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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

 

Research

Research in the KopečekBiomedical Polymers Laboratory focuses on: a) Macromolecular therapeutics with emphasis on combination chemotherapy and immunotherapy; b) Macromolecular therapeutics for brain delivery; c) Antibody-drug conjugates; d) Drug-free macromolecular therapeutics – a new paradigm in nanomedicine where apoptosis is initiated by biorecognition of nanoconjugates at the cell surface and receptor crosslinking; no low molecular weight drug is needed.

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Combination chemotherapy and immunotherapy

To develop methods for the treatment of immunosuppressive cancers we combine polymer-drug conjugates with polymer – checkpoint inhibitor conjugates. Newly designed backbone degradable HPMA [N-(2-hydroxypropyl)methacrylamide] copolymer – anticancer drug conjugates possess long-circulating pharmacokinetics and enhanced antitumor activities, while keeping excellent biocompatibility. The conjugates induce immunogenic cell death in murine cancer models and convert “cold” tumors to “hot” ones that are susceptible to PD-L1 degradation immunotherapy. Original design of a new multivalent PD-L1 antagonist not only acts as a traditional checkpoint inhibitor, but mediates the surface crosslinking of PD-L1, biases its subcellular fate to lysosomes for degradation, and exhibits persistent suppression. Pre-clinical evaluation of the leading HPMA copolymer-epirubicin conjugate (KT-1) is being executed at the Nanotechnology Characterization Laboratory at NCI.

Macromolecular therapeutics for brain delivery

Nanomedicines designed for brain delivery/action have a difficult hurdle to overcome; they need to cross the blood brain barrier. We focus on receptor binding peptides that transcytose bound cargo into the brain. In particular, angiopep-2 (TFFYGGSRGKRNNFKTEEY) binds to LDLR (low-density lipoprotein receptor)-related protein(LRP)-1 followed by transcytosis. In collaboration with the University of Utah Department of Radiology we are developing conjugates suitable for the treatment of traumatic brain injury and Alzheimer disease.

Antibody-drug conjugates

A novel design of antibody-drug conjugates composed of antibodies and semitelechelic HPMA copolymer – drug conjugates are being studied. This design integrates the high specificity of antibody-drug conjugates with advantages of macromolecular therapeutics. The new design increases the drug-to-antibody ratio. Consequently, it has the potential to enhance the treatment efficacy and decrease the off-target toxic effects.

Drug-free macromolecular therapeutics (DFMT)

Our present studies evaluate the 2nd generation of DMFT. Anti-CD20 antibodiesare divided into Type I such as rituximab (RTX) and Type II such as obinutuzumab (OBN); they have different patterns of binding to CD20 receptor. RTX binds between CD20 tetramers resulting in accumulation in lipid rafts, calcium influx and caspase activation. OBN binds within one tetramer with the conformation compatible with homotypic adhesion regions, leading to actin cytoskeleton remodeling and lysosome disruption. Our design enhances the activity of Type II OBN by triggering the apoptosis activation pathways of both types of antibodies. This new system is composed of two nanoconjugates: a) bispecific engager, OBN-MORF1 (OBN conjugated to one morpholino oligonucleotide MORF1); and b) a crosslinking (effector) component HSA-(MORF2)X (human serum albumin (HSA) grafted with multiple copies of complementary morpholino oligonucleotide 2). Modification of OBN with one MORF1 does not impact the binding of OBN-MORF1 to CD20 and following binding to CD20 Type II effects occur. Further exposure to multivalent effector HSA-(MORF2)X results in clustering the OBN-MORF1-CD20 complexes into lipid rafts and Type I effects occur. This new approach combines effects of both antibody types resulting in very high apoptotic levels.

DFMT are efficient in vitro, on animal models, and on cells isolated from patients diagnosed with various B cell malignancies. DFMT is a platform; it is also efficient in crosslinking of CD38, DR5, combination of CD20 and CD38 as well as treatment of rheumatoid arthritis.

References

  1. Wang, Yang J, Kopeček J (2022) Nanomedicines in B Cell-Targeting Therapies. Acta Biomater. 137:1-19; https://doi.org/10.1016/j.actbio.2021.10.024.
  2. Gambles MT, Li J, Wang J, Sborov D, Yang J, Kopeček J (2021) Crosslinking of CD38 Receptors Triggers Apoptosis of Malignant B Cells. Molecules 26:4658; https://doi.org/10/3390/molecules26154658.
  3. Li Y, Li L, Wang J, Radford DC, Gu Z, Kopeček J, Yang J (2021) Dendronized Polymer Conjugates with Amplified Immunogenic Cell Death for Oncolytic Immunotherapy. J.
  4. Controlled Release 329:1129-1138; https://doi.org/10.1016/j/jconrel.2020.10.041.
  5. Li L, Wang J, Radford DC, Kopeček J, Yang J (2021) 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; https://doi.org/10.1016/j.jconrel.2021.02.011.
  6. Kopeček J, Yang J (2020) Polymer Nanomedicines. Adv. Drug Deliv. Rev. 156:40-66 https://doi.org/10/1012/j.addr.2020.07.020.
  7. Li L, Li Y, Yang CH, Radford DC, Wang J, Janát-Amsbury M, Kopeček J, Yang J (2020) Inhibition of Immunosuppresive Tumors by Polymer-Assisted Inductions of Immunogenic Cell Death and Multivalent PD-L1 Crosslinking. Adv. Funct. Mater. 30:1908961; doi: 10.1002/admf.201908961.
  8. Radford DC, Yang J, Doan M, Li L, Dixon AS, Owen SC, Kopeček J (2020) Multivalent HER2-Binding Polymer Conjugates Facilitate Rapid Endocytosis and Enhance Intracellular Drug Delivery. J. Controlled Release 319:285-299.
  9. Wang J, Li Y, Li L, Yang J, Kopeček J (2020) Exploration and Evaluation of Therapeutic Efficacy of Drug-Free Macromolecular Therapeutics in Collagen-Induced Rheumatoid Arthritis Mouse Model. Macromol. Biosci. 20:1900445; doi: 10.1002/mabi.201900445.
  10. Li L, Wang J, Li Y, Radford DC, Yang J, Kopeček J (2019) Broadening and Enhancing Functions of Antibodies by Self-Assembling Multimerization at Cell Surface. ACS Nano 13:11422-11432; doi.10.1021/acsnano.9b04868.
  11. Yang J, Li L, Kopeček J (2019) Biorecognition: A Key to Drug-free Macromolecular Therapeutics. Biomaterials 190-191:11-23.
  12. Wang J, Li L, Yang J, Clair PM, Glenn M, Stephens DM, Radford DC, Kosak KM, Deininger MW, Shami PJ, Kopeček J (2019) Drug-free Macromolecular Therapeutics Induce Apoptosis in Cells Isolated from Patients with B Cell Malignancies with Enhanced Apoptosis Induction by Pretreatment with Gemcitabine. Nanomedicine: NBM 16:217-225. https://doi.org/10.1016/j.nano.2018.12.011.
  13. Li L, Yang J, Soodvilai S, Wang J, Opanasopit P, Kopeček J (2019) Drug-Free Albumin-Triggered Sensitization of Cancer Cells to Anticancer Drugs. J. Controlled Release 293:84-93.
  14. Zhang L, Fang Y, Li L, Yang J, Radford DC, Kopeček J (2018) Human Serum Albumin Based Drug-Free Macromolecular Therapeutics: Apoptosis Induction by Coiled-Coil-Mediated Cross-Linking of CD20 Antigens on Lymphoma B Cell Surface. Macromol. Biosci. 18:1800224; https://doi.org/10.1002/mabi.201800224.
  15. Li L, Yang J, Wang J, Kopeček J (2018) Amplification of CD20 Crosslinking in Rituximab Resistant B-lymphoma Cells Enhances Apoptosis Induction by Drug-Free Macromolecular Therapeutics. ACS Nano 12:3658-3670.
  16. Li L, Yang J, Wang J, Kopeček J (2018) Drug-Free Macromolecular Therapeutics Induce Apoptosis via Calcium Influx and Mitochondrial Signaling Pathway. Macromol. Biosci. 18(1):1700196; doi:10.1002/mabi.201700196.
  17. Yang J, Kopeček J (2017) The Light at the End of the Tunnel – Second Generation HPMA Conjugates for Cancer Treatment. Curr. Opin. Colloid Interface Sci. 31:30-42.
  18. Zhang L, Fang Y, Kopeček J, Yang J (2017) A New Construct of Antibody-Drug Conjugates for Treatment of Non-Hodgkin’s Lymphoma. Eur. J. Pharm. Sci. 103:36-46.
  19. Yang J, Zhang R, Pan H, Li Y, Fang Y, Zhang L, Kopeček J (2017) 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.
  20. Zhang L, Fang Y, Yang J, Kopeček J (2017) Drug-Free Macromolecular Therapeutics: Impact of Structure on Induction of Apoptosis in Raji B Cells. J. Controlled Release 263:139-150.
  21. Zhang R, Yang J, Radford DC, Fang Y, Kopeček J (2017) FRET Imaging of Enzyme-Responsive HPMA Copolymer Conjugate. Macromol. Biosci. 17:1600125; doi: 10.1002/mabi.201600125.
  22. Hartley JM, Zhang R, Gudheti M, Yang J, Kopeček J (2016) Tracking and Quantifying Polymer Therapeutic Distribution on a Cellular Level Using 3D dSTORM. J. Controlled Release 231:50-59.
  23. Zhang L, Zhang R, Yang J, Wang J, Kopeček J (2016) Indium-based and Iodine-based Labeling of HPMA Copolymer-Epirubicin Conjugates: Impact of Structure on the In Vivo Fate. J. Controlled Release 235:306-318.
  24. Yang J, Zhang R, Radford DC, Kopeček J (2015) FRET-Trackable Biodegradable HPMA Copolymer-Epirubicin Conjugates for Ovarian Carcinoma Therapy. J. Controlled Release 218:36-44.
  25. Chu TW, Feng J, Yang J, Kopeček J (2015) Hybrid Polymeric Hydrogels via Peptide Nucleic Acid (PNA)/DNA Complexation. J. Controlled Release 220:608-616.
  26. Chu TW, Zhang R, Yang J, Chao MP, Shami PJ, Kopeček J (2015) A Two-Step Pretargeted Nanotherapy for CD20 Crosslinking May Achieve Superior Anti-Lymphoma Efficacy to Rituximab. Theranostics 5:834-846.
Last Updated: 9/7/22