Delivering Immunotherapy to Solid Tumors using an Engineered Peptide-Immunostimulant Conjugate
Caitlyn Miller
Entrepreneur-In-Residence, Stanford University
Tumor-targeted delivery of immunostimulants is an emerging therapeutic strategy that aims to promote immune activation within the tumor microenvironment and elicit anti-tumor immunity. In contrast to antibody-based conjugates, using peptides for targeted immunostimulant delivery enables synthetic manufacturing and facile site-specific conjugation chemistry; in addition, their faster plasma half-life may be advantageous for safety, especially given that immunostimulants do not require continuous target saturation for therapeutic efficacy.
We developed a fully-synthetic, tumor-targeting immunostimulant conjugate, referred to as PIP-CpG, to enable rapid tumor uptake and short systemic exposure. PIP-CpG consists of a unique tumor-targeting peptide (PIP) conjugated to an immune-stimulating TLR9 agonist (CpG), which enables immunostimulant delivery to multiple tumor sites following IV administration (1). The targeting agent, PIP, is an engineered knottin peptide that binds with strong affinity (low to sub nM) to five integrin receptors that are overexpressed in numerous types of solid tumors. IV delivery of PIP-CpG promotes extensive tumor microenvironment remodeling and elicits tumor-specific T cell mediated immunity capable of promoting tumor regression and prolonging survival in various murine implanted and spontaneous tumor models (1, 2). Overall, these results illustrate the potential of promoting immune activation in the tumor microenvironment and demonstrate that conjugating an immunostimulant to a tumor-targeting peptide is a viable therapeutic strategy to achieve this goal.
1. Miller, C.L., Sagiv-Barfi, I., Neuhöfer, P., Czerwinski, D.K., Artandi, S.E., Bertozzi, C.R., Levy, R., and Cochran, J.R. (2022). Systemic delivery of a targeted synthetic immunostimulant transforms the immune landscape for effective tumor regression. Cell Chemical Biology 29, 451-462.e8. 10.1016/j.chembiol.2021.10.012.
2. Miller, C.L., Sagiv-Barfi, I., Neuhöfer, P., Czerwinski, D.K., Bertozzi, C.R., Cochran, J.R., and Levy, R. (2023). Targeted TLR9 Agonist Elicits Effective Antitumor Immunity against Spontaneously Arising Breast Tumors. The Journal of Immunology, ji2200950. 10.4049/jimmunol.2200950.