Invented at Let There Be Hope Medical Research Foundation, a California 501 c 3 nonprofit foundation, the technology is being developed for clinical applications by the foundation’s scientists and founders of Augustus BioTarget, Inc. and Rodos BioTarget GmbH, Dr. Michael Scolaro, M.D., Dr. Robert Gieseler, Ph.D., and Dr. Sean Sullivan, Ph.D.
The objective of the initial research was to target C-type lectin receptors, a family of cell surface receptors on Antigen-presenting Cells (APCs) of the immune system and deliver a therapeutic agent intracellularly into the APC’s Dendritic Cells to eradicate HIV and Hepatitis C virus. The successful outcome of this targeting technology led to applications for international patents, subsequently sold to Rodos BioTarget GmbH in Germany for clinical and commercial development for a variety of other infectious and clinical diseases.
The CLR-TargoSphere® is well-tolerated and poorly immunogenic. It is designed with an aqueous core and a capsule composed of a lipid bilayer embedded with targeting anchors that enable the nanocarrier to bind exclusively to C-type lectin receptors (CLRs) predominantly expressed on the surface of antigen-presenting cells (APCs) of the immune system.
It can be produced in defined sizes, and offers an excellent payload capacity. It has been fully preclinically validated and no adverse effects on any major organ systems have been observed. Additionally, the production of the CLR-TargoSphere® has been scaled up to industrial batch sizes of greater than 20 liters under cGMP conditions. A first-in-man study of a non-loaded CLR-TargoSphere® has been approved by the MHRA (British regulatory authorities).
Key Advantages of the CLR-TargoSphere® over other Nanocarriers
- Encapsulated drugs in the CLR-TargoSphere® enter the immune system’s APCs by means of a non-phagocytic pathway, specifically by clathrin-mediated endocytosis, and subsequently enter the early endosomes within the intracellular matrix.
- Drugs encapsulated in the CLR-TargoSphere® escape from the early endosomes prior to endolysosomal fusion and enzymatic degradation, and unmodified drug(s) are delivered directly to sites of disease for therapeutic interventions by means of circulating immune cells (APCs).
- The CLR-TargoSphere® crosses the Blood Brain Barrier (BBB) and is concentrated in perivascular spaces, with intracellular uptake of the active pharmaceutical agent into astrocytes (as demonstrated by co-staining for glial fibrillary acidic protein or GFAP).
- Non-targeted nanocarriers enter the APCs by micropinocytosis, phagocytosis, clathrin-mediated and caveolae-mediated endocytosis, resulting in degradation and loss of large proportion of encapsulated drug(s) before reaching target sites.
- The most significant advantage over other competing targeted and non-targeted nanocarrier systems is that the TargoSphere® addresses all C-type lectin receptors, thereby entering all CLR-mediated cellular entry ports and all myeloid APC species (i.e., dendritic cells and macrophages of all developmental and tissue stages as well as blood monocytes).
- A maximal clinical effect can thus be achieved as opposed to other targeted nanocarriers that target only one APC receptor site, e.g.,targeting only DC-SIGN limits entry exclusively to immature dendritic cells only, resulting in a sub-optimal clinical response.
- CLR-TargoSphere®-directed targeting of all C-type lectin receptors results in more concentrated drug uptake into all APCs than is achieved with non-labeled nanocarriers.
- The CLR targeting specificity of our drug delivery system and absence of intracellular lysosomal degradation permits the following additional clinical advantages over competing nanocarriers that target more indiscriminately:
- Limited systemic distribution;
- Limited systemic toxicities to innocent bystander cells;
- Improved therapeutic response with lowered dosages;
- Longer periods of administration may be attempted when necessary;
- The CLR-TargoSphere® is less expensive to manufacture than other nanocarriers;
- The CLR-TargoSphere® permits highly specific therapeutic interventions for a variety of malignant, infectious, autoimmune, and neurodegenerative diseases, representing a major breakthrough in targeted drug delivery.
The Antigen-Presenting Cells (APCs)
APCs are a family of immune cells distributed within all lymphoid and non-lymphoid tissues. They are present in the primary lymphoid organs (bone marrow and thymus) and secondary lymphoid organs, including the lymph nodes, tonsils, spleen, Peyer’s patches, and mucosa-associated lymphoid tissue (MALT). They are also distributed to the liver, a semi-lymphoid organ; and non-lymphoid organs which include the skin, kidneys, heart, and the central and peripheral nervous systems.
The APCs are a broad array of communicating immune cells that are responsible for inducing primary and secondary antigen-specific immunity as well as bridging the innate and adaptive branches of immunity. They are therefore vital to maintaining host response to disease. These cells comprise:
- Immature myeloid Dendritic cells (mDCs) found in the non-lymphoid organs and primary lymphatic organs (bone marrow and thymus gland);
- Mature myeloid Dendritic Cells (mDCs) and the mDC-instructed Cytotoxic T-Lymphocytes (CTLs) found in secondary lymphatic organs (lymph nodes, tonsils, spleen, Peyer’s patches, and mucosa-associated lymphoid tissue (MALT); The CTLs are critical to developing antibody defense against tumors. Cancers neutralize their activity by producing Programmed Death (PD-L1 and PD-L2) proteins on their cell surface which bind to and inactivate the CTL’s apoptosis (killer) surface antibodies designed to attack and kill tumor cells;
- Kupffer cells in the liver as the local macrophage population;
- Follicular Dendritic Cells (FDCs), a non-migratory population of dendritic cells found in primary and secondary follicles of B-cell areas of lymph nodes, spleen, and mucosa-associated lymphoid tissue (MALT);
- Migrating monocytes, macrophages, and Tumor-Associated Macrophages (TAM type- 1 and TAM type-2) which act as M1 (tumor-suppressing, pro-inflammatory) and/or M2 (tumor-promoting, anti-inflammatory) in tumor nests and stroma, and which are associated with a broad array of growth factors and cytokines that play a critical role in developing either suppression or aggressive growth of the tumor. Upon being instructed by cancer cells, TAMs are transformed from being immunostimulatory and tumoricidal in function to becoming immunosuppressive and tumorigenic, stimulated to release a vast variety of tumor-promoting cytokines, growth factors, enzymes, transcription factors, inflammatory mediators, and protein kinases resulting in tumor growth, invasion, transformation, metastasis, angiogenesis, and multiple drug resistance.