ ID No. 5 to SEQ ID No. 7 or with asequence identity of at least 95 % with one of the sequences selected from SEQ ID No. 5 toSEQ ID No.7.

15. The kit according to one of the claims 11 to 14, wherein the length of the targeting module isin the range of 200 to 1600 amino acids.

16. The kit according to one of the claims 11 to 15, wherein the targeting module comprises atleast three chains comprising -one amino acid sequence selected from the group comprising SEQ ID No. 39, SEQID No.46, SEQ ID No.47, SEQ ID No.72, SEQ ID No.73, SEQ ID No.74, SEQ ID No.75, and SEQ ID No.76, and -one amino acid sequence selected from the group comprising SEQ ID No. 44 andSEQ ID No. 45, and- one amino acid sequence selected from the group comprising SEQ ID No. 48, SEQID No.49, SEQ ID No.50, SEQ ID No.51, SEQ ID No.52, SEQ ID No.53, SEQ ID No.54, SEQ ID No.55, SEQ ID No.56, SEQ ID No.57, SEQ ID No.58, SEQ ID No. 59, SEQ ID No.60, SEQ ID No.61, SEQ ID No.62, SEQ ID No.63, SEQ ID No.64, SEQ ID No.65, SEQ ID No.66, SEQ ID No.67, SEQ ID No.68, SEQ ID No.69, SEQ ID No.70, and SEQ ID No.71.

17. The kit according to one of the claims 11 to 16, wherein the extracellular hinge and atransmembrane domain is selected from the group comprising a hinge and transmembrane domain of human CD8α, CD28, ICOS (CD278), parts of a NK cell receptor, parts of the constant region of an antibody or mutants and combinations thereof.

18. The kit according to one of the claims 11 to 17, wherein the signal transduction domaincomprises at least two signal transduction domains independently selected from acytoplasmic region of a CD3 chain, CD28, CD137 (4-1BB), CD134 (OX40), CD278 (ICOS),DAP10, CD27, programmed cell death-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), DAP12, CD122 (interleukin-2 receptor β), CD132 (interleukin-2 receptor γ), CD127 (interleukin-7 receptor α), CD360 (interleukin-21 receptor), an activating Fc receptor and mutants thereof.

19. The kit according to one of the claims 11 to 18 further comprising at least one further targetingmodule, wherein the at least one further targeting module comprises at least one target cell-binding domain and a tag-binding domain or a tag, wherein the at least one target cell-binding domain is an antibody, antibody fragment, a protein, a peptide or a low molecular weight organic ligand that binds to surface antigens selected from the group comprising CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD15, CD22, CD23, CD25, CD30, CD33, CD38, CD44, CD44v6, CD52, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD90, CD99, CD123, CD133, CD135, CD150, CD181, CD182, CD184,CD223, CD229, CD269, CD273, CD274, CD276, CD279, CD319, CD366, CD371, cytokine receptors, CXCR4, c-Met, mesothelin, a member of the epidermal growth factor receptor family or a mutant thereof, a member of the tumor necrosis factor receptor superfamily, a claudin, ephrin, an ephrin receptor, a fucosyl transferase, a prostate specific antigen, an embryonic antigen, a member of the vascular endothelia growth factor family, epithelial cell adhesion molecule, alpha-fetoprotein, a member of the intercellular adhesion molecule family, a C-type lectin, an integrin, a member of the mucin protein family, a follicle-stimulating hormone receptor, a high molecular weight-melanoma associated antigen, a folate binding protein, a folate receptor, a somatostatin receptor, a ligand of the NKG2D receptor, a member of the epithelia glycoprotein family, a diasialoganglioside, a glypican, a G protein-coupled receptor, a human papillomavirus protein, cancer / testis antigen, fibroblast activation protein, member of the carbonic anhydrase family, member of the carbohydrate antigen family, Notch ligand, melanoma-associated chondroitin sulfate proteoglycan, glycoprotein A33, guanylate cyclase 2C and tumor-specific glycan, wherein the targeting module and the at least one further targeting module comprise different target cell-binding domains, and identical tag-binding domains or tags.

20. The kit according to one of the claims 11 to 19, wherein the targeting module and / or the cellcomprising a nucleotide sequence encoding a switchable chimeric antigen receptor are in the form of a pharmaceutical composition.

21. The kit according to one of the claims 11 to 20 for use in the treatment of cancer, infectiousdisease or autoimmune disease.

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