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EP-3634474-B1 - TARGETING MODULES FOR UNIVERSAL CHIMERIC ANTIGEN RECEPTOR EXPRESSING IMMUNE CELLS AND USE IN THE TREATMENT OF CANCER INFECTIONS AND AUTOIMMUNE DISORDERS

EP3634474B1EP 3634474 B1EP3634474 B1EP 3634474B1EP-3634474-B1

Inventors

  • Ehninger, Armin

Dates

Publication Date
20260506
Application Date
20180608

Claims (10)

  1. A targeting module comprising a chemically synthesized peptide binding moiety specific for a human cell surface protein or protein complex, and a tag, wherein the tag is a peptide from a human nuclear La protein, wherein the targeting module is a peptide comprising 10 to 120 amino acids, wherein the targeting module is selected from a structure according to Formula (I) or Formula (II): wherein Z is a single chelator or aromatic amino acid or multiple thereof and O being a linker of 2 or more repeats.
  2. The targeting module according to claim 1 comprising a chelator as Z.
  3. The targeting module according to claim 1 or 2 for use in the treatment of cancer, infections, inflammatory and autoimmune disorders.
  4. A kit comprising a) a targeting module according to claim 1 or 2 and b) a vector or a cell comprising a nucleic acid encoding a universal chimeric antigen receptor, wherein the universal chimeric antigen receptor comprises three domains, wherein - the first domain is a tag-binding domain, - the second domain is an extracellular hinge and a transmembrane domain and - the third domain is a signal transduction domain, wherein tag-binding domain binds to the tag of the targeting module according to claim 1 or 2, wherein the tag-binding domain is an antibody or an antigen-binding fragment.
  5. The kit according to claim 4, wherein the tag-binding domain constitutes an anti-La epitope scFv, preferably an anti-La epitope scFv according to SEQ. ID NO. 21 and 22 or SEQ. ID NO. 23 and 24.
  6. The kit according to claim 4 or 5, wherein the extracellular hinge and transmembrane domain is selected from hinge and transmembrane domains of human CD28 molecule, CD8a chain NK cell receptors, preferably natural killer group NKG2D; or parts of the constant region of an antibody and combinations thereof.
  7. The kit according to one of the claims 4 to 6, wherein the signal transduction domain is selected from cytoplasmic regions of CD28, CD137 (4-1BB), CD134 (OX40), DAP10 and CD27, programmed cell death-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), cytoplasmic regions of CD3 chains, DAP12 and activating Fc receptors.
  8. The kit according to one of the claims 4 to 7, wherein the nucleic acid is SEQ. ID NO. 1, 9, 13 or 16 encoding for a universal chimeric antigen receptor with an amino acid sequence according to SEQ. ID NO.17, 18, 19 or 20.
  9. A pharmaceutical composition comprising a kit according to one of the claims 4 to 8.
  10. The kit according to one of the claims 4 to 8 or a pharmaceutical composition of claim 9 for use in the treatment of cancer, infections, inflammatory and autoimmune disorders.

Description

The present invention relates to a targeting module comprising a chemically synthesized peptide binding moiety specific for a human cell surface protein or protein complex a kit comprising the targeting module and a vector or a cell comprising a nucleic acid encoding a universal chimeric antigen receptor, a pharmaceutical composition comprising said kit, and said kit or said pharmaceutical composition for use for the treatment of cancer, infections and autoimmune disorders. Chimeric antigen receptors (CARs) are artificial receptors consisting of a binding moiety, which provides the antigen-specificity and one or several signaling chains derived from immune receptors (Cartellieri et al. 2010). These two principal CAR domains are connected by a linking peptide chain including a transmembrane domain, which anchors the CAR in the cellular plasma membrane. Immune cells, in particular T and NK lymphocytes, can be genetically modified to express CARs inserted into their plasma membrane. If such a CAR modified immune cell encounters other cells or tissue structures expressing or being decorated with the appropriate target of the CAR binding moiety, upon binding of the CAR binding moiety to the target antigen the CAR modified immune cell is cross-linked to the target. Cross-linking leads to an induction of signal pathways via the CAR signaling chains, which wil change the biologic properties of the CAR engrafted immune cell. The adoptive transfer of immune cells engineered with chimeric antigen receptors (CARs) is currently considered as a highly promising therapeutic option for treatment of otherwise incurable malignant, infectious or autoimmune diseases. First clinical trials demonstrated both the safety and the feasibility of this treatment strategy (Lamers et al. 2006, Kershaw et al. 2006). However, the conventional CAR technology comes along with a number of critical safety issues. The immune responses of T cells engineered with conventional CARs are difficult to control after infusion into the patient, in particular unexpected target gene expression on healthy tissue may provoke an immune reaction of engineered T cells against healthy cells, which can cause severe side effects (Lamers et al. 2006, Morgan et al. 2010). 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 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 (Grupp et al. 2013). WO 2012082841 A2 discloses universal anti-tag chimeric antigen receptor-expressing T cells and methods of treating cell related disorders, e.g. cancer. Furthermore, WO 2013044225 A1 discloses a universal immune receptor expressed by T cells for the targeting of diverse and multiple antigens. Both methods describe the use of modified T cells expressing universal anti-tag immune receptors. These T cells can be redirected to disease-related cell surface antigens by additionally applying modules binding these surface antigens and carrying the respective tag. The disadvantage is the redirection of the genetically modified T cells using exogenous tags, which are likely immunogenic and therefore put patients in danger and negatively affect efficacy of treatment. Alternatively, EP 2 990 416 A1 discloses a genetically modified immune cell, in particular T- and NK-cell based therapies, that allows a redirection against diverse disorders in a safe and efficient manner using endogenous tags based on nuclear proteins. In particular, EP 2 990 416 A1 discloses a nucleic acid encoding a universal chimeric antigen receptor (UniCAR) and a targeting module composed of a binding moiety specific for a certain human cell surface protein or protein complex and a tag, wherein the tag is derived from any human nuclear protein and their use for stimulating an immune response in mammals. In contrast to conventional CARs, the scFv in universal CARs does not recognize a cell surface antigen but a short nonimmunogenic peptide motif derived from a human nuclear protein. Thus, T cells engineered to express UniCARs remain inactive after reinfusion, as this UniCAR target is not available on the surface of intact cells under physiological conditions (Fig. 1). The targeting modules are based on recombinant proteins including antibody fragments (i.e. scFvs or Fabs), ligands or soluble receptors. A disadvantage of the disclosed method is the highly complex production and purification procedure, which needs to be established and performed, to obtain clinical-grade targeting modules. This includes recombinant expression in prokaryotic or mammalian cell culture systems, complex multi-step chromatography procedures for purification and extensive analytical panels for quality control. Moreover, the stability of the targeti