Modified Hyaluronic Acid Hydrogels Containing Hyaluronidase for the Time‐Controlled and Targeted Release of anti-CTLA-4 and other Therapeutic Antibodies (UCLA Case No. 2016-526)

UCLA researchers from the Department of Medicine have developed a novel therapeutic platform for the administration of low-dose Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) antibody for cancer immunotherapy that synergizes with conventional PD-1 therapy while sparing systemic autoimmune toxicity.

BACKGROUND: Immune checkpoint inhibitor (CPI) proteins are upregulated by certain cancer cells to evade the host’s immune system, reducing the capacity for immune cells to eliminate cancer. Combination therapy with intravenous infusions of anti-CPI antibodies that target both the PD-1 and CTLA-4 pathways is FDA-approved and provides the optimal treatment for several cancers. However, in clinical practice, this combination is often limited by severe autoimmune toxicity that reduces its overall utility.  To overcome this challenge, UCLA researchers have re-imagined the administration of anti-CTLA-4 so that a small fraction of the usual dose is capable of  fully synergizing with conventional systemic anti-PD-1 therapy to produce superior tumor control while sparing autoimmune toxicity.

INNOVATION: Researchers at UCLA have developed a biocompatible hyaluronic acid (HA)-based hydrogel platform that is prepared as a liquid and rapidly self-polymerizes into a drug reservoir at the site of tissue injection. Its unique formulation allows loading with a therapeutic mAb and promotes the complete release of its cargo over 72-96 hrs. After injection into the soft tissue adjacent to a tumor (a peri-tumor injection), the incorporated hyaluronidase promotes lymphatic uptake and specifically targets tumor draining lymph nodes (TDLN), which are a primary site of biologic action. In pre-clinical animal testing, anti-CTLA-4 saturation within TDLN occurred faster, reached higher levels and was more sustained than that occurring with high-dose systemic delivery. Despite the low dose, and the resulting limited systemic exposure, there was a rapid T cell expansion within the TDLN of treated animals and a subsequent marked increase in tumor-infiltrating CD8⁽⁺⁾/CTLA-4^(-) effector T cells. Tumor-bearing animals experienced anti-tumor responses and survival rates equal-to or greater-than those treated with conventional high-dose systemic administration. Furthermore, synergistic tumor responses occurred following co-administration with systemic anti-PD-1 that surpassed those occurring after conventional systemic combination therapy. When evaluated in animals prone to autoimmune thyroiditis, marked increases in autoimmune antibody responses were observed following conventional systemic therapy but not when anti-CTLA-4 was delivered using this low-dose hydrogel injection. To facilitate repeated monthly administration at the same site, this unique hydrogel is formulated to self-resorb within weeks after administration.  As an initial step toward clinical application, the formulation originally tested in mice has been successfully “humanized” using all clinical-grade reagents to deliver human anti-CTLA-4 at levels up to 15 mg/ml of injection. All constituents incorporated into this novel hydrogel reagent have already been FDA-approved with respect to their individual use.  In summary, the UCLA team has demonstrated that this hydrogel delivery platform, when compared to systemic dosing, requires only low-doses of anti-CTLA-4 in animal models, produces superior exposure and T cell activation within TDLN, synergizes with conventional anti-PD-1 therapy with respect to tumor efficacy, but has limited systemic exposure and limited risk for systemic autoimmune toxicity. In addition, the formulation is designed to self-resorb, allowing for repeated injection cycles. Given its use of FDA-approved constituents, an expedited pathway toward clinical testing is anticipated.

POTENTIAL APPLICATIONS:

• Cancer immunotherapy employing anti-CTLA-4 and other CPI antibodies
• Other immune regulation/therapeutic mAb approaches applicable to targeted therapy

ADVANTAGES:

• This anti-CTLA-4 delivery platform is composed of biocompatible components that have already received FDA-approval in other settings, but integrated together using a novel UCLA platform design
• The platform design integrates the safe loading and release of proteins, including therapeutic mAbs, provides controlled local perfusion that targets tissue-draining lymph nodes, and the administered hydrogel self-resorbs afterwards.
• Anti-CTLA-4 delivery via this platform requires only a fraction of the usual systemic dose, producing limited systemic exposure in pre-clinical animal models, yet simultaneously yielding superior efficacy and safety
• A humanized formulation can deliver up to 15 mg/ml of therapeutic mAb.

DEVELOPMENT-TO-DATE:  UCLA researchers have developed a novel HA-based hydrogel that has been optimized in an in vitro setting, demonstrated efficacy and safety in pre-clinical animal models, and is readily formulated to deliver high concentrations of human mAb employing clinical-grade reagents.

Related Papers (from the inventors only)

1. Harui A, Roth MD. Hyaluronidase Enhances Targeting of Hydrogel-Encapsulated Anti-CTLA-4 to Tumor Draining Lymph Nodes and Improves Anti-Tumor Efficacy. Gels. 2022.
2. Harui A et al., Peri-tumor administration of controlled release anti-CTLA-4 synergizes with systemic anti-PD-1 to induce systemic antitumor immunity while sparing autoimmune toxicity. Cancer Immunol Immunother. 2020.
3. Harui A, Roth MD. Employing a glutathione-s-transferase-tag and hyaluronidase to control cytokine retention and release from a hyaluronic acid hydrogel matrix. J Biomater Appl. 2019.

KEYWORDS: cancer immunotherapy, checkpoint inhibitor, monoclonal antibody, therapeutic antibody, CTLA-4, PD-1, combination therapy, synergistic, autoimmune toxicity, hyaluronic acid, hydrogel, biologic agents, low dose, local injection, peri-tumor injection, self-resorbing, tumor draining lymph node, tumor infiltrating lymphocytes, biomaterials