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JP-7856286-B2 - Compounds for isolating undesirable antibodies in patients

JP7856286B2JP 7856286 B2JP7856286 B2JP 7856286B2JP-7856286-B2

Inventors

  • スムルツカ、オスカー
  • ヴァンコ、ベッティーナ

Assignees

  • アブレヴィア バイオテック ゲーエムベーハー

Dates

Publication Date
20260511
Application Date
20200323
Priority Date
20190323

Claims (20)

  1. • A biomolecular scaffold, and at least • a first peptide n-mer of the following general formula: P(-S-P) (n-1) and the second peptide n-mer of the following general formula: P(-S-P) (n-1) A compound containing, P is a peptide with a sequence length of 5 to 13 amino acids, and S is a non-peptide spacer. For each of the aforementioned peptide n-mers, independently, n is an integer greater than or equal to 1. Each of the peptide n-mers is covalently bonded to the biopolymer scaffold via a linker. The aforementioned biopolymer scaffold is transferrin. The aforementioned compound.
  2. The compound according to claim 1, wherein n is 1.
  3. The compound according to claim 1, wherein n is 2.
  4. The compound according to claim 1, wherein n is an integer of 3 or greater.
  5. The compound according to any one of claims 1 to 4, wherein at least one P is a cyclic peptide.
  6. P is independently either P a or P b , Pa is a peptide having a sequence length of 5 to 13 amino acids. Pb is a peptide having a sequence length of 5 to 13 amino acids. The first peptide n-mer is Pa -S- Pa , and the second peptide n-mer is Pa -S- Pa , The first peptide n-mer is Pa -S- Pa , and the second peptide n-mer is Pb -S- Pb , The first peptide n-mer is Pb -S- Pb , and the second peptide n-mer is Pb -S- Pb , The first peptide n-mer is Pa -S- Pb , and the second peptide n-mer is Pa -S- Pb , The first peptide n-mer is Pa -S- Pb and the second peptide n-mer is Pa -S- Pa , or the first peptide n-mer is Pa -S- Pb and the second peptide n-mer is Pb -S- Pb The compound according to claim 1.
  7. The compound according to claim 6, wherein at least one P is a cyclic peptide.
  8. The compound according to claim 6 or claim 7, wherein the peptide P a and the peptide P b are two different epitopes of the same antigen, or two different epitope portions of the same epitope.
  9. The compound according to any one of claims 1 to 8, wherein the biopolymer scaffold is human transferrin.
  10. The compound according to any one of claims 1 to 9, wherein the compound is non-immunogenic in mammals.
  11. The compound according to claim 10, wherein the compound is non-immunogenic in non-human primates.
  12. The compound according to claim 10, wherein the compound is non-immunogenic in humans.
  13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, and at least one pharmaceutically acceptable excipient.
  14. The pharmaceutical composition according to claim 13, which is non-immunogenic in humans.
  15. A pharmaceutical composition according to claim 13 or claim 14, for use in therapeutic purposes.
  16. A pharmaceutical composition according to claim 15, for use in the prevention or treatment of an autoimmune disease in an individual having an autoimmune disease or being at risk of developing such a disease, wherein the pharmaceutical composition is non-immunogenic in the individual.
  17. A pharmaceutical composition according to claim 15, for use in the prevention or treatment of graft rejection in an individual having or being eligible for graft, wherein the pharmaceutical composition is non-immunogenic in the individual.
  18. In individuals receiving or eligible for drug therapy, or in individuals receiving or eligible for gene therapy, In the prevention or treatment of adverse reactions based on anti-drug antibodies or anti-gene delivery vector antibodies, A pharmaceutical composition according to claim 15 for use, wherein the pharmaceutical composition is non-immunogenic in the organism.
  19. The pharmaceutical composition according to claim 18, wherein the drug is a peptide or a protein.
  20. The pharmaceutical composition according to claim 19, wherein the drug is selected from the group consisting of enzymes, enzyme inhibitors, antibodies, antibody fragments, antibody mimetics, antibody-drug conjugates, hormones, growth factors, coagulation factors, and cytokines.

Description

The present invention relates to compounds for sequestrating undesirable antibodies within an organism, such as antibodies involved in autoimmune diseases. Generally, antibodies are essential components of the humoral immune system, providing protection against infections caused by foreign organisms such as bacteria, viruses, fungi, or parasites. However, in certain situations, such as autoimmune diseases, organ transplants, blood transfusions, or the administration of biomolecular drugs or gene delivery vectors, antibodies can target the patient's own body (or foreign tissues or cells, or the biomolecular drug or vector immediately after administration), becoming harmful or disease-causing. Some antibodies may also interfere with imaging probes. Hereinafter, such antibodies will be collectively referred to as "undesirable antibodies" or "unwanted antibodies." With few exceptions, selective removal of unwanted antibodies has not reached clinical practice. Currently, indications are extremely limited. One known (but not widely established) technique for selective antibody removal is immunoapheresis. In contrast to immunoapheresis (which removes immunoglobulins), selective immunoapheresis involves filtering plasma through an extracorporeal selective antibody adsorption cartridge that depletes unwanted antibodies by selective binding to their antigen-binding sites. Selective immunoapheresis has been used, for example, to remove anti-A or anti-B antibodies from blood prior to ABO-incompatible transplantation, or for indications in transfusion medicine (Teschner et al). While selective apheresis has also been experimentally applied to other indications such as neuroimmunological conditions (Tetala et al) or myasthenia gravis (Lazaridis et al), it has not yet been established as a clinical routine. One reason selective immunoapheresis is only applied passively is that it is a high-cost and cumbersome treatment intervention requiring specialized medical care. Furthermore, conventional techniques do not know how to rapidly and efficiently deplete unwanted antibodies. Independent of apheresis, Morimoto et al. disclose dextran as a multivalent scaffold generally applicable for improving the immunoglobulin binding affinity of peptides and peptide-mimicking ligands such as FLAG peptides. International Publication No. 2011/130324 relates to a compound for the prevention of cytotoxicity. European Patent Application Publication No. 3059244 relates to a C-met protein agonist. As mentioned above, apheresis is applied in vitro. On the other hand, several conventional approaches have been proposed to deplete undesirable antibodies within the body, and these are mostly related to certain autoimmune diseases involving autoantibodies or anti-drug antibodies. Lorentz et al. have disclosed a technique for in situ charging erythrocytes with a tolerogenic payload to induce antigen-specific T cell depletion. This is thought to ultimately reduce undesirable humoral responses to model antigens. A similar approach has been proposed by Pishesha et al., in which peptide antigen constructs are covalently loaded onto the surface of erythrocytes ex vivo and then reinjected into animal models for general immune tolerance induction. International Publication No. 92/13558 relates to a complex of a stable, non-immunogenic polymer and an immunogen analog, the complex having specific B-cell binding ability to the immunogen and inducing humoral anergy to the immunogen upon introduction into an organism. These complexes are therefore disclosed to be useful for treating antibody-mediated symptoms caused by exogenous or autoimmunogens. In connection with this, see also European Patent Application Publication No. 0498658. Taddeo et al. disclose a method that uses an anti-CD138 antibody derivative fused to an ovalbumin model antigen to selectively induce receptor crosslinking and cell suicide in antibody-producing plasma cells expressing antibodies against the model antigen, thereby selectively depleting those cells. Apitope International NV (Belgium) is currently developing soluble toxicogenic T cell epitope peptides that can suppress antibody responses by inducing low levels of co-stimulatory molecules from tolerance-inducing antigen-presenting cells (see, e.g., Jansson et al.). These products are currently undergoing preclinical and early clinical evaluation for multiple sclerosis, Graves' disease, intermediate uveitis, and other autoimmune conditions, as well as factor VIII intolerance. Similarly, Selecta Biosciences, Inc. (USA) is currently researching tolerance induction strategies using so-called synthetic vaccine particles (SVPs). The SVP rapamycin is thought to induce tolerance by selectively inducing regulatory T cells, thereby preventing the production of undesirable antibodies (see Mazor et al.). Mingozzi et al. have disclosed a decoy adenovirus (AAV) capsid that adsorbs antibodies but cannot penetrate target cells. International Publication