Sustained delivery and molecular targeting of a therapeutic monoclonal antibody to metastases in the central nervous system of mice

Abstract

Approximately 15-40% of all cancers develop metastases in the central nervous system (CNS), yet few therapeutic options exist to treat them. Cancer therapies based on monoclonal antibodies are widely successful, yet have limited efficacy against CNS metastases, owing to the low levels of the drug reaching the tumour site. Here, we show that the encapsulation of rituximab within a crosslinked zwitterionic polymer layer leads to the sustained release of rituximab as the crosslinkers are gradually hydrolyzed, enhancing by approximately 10-fold the CNS levels of the antibody with respect to the administration of naked rituximab. When the nanocapsules are functionalized with CXCL13, the ligand for the chemokine receptor CXCR5 frequently found on B-cell lymphoma, a single dose led to improved control of CXCR5-expressing metastases in a murine xenograft model of non-Hodgkin lymphoma, and eliminated lymphoma in a xenografted humanized bone-marrow-liver-thymus mouse model. Encapsulation and molecular targeting of therapeutic antibodies could become an option for the treatment of cancers with CNS metastases. Treatments for cancer metastases, especially those of the central nervous system (CNS), are less successful than those for primary tumors 1. Approximately 15%−40% of all cancers develop a CNS metastasis 2,3 , which most commonly arises from lung cancer, melanoma, breast cancer, and colorectal cancer. Therapeutic monoclonal antibodies (mAbs) have revolutionized the treatment of cancer; however, their efficacy is limited in patients with CNS metastases due to insufficient mAb CNS delivery-typically 0.1% of the levels in plasma 4. By bypassing the blood-brain barrier (BBB) through intrathecal or intraventricular administration, mAb therapy has shown some effectiveness against CNS tumor metastases 4-10. However, direct CNS administration is invasive, with potential for neurotoxicity, and is limited by rapid efflux of antibodies from the CNS within hours 5,10,11. Therefore, novel approaches for mAbs delivery are preferable to maintain systemic therapeutic effect in the CNS with improved efficiency.

Enhanced Delivery of Rituximab Into Brain and Lymph Nodes Using Timed-Release Nanocapsules in Non-Human Primates

“…In order to show that this nanocapsule platform improves brain delivery efficiency of therapeutic antibodies through systemic injection without inducing liver toxicity, three liver enzymes indicating acute liver toxicity were closely measured over the course of experiments: alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ( Figure 5A). As we confirmed in mice previously (34), no notable differences exist in levels between animals treated with RTX or n-RTX. Neither a complete liver function assay including serum globulin (GLB), indirect bilirubin (IBIL), gamma-glutamyl transferase (γ-GT), total protein (TP), and albumin (ALB), nor a blood chemistry test for white blood cell (WBC) count, lymphocyte count, monocyte count, neutrophil count, hemoglobin (HGB), hematocrit (HCT), and platelet counts (PLT), showed major differences between those animals ( Figure S2).…”

“…RTX administration contributes significant advancements toward systemic CD20+ NHL control, but treatment of primary and relapsed CNS lymphomas is inefficient due to poor penetration through the BBB (4). We recently demonstrated clearance of human B-cell tumors with brain metastases in xenograft humanized NOD-SCID-IL2receptor γ null (NSG) mouse models by RTX nanocapsules (n-RTX) (34). Though these results are promising, further studies are limited by the challenge in collecting successive samples of cerebrospinal fluid (CSF) from the same mouse for analysis; moreover, the delivery into LNs, which are highly atrophic, cannot be confirmed in NSG mice.…”

Development of Magnet‐Driven and Image‐Guided Degradable Microrobots for the Precise Delivery of Engineered Stem Cells for Cancer Therapy

“…Cell-based therapy has demonstrated a great potential for disease treatment. [1,2] Compared with passive chemical methods, [3][4][5] cells can sense and respond to diseases dynamically with fewer side effects in the host. [6,7] However, targeting therapeutic cells (e.g., stem cells) to the diseased site in vivo is a challenge.…”

An Antioxidant Enzyme Therapeutic for COVID‐19

“…The thin shell protects the enzyme, while allowing H 2 O 2 to rapidly transport through, endowing n(CAT) with high enzyme activity, augmented stability, and improved plasma half-life. [30] As shown in Figure 1A,B, n(CAT) shows a size distribution centered at 25 nm and a zeta potential of 1.5 mV, in comparison with those of native catalase (10 nm and -4.0 mV); TEM image confirms that n(CAT) has an average size of 20-30 nm ( Figure 1C). Compared with native catalase, n(CAT) exhibits a similar enzyme activity ( Figure S1A, Supporting Information), yet with significantly improved enzyme stability.…”