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TCR-m Antibodies to Intracellular Protein Targets; Epitope Regulation

Nearly all protein targets are inside the cancer cell and are not currently druggable. Human antibodies are designed to react with peptide fragments of oncogenic proteins presented on the cell surface to kill cancer cells.(1)(2)  Such TCRm can be made into CAR T cells or bispecific antibodies as well. (3)  The regulation of antigen presentation and prediction of epitope targets of TCR’s is also studied. (4,5,6)

Targeted Alpha Particle Therapy

Alpha particles are short-ranged high-energy radiations capable of killing in a range of 1 to 3 cells. We are attempting to deliver alpha-emitting isotopes to leukemia cells and small solid tumors using engineered cells and antibodies as ligands. Bi-213 and Ac-225 are purified and chelated to the Ig. Biochemistry of the agents, radiobiology, and pharmacology are studied. Model systems under study include myeloid leukemias, prostate cancer, and lymphoma. Several human trials have been initiated. (7)

Innovative Next Generation CAR T cells

Smarter CAR T cells that secrete biologic agents or small molecule drugs or can be selectively controlled or gated are under development.(11)  Engineered cells that block host defenses are in development.

Oncogenic Protein Vaccines

The amino acid sequences of  overexpressed oncogenic proteins, or mutated sequences, can be used to develop tumor-specific vaccines for treating humans. One  such vaccine for treating a variety of cancers and leukemia directed to WT1 was developed by our laboratory and is currently being used to treat patients. We are also examining the use of mutated heteroclitic peptides with higher avidity for the HLA molecule to use as immunogens. (8)

 

 

  1. Dao T, Yan S, Veomett N, Pankov D, Zhou L, Korontsvit T, Scott A, Whitten J, Maslak P, Casey E, Tan T, Liu H, Zakhaleva V, Curcio M, Doubrovina E, O’Reilly RJ, Liu C, Scheinberg DA. Targeting the intracellular WT1 oncogene product with a therapeutic human antibody. Science translational medicine. 2013;5(176):176ra33. Doi: 10.1126/scitranslmed.3005661. PubMed PMID: 23486779; PMCID: PMC3963696.
  2. Chang AY, Dao T, Gejman RS, Jarvis CA, Scott A, Dubrovsky L, Mathias MD, Korontsvit T, Zakhaleva V, Curcio M, Hendrickson RC, Liu C, Scheinberg DA. A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens. J Clin Invest. 2017;127(7):2705-18. Epub 2017/06/20. doi: 10.1172/jci92335. PubMed PMID: 28628042; PMCID: PMC5490756.
  3. Dao T, Pankov D, Scott A, Korontsvit T, Zakhaleva V, Xu Y, Xiang J, Yan S, de Morais Guerreiro MD, Veomett N, Dubrovsky L, Curcio M, Doubrovina E, Ponomarev V, Liu C, O’Reilly RJ, Scheinberg DA. Therapeutic bispecific T-cell engager antibody targeting the intracellular oncoprotein WT1. Nature biotechnology. 2015;33(10):1079-86. Doi: 10.1038/nbt.3349. PubMed PMID: 26389576; PMCID: PMC4600043.
  4. Brea EJ, Oh CY, Manchado E, Budhu S, Gejman RS, Mo G, Mondello P, Han JE, Jarvis CA, Ulmert D, Xiang Q, Chang AY, Garippa RJ, Merghoub T, Wolchok JD, Rosen N, Lowe SW, Scheinberg DA. Kinase Regulation of Human MHC Class I Molecule Expression on Cancer Cells. Cancer immunology research. 2016; 4(11):936-47. Doi: 10.1158/2326-6066.CIR-16-0177. PubMed PMID: 27680026; PMCID: PMC5110210.
  5. Gejman RS, Chang AY, Jones HF, DiKun K, Hakimi AA, Schietinger A, Scheinberg DA. Rejection of immunogenic tumor clones is limited by clonal fraction. eLife, 2018; 7:e41090. DOI: https://doi.org/10.7554/eLife.41090. PMID: 30499773; PMCID: 6269121.
  6. Gejman RS, Jones HF, Klatt MG, Chang AY, Oh CY, Chandran SS, Korontsvit T, Zakahleva V, Dao T, Klebanoff CA, Scheinberg DA. Identification of the Targets of T-cell Receptor Therapeutic Agents and Cells by Use of a High-Throughput Genetic Platform. Cancer Immunol Res. 2020 May;8(5):672-684. doi: 10.1158/2326-6066.CIR-19-0745. Epub 2020 Mar 17. PMID: 32184297; PMC7310334.
  7. McDevitt MR, Ma D, Lai LT, Simon J, Borchardt P, Frank RK, Wu K, Pellegrini V, Curcio MJ, Miederer M, Bander NH, Scheinberg DA. Tumor therapy with targeted atomic nanogenerators. Science. 2001; 294:1537-1540. DOI: 10.1126/science.1064126. PMID:11711678.
  8. Maslak PG, Dao T, Bernal Y, Chanel S, Zhang R, Frattini M, Rosenblat T, Jurcic J, Brentjens R, Arcila ME, Rampal R, Park J. Douer D, Katz LM, Sarlis NJ, Tallman M, Scheinberg DA.  Prolonged survival in acute myeloid leukemia with galinpepimut-S, a WT1 peptide vaccine, given after achievement of CR1. Blood Advances. 2018; PMID: 29386195; PMCID: PMC5812332
  9. Mulvey JJ, Villa CH, McDevitt MR, Escorcia FE, Casey E, Scheinberg DA. Self-assembly of carbon nanotubes and antibodies on tumours for targeted amplified delivery. Nature Nanotechnology. 2013; 8(10):763-71. PMID: 2407702; PMCID: PMC3798027.
  10. Alidori S, Akhavein N, Thorek DL, Behling K, Romin Y, Queen D, Beattie BJ, Manova-Todorova K, Bergkvist M, Scheinberg DA, McDevitt MR. Targeted fibrillar nanocarbon RNAi treatment of acute kidney injury. Science Translational Medicine. 2016; 8(331):331ra39. PMID: 27009268; PMCID: PMC5004247.
  11. Rafiq S, Purdon TJ, Daniyan AF, Koneru M, Dao T, Liu C, Scheinberg DA, Brentjens RJ. Optimized T-cell receptor-mimic chimeric antigen receptor T cells directed toward the intracellular Wilms Tumor 1 antigen. Leukemia. 2017. Doi: 10.1038/leu.2016.373. PMID: 27924074 PMCID: PMC5495623.