Jindřich Henry Kopeček

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 2^nd 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.