Targeted antibody and cytokine cancer immunotherapies through collagen affinity

Abstract

Cancer immunotherapy with immune checkpoint inhibitors (CPI) and interleukin (IL)-2 has demonstrated clinical efficacy but is frequently accompanied with severe adverse events caused by excessive and systemic immune system activation. Here, we addressed this need by targeting both the CPI antibodies anti-cytotoxic T-lymphocyte antigen 4 antibody (αCTLA4) + anti-programmed death-ligand 1 antibody (αPD-L1) and the cytokine IL-2 to tumors via conjugation (for the antibodies) or recombinant fusion (for the cytokine) to a collagen-binding domain (CBD) derived from the blood protein von Willebrand factor (VWF) A3 domain, harnessing the exposure of tumor stroma collagen to blood components due to the leakiness of the tumor vasculature. We show that intravenously (i.v.) administered CBD protein accumulated mainly in tumors. CBD conjugation or fusion decreases the systemic toxicity of both αCTLA4+αPD-L1 combination therapy and IL-2, for example eliminating hepatotoxicity with the CPI molecules and ameliorating pulmonary edema with IL-2. Both CBD-CPI and CBD-IL-2 suppressed tumor growth compared to their unmodified forms in multiple murine cancer models, and both CBD-CPI and CBD-IL-2 increased tumor-infiltrating CD8+ T cells. In an orthotopic breast tumor model, combination treatment with CPI and IL-2 eradicated tumors in 9 of 13 animals with the CBD-modified drugs, whereas it did so in only 1 of 13 animals with the unmodified drugs. Thus, the A3 domain of VWF can be used to improve safety and efficacy of systemically-administered tumor drugs with high translational promise.

Tumor microenvironment complexity and therapeutic implications at a glance

“…This formulation allowed drug targets to bind to the tumor stroma to exert their effects locally and gained a promising efficacy and safety profile compared to the unconjugated molecules tested in several mouse models. Importantly, combination treatment with CPI and IL-2 resulted in complete elimination of tumors in a considerable number of animals (9 of 13) bearing orthotopic breast cancer [137].…”

The role of collagen in cancer: from bench to bedside

“…Fusion of the collagen-binding protein lumican and cytokines increased the efficacy of systemic immunotherapies in a melanoma model [223]. The therapeutic use of immune checkpoint inhibitors and interleukin-2 by conjugation (for antibodies) or recombinant fusion (for cytokine) to the von Willebrand factor A3 domain (a collagen-binding domain) eradicated tumors and exhibited obvious safety and efficacy in a breast cancer model [225]. Cancer-collagen-targeting immunoconjugate therapy was evidently applicable to anticancer therapy [226].…”

Vascular modulation through exercise improves chemotherapy efficacy in Ewing sarcoma

“…This work is also limited by using subcutaneous models. Although subcutaneous tumor models have proven to be useful for evaluating molecular mediators of tumor vasculature and novel therapies for the treatment of ES, the findings reported here should be strengthened using orthotopic ES tumors. Additionally, our studies provided a limited number of days of exercise in a nonvariable fashion with controlled settings on a treadmill.…”