October 2018

NEWS & OPINION

Insights
Of exosomes and Centyrins


by J.C. Noreika, MD, MBA


J.C. Noreika, MD, MBA

Monoclonal antibodies promise to revolutionize the treatment of disease, reduce morbidity, extend life, and enhance its quality. What’s next?

Medicine’s art imparts hope and compassion. Its science contests morbidity and mortality. It has been less than 70 years since Linus Pauling sent a paper to his son, a student at Cambridge, describing the triple helix of DNA. Reading the paper, Jim Watson realized that Pauling had gotten the chemistry wrong but the concept right. Watson and Crick went on to elaborate the correct molecular structure of the helical strand. Everything changed.
Beginning in 1990, an international consortium—the world’s largest collaborative biologic project—built a mosaic of the human genome. Completed in 2003, its map contains more than 3 billion nucleotides. Functionally evolving, this achievement transformed biology, genetics, and medicine. Diseases that had vexed humans for millennia are unmasked at their most elemental. Immunotherapeutics—precision medicine—integrate genetics, epigenetics, and idiosyncratic risk factors that define individual uniqueness. This is not your father’s pharmacology.
The first monoclonal antibody (mAb) was generated in a murine model in 1975. In 1984, discoverers Neils Jerne, Georges J.F. Köhler, and César Milstein shared the Nobel Prize for Physiology and Medicine. The FDA approved the first therapeutic mAb, Orthoclone OKT3 (muromonab-CD3), to prevent kidney transplant rejection in 1992. But infusion of Orthoclone often resulted in side effects and sometimes death. Immunogenicity with production of anti-mouse antibodies in 50% of patients also proved a treatment impediment. Orthoclone was withdrawn from clinical use due to its low therapeutic index. Later in the decade, a murine monoclonal antibody was found to inhibit vascular endothelial growth factor (VEGF) known to mediate angiogenesis in tumors, diabetic retinopathy, and age-related macular degeneration. Using recombinant DNA techniques, a humanized form of the antibody, bevacizumab, was conceived and found to have biologic affinities similar to murine compounds.1
The genie was out of the bottle. As of May 2018, the FDA had approved 80 mAbs for treatment of diseases as diverse as cancer, psoriasis, collagen vascular diseases such as rheumatoid arthritis, lupus and ulcerative colitis, migraine, and of course, age-related macular degeneration. Today, nearly 20 antibody drug conjugates (ADCs) that deliver cytotoxic drugs with tumor cell specificity and potency unmatched by other chemotherapeutic agents have been approved or are in late-phase clinical testing.
CART (chimeric antigen receptor therapy) is a modality using T-cells with genetically engineered receptors to enhance the body’s immune response. CART cell therapy has been approved by the FDA to treat leukemia and lymphoma. Eureka Therapeutics recently reported a novel CART approach to intracellularly attack solid tumors. For the latter, checkpoint inhibitors are typically deployed. These are mAbs that enhance the body’s immune system by activating T-cells that ordinarily remain quiescent. T-cells have a surface checkpoint protein PD-1 that prevents them from attacking normal cells. Binding to PD-L1 receptors found on some of the body’s normal cells, T-cells stand down. Some cancer cells have PD-L1 receptors.
Both CART and checkpoint inhibitors cause significant complications. Immuno-oncologists refer to these as on-target and off-target effects. On-target effects specifically impact neoplastic cells and are beneficial in reducing or eliminating tumor load. But CART can cause B-cell aplasia, an on-target, off-tumor complication. Off-target effects can range from moderate discomfort (fever and rash) to death. Cytokine release syndrome is caused by the destruction of the targeted cells by aggregating immune cells. Cytokines can cause fever, nausea, hypotension, headache, neurologic changes, and other symptoms. Life-threatening complications can occur affecting the heart, lungs, kidneys, liver, central nervous and coagulation systems.
Ophthalmologists consulting on the oncology floor have noticed rare but serious ocular and orbital complications of checkpoint-inhibition therapy.2 Resembling the pathology of autoimmune disease, keratitis, uveitis, uveal effusions, choroidal neovascularization, Vogt-Koyanagi-Harada syndrome, melanoma-associated retinopathy (MARs), optic neuropathy, cranial nerve palsies, Graves-like ophthalmopathy, and other conditions have been reported.
“Advances in T-cell engineering, genetic editing, the selection of the most functional lymphocytes, and cell manufacturing have the potential to broaden T-cell-based therapies and foster new applications beyond oncology in infectious diseases, organ transplantation, and autoimmunity.”3 Two intriguing areas of research impelling scientific inquiry and economic investment are scaffold proteins and exosomes. Because of their low molecular weight and lack of immunogenicity, they may mitigate mAbs’ production complexity, exorbitant cost and side effects.
Centyrins are tiny (10 kDa) non-antibody proteins that can deliver covalently linked therapeutic or diagnostic agents to specific tissues and cell types. A recent study found that an epidermal growth factor receptor-binding Centyrin yielded 26 of 94 peptides “ideal for cysteine modification, conjugation and drug delivery.” Although ADCs remain the dominant targeted delivery platform, “alternative scaffold proteins” show promise because they exhibit better tissue penetration, incite little or no immunologic effect, are highly stable and, readily expressed in Escherichia coli, can be produced commercially.
Exosomes are naturally occurring lipid vesicles coursing through the blood stream while carrying genetic information and other proteins between cells. In 2007, Swedish scientist Jan Lötvall found that cells use these messengers to transfer protein-producing messenger RNAs and gene expression regulating microRNAs to other cells. They can spread diseases like cancer but may be harnessed to deliver small molecule drugs and proteins, RNA and viral gene therapies, even CRISPR gene-editing tools.
Fantasy? Toxoplasmosis, retinoblastoma, ocular melanoma, diabetic retinopathy, and other tragedies may one day yield to safe, inexpensive treatments now thought unimaginable. Arthur C. Clarke observed that, “science fiction is something that could happen—but usually you wouldn’t want it to. Fantasy is something that couldn’t happen—though often you only wish that it could.” It just might.

References

1. Presta LG, et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997;57:4593–9.
2. Dalvin LA, et al. Checkpoint inhibitor immune therapy: systemic indications and ophthalmic side effects. Retina. 2018;38:1063–1078.
3. June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379:64–73.

Editors’ note: Dr. Noreika has practiced ophthalmology since 1981. He has been a member of ASCRS for more than 35 years.

Contact information

Noreika: jcnmd@aol.com

Of exosomes and Centyrins Of exosomes and Centyrins
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