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Jindřich Henry Kopeček

Distinguished Professor of Molecular Pharmaceutics and Distinguished Professor of Biomedical Engineering

Biorecognition, Drug Delivery

Kopecek Photo

 

Biological Chemistry Program

Education

M.S. Institute of Chemical Technology, Czechoslovakia

Ph.D. Institute of Macromolecular Chemistry, Czechoslovakia

D.Sc. Czechoslovak Academy of Sciences, Czechoslovakia

Links

Lab Page

PubMed Literature Search

Jindřich.Kopecek@utah.edu

 

Research

Research in the Kopeček/Yang Laboratory focuses on the design, synthesis, and characterization of biorecognizable macromolecules.

Multi-Antigen T Cell Hybridizers (MATCH)

In this innovative design hybridization of morpholino oligonucleotides (MORF)s mediates T cell recruitment and activation against malignant B cells. MATCH involves the creation of a cancer cell targeting motif minilibrary (based on the antigen profile on target cells) composed of antibody fragment-MORF1 conjugates (e.g., Fab’CD20-MORF1, Fab’CD19-MORF1, Fab’CD38-MORF1, Fab’BCMA-MORF1, Fab’SLAMF7-MORF1) that dimerize with T cell-engaging Fab’ conjugate containing a complementary MORF2 (Fab’CD3-MORF2). MORF hybridization in MATCH creates a synapse between a target cell and an effector T cell by using Fab’ fragments capable of binding antigens on both cells. MATCH’s two-component “split-antibody” design offers a modular, customizable platform for designing bi- and multi-specific T cell recruitment therapies for lymphoma, leukemia, and multiple myeloma. Its key advantages include: (a) cell-specific targeting through interchangeable cancer cell-targeting motifs to address tumor heterogeneity; (b) reduced cytokine release and T cell exhaustion; and (c) personalized therapeutic strategies.

Polymer-Enhanced Antibody-Drug Conjugates (pADCs)

Classic ADCs greatly improve the therapeutic index compared to traditional chemotherapeutic agents. However, the limited payload on a single antibody (drug-to-antibody ratio, or DAR) has been driving investigators to use extremely toxic agents; even very low off-target binding of these ADCs may induce severe side-effects. Polymer-enhanced antibody drug conjugates (pADCs) represent a promising next-generation therapeutic platform that integrates the specificity of mAbs with the controlled drug delivery benefits of polymer-based carriers. Unlike conventional ADCs that use small-molecule linkers with a limited DAR, pADCs utilize semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug conjugates, which enables a significant increase in the DAR, reaching up to 40. The hydrophilicity and excellent solubility of the HPMA copolymer backbone enhance stability and pharmacokinetics of pADCs, preventing aggregation issues commonly seen in highly loaded ADCs while maintaining efficient drug delivery. HPMA-based pADCs offer a safer and more effective drug delivery approach compared to conventional ADCs.

Macromolecular Therapeutics

Combination chemotherapy and immunotherapy with macromolecular therapeutics – design of multivalent polymer-peptide PD-L1 antagonists.

We designed Multivalent Polymer-Peptide PD-L1 Antagonist (MPPA), a new, effective PD-1/PD-L1 inhibitor based on multivalency and receptor crosslinking. A PD-L1 antagonist peptide (PPA-1; NYSKPTDRQYHF) attached in multiple copies to HPMA copolymer hyper-crosslinks the cell surface PD-L1 receptors and efficiently traffics the complex to the lysosomes for degradation resulting in decreased PD-L1 expression at cell surface and enhanced antitumor activity.

Combination chemotherapy and immunotherapy with backbone degradable HPMA copolymer-epirubicin conjugate (2P-EPI; KT-1) and MPPA is effective in the treatment of triple negative 4T1 breast cancer (10/10 complete tumor regressions), in a clinically relevant model of transgenic MMTV-PyMT breast tumor that closely mimics the development of human breast cancer in an immunocompetent background, and in a murine melanoma model.

Brain Delivery of Macromolecular Therapeutics

Nanomedicines designed for brain delivery/action have a difficult hurdle to overcome; they need to cross the blood brain barrier (BBB). We focus on receptor binding peptides that transcytose bound cargo into the brain. In particular, angiopep-2 (AP-2; TFFYGGSRGKRNNFKTEEY) binds to LDLR (low-density lipoprotein receptor)-related protein 1(LRP-1) followed by transcytosis. N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer – AP-2 conjugates are evaluated for the treatment of primary central nervous system lymphoma (PCNSL) and Alzheimer disease (AD).

References

  1. Li, J. Li, H. Al Faruque, P. Shami, B. Knoechel, J. Lohr, D. Sborov, J. Yang, J. Kopeček, Self-Assembling Multi-Antigen T Cell Hybridizers for Precision Immunotherapy of Multiple Myeloma. Adv. Healthcare Mat. e02156 (2025); https://doi.org/10.1002/adhm.202502156.
  2. T. Gambles, I. Kendell, J. Li, K. Spainhower, D. Sborov, S. Owen, A. Stark, D. Bearss, J. Yang, J. Kopeček, Two-Component T-Cell Immunotherapy Enables Antigen Pre-Targeting to Reduce Cytokine Release Without Forfeiting Efficacy. Nanomedicine: Nanotechnology, Biology, and Medicine 67 (2025) 102825; https://doi.org/10.1016/j.nano.2025.102825.
  3. Li, S. Li, H. Al Faruque, J. Kopeček, D.W. Sborov, J. Yang, CD38-Targeted Antibody-Polymer Drug Conjugates for Enhanced Treatment of Multiple Myeloma. Biomaterials 324 (2026) 123464; https://doi.org/10.1016/j.biomaterials.2025.123464.
  4. A. Ljubimov, T. Sun, J. Wang, L. Li, P.Z. Wang, A.V. Ljubimov, E. Holler, K.L. Black, J. Kopeček, J.Y. Ljubimova, J. Yang, Blood-brain Barrier Crossing Biopolymer Targeting c-Myc and Anti-PD-1 Activate Primary Brain Lymphoma Immunity: Artificial Intelligence Analysis. J. Controlled Release 381, 113611 (2025); https://doi.org/j.jconrel.2025.113611.
  5. Li, H. Al Faruque, S. Li, M. Sima, D. Sborov, S. Hu-Lieskovan, T. Werner, J. Kopeček, J. Yang, PD-L1 Targeted Antibody-Polymer-Epirubicin Conjugate Prolongs Survival in a Preclinical Murine Model of Advanced Ovarian Cancer. J. Controlled Release 382, 113682 (2025); https://doi.org/j.jconrel.2025.113682.
  6. Li, J. Arnold, M. Sima, H. Al Faruque, J. Galang, S. Hu-Lieskovan, J. Kopeček, J. Yang, Combination of Multivalent DR5 Receptor Clustering Agonists and Histone Deacetylase Inhibitors for Treatment of Colon Cancer. J. Controlled Release 376, 1014-1024 (2024); https://doi.org/10.1016/j.conrel.2024.10.062.
  7. T. Gambles, S. Li, I. Kendell, J. Li, D. Sborov, P. Shami, J. Yang, J. Kopeček, Multiantigen T-Cell Hybridizers: A Two Component T-Cell Activating Therapy. ACS Nano 18, 23341-23353 (2024); https://doi.org/10.1021/acsnano.4c06500.
  8. Li, M.T. Gambles, B. Jones, J.A. Williams, N.J. Camp, P.J. Shami, J. Yang, J. Kopeček, Human Serum Albumin-Based Drug-Free Macromolecular Therapeutics Induce Apoptosis in Chronic Lymphocytic Leukemia Patient Cells by Crosslinking of CD20 and/or CD38 Receptors. Drug Delivery Translational Res. 14, 2203-2215 (2024); https://doi.org/10.1007/s13346-024-01629-3.
  9. Kopeček, Hydrophilic Biomaterials: From Crosslinked and Self-Assembled Hydrogels to Polymer-Drug Conjugates and Drug-Free Macromolecular Therapeutics. J. Controlled Release 373, 1-22 (2024); https://doi.org/10.1016/j.jconrel.2024.05.012. Invited “Magnum Opus” manuscript.
  10. T. Gambles, D. Sborov, P. Shami, J. Yang, J. Kopeček, Obinutuzumab-Based Drug-Free Macromolecular Therapeutics Synergizes with Topoisomerase Inhibitors. Macromol. Biosci. (2023) 2300375; https://doi.org/10.1002/mabi.202300375.
  11. T. Gambles, J. Yang, J. Kopeček, Multi-Targeted Immunotherapeutics to Treat B Cell Malignancies. J. Controlled Release 358, 232-258 (2023); https://doi.org/10/1016/j.jconrel.2023.04.048.
  12. -H. Peng, C.M. Jogdeo, J. Li, Y. Xie, Y. Wang, Y.M. Sheinin, J. Kopeček, D. Oupický, Tumor Microenvironment-Responsive Polymeric iRGD and Doxorubicin Conjugates Reduce Spontaneous Lung Metastasis in an Orthotopic Breast Cancer Model. Pharmaceutics 14, 1725 (2022); https://doi.org/10.3390/pharmaceutics14081725.
  13. T. Gambles, J. Li, D.C. Radford, D. Sborov, P. Shami, J. Yang, J. Kopeček, Simultaneous Crosslinking of CD20 and CD38 Receptors by Drug-Free Macromolecular Therapeutics Enhances B Cell Apoptosis In Vitro and In Vivo. J. Controlled Release 350, 584-599 (2022); https://doi.org/10.1016/j.jconrel.2022.08.045.
  14. Wang, J. Yang, J. Kopeček, Nanomedicines in B Cell-Targeting Therapies. Acta Biomater. 137, 1-19 (2022); https://doi.org/10.1016/j.actbio.2021.10.024.
  15. T. Gambles, J. Li, J. Wang, D. Sborov, J. Yang, J. Kopeček, Crosslinking of CD38 Receptors Triggers Apoptosis of Malignant B Cells. Molecules 26, 4658 (2021); https://doi.org/10.3390/molecules26154658.
  16. Li, J. Wang, D.C. Radford, J. Kopeček, J. Yang, Combination Treatment with Immunogenic and Anti-PD-L1 Polymer-Drug Conjugates of Advanced Tumors in a Transgenic MMTV-PyMT Mouse Model of Breast Cancer. J. Controlled Release 332, 652-659 (2021); https://doi.org/10.1016/j.jconrel.2021.02.011.
  17. Li, L. Li, J. Wang, D.C. Radford, Z. Gu, J. Kopeček, J. Yang, Dendronized Polymer Conjugates with Amplified Immunogenic Cell Death for Oncolytic Immunotherapy. J. Controlled Release 329, 1129-1138 (2021); https://doi.org/10.1016/j/jconrel.2020.10.041.
  18. Kopeček, J. Yang, Polymer Nanomedicines. Adv. Drug Deliv. Rev. 156, 40-64 (2020); https://doi.org/10/1012/j.addr.2020.07.020.
  19. Wang, Y. Li, L. Li, J. Yang, J. Kopeček, Exploration and Evaluation of Therapeutic Efficacy of Drug-Free Macromolecular Therapeutics in Collagen-Induced Rheumatoid Arthritis Mouse Model. Macromol. Biosci. (2020) 1900445; doi: 10.1002/mabi.201900445.
  20. C. Radford, J. Yang, M. Doan, L. Li, A.S. Dixon, S.C. Owen, J. Kopeček, Multivalent HER2-Binding Polymer Conjugates Facilitate Rapid Endocytosis and Enhance Intracellular Drug Delivery. J. Controlled Release 319, 285-299 (2020); https://doi.org/10.1016/j.conrel.2019.12.049.
  21. Li, Y. Li, C.-H. Yang, D.C. Radford, J. Wang, M. Janát-Amsbury, J. Kopeček, J. Yang, Inhibition of Immunosuppresive Tumors by Polymer-Assisted Inductions of Immunogenic Cell Death and Multivalent PD-L1 Crosslinking. Adv. Funct. Mater. 30, 1908961 (2020); doi: 10.1002/admf.201908961.
  22. Li, J. Wang, Y. Li, D.C. Radford, J. Yang, J. Kopeček, Broadening and Enhancing Functions of Antibodies by Self-Assembling Multimerization at Cell Surface. ACS Nano 13, 11422-11432 (2019); doi.10.1021/acsnano.9b04868. ACS Editor Choice.
  23. Wang, L. Li, J. Yang, P.M. Clair, M. Glenn, D.M. Stephens, D.C. Radford, K.M. Kosak, M.W. Deininger, P.J. Shami, J. Kopeček, Drug-free Macromolecular Therapeutics Induce Apoptosis in Cells Isolated from Patients with B Cell Malignancies with Enhanced Apoptosis Induction by Pretreatment with Gemcitabine. Nanomedicine: Nanotechnology, Biology, and Medicine16, 217-225 (2019). https://doi.org/10.1016/j.nano.2018.12.011.
  24. Yang, R. Zhang, H. Pan, Y. Li, Y. Fang, L. Zhang, J. Kopeček, Backbone Degradable HPMA Copolymer Conjugates with Gemcitabine and Paclitaxel: Impact of Molecular Weight on Activity toward Human Ovarian Carcinoma Xenografts. Mol. Pharmaceutics 14, 1384-1394 (2017).
  25. M. Hartley, T.-W. Chu, E.M. Peterson, R. Zhang, J. Yang, J. Harris, J. Kopeček, Super-Resolution Imaging and Quantitative Analysis of Membrane Protein/Lipid Raft Clustering Mediated by Cell Surface Self-Assembly of Hybrid Nanoconjugates. ChemBioChem 16, 1725-1729 (2015).
Last Updated: 8/23/25