PD-1 bike: targeting and depleting PD-1 positive cells for autoimmune disease treatment

The University of Utah received a $423,500 Project Grant award from the National Institute of Allergy and Infectious Diseases (NIAID) under the Allergy and Infectious Diseases Research program (CFDA 93.855), with an award date of July 22, 2025 and completion date of June 30, 2027. The grant funds research development of bispecific killer cell engagers (BiKEs)—a novel class of antibodies designed to selectively deplete programmed death-1 (PD-1) positive lymphocytes for autoimmune disease treatment. This targeted approach aims to halt autoimmune attacks while preserving naive lymphocytes and avoiding the broad immunosuppression associated with conventional immunosuppressive therapies, thereby reducing patient susceptibility to infections and malignancies.

The research project will advance the development of clinically viable agents for targeted lymphocyte depletion by leveraging BiKE technology, which enhances natural killer cell engagement with target cells through simultaneous binding of target cell antigens and natural killer cell receptors. This mechanism has demonstrated superior efficacy compared to conventional depleting antibodies in both clinical and preclinical settings, positioning the research to potentially improve treatment outcomes for patients with type 1 diabetes, multiple sclerosis, and other autoimmune disorders that currently lack effective disease-halting therapies.

Abstract

Autoimmune diseases (ADS) arise due to a misguided immune response, where autoreactive lymphocytes launch attacks on the body's own tissues. Many ad patients, such as those of type-1 diabetes and multiple sclerosis, still suffer from ineffective treatments that fail to halt disease progression. Moreover, current ad treatments often employ an indiscriminate approach by suppressing both activated and naive lymphocytes. This leads to long-term lymphopenia, broad immunosuppression, and increased susceptibility to infections and malignancies. A promising alternative involves the targeted depletion of lymphocytes expressing programmed death-1 (PD-1), offering a novel solution to halt auto-attacks while avoiding long-term lymphopenia or immunosuppression. Additionally, IT spares naive lymphocytes that are PD-1 negative, preserving the lymphocyte repertoire and allowing patients to quickly regain full immune protection once the depleting agents are cleared. Additionally, the depletion will spare naive lymphocytes that are PD-1 negative. The preservation of naive cells and lymphocyte repertoires will quickly RE-gear treatment subjects with full immune protection after the cell depleting agents are cleared. Importantly, the use of an immunotoxin to deplete PD-1+ cells has confirmed these advantages. Together, these findings support the development of clinically viable agents for targeted lymphocyte depletion. In pursuit of this goal, we focused on a class of antibodies called bispecific killer cell engagers (bikes). Bikes are designed to enhance the interaction of natural killer (NK) cells and target cells by simultaneously binding target cell antigens and NK cell receptors. Bikes have shown considerable success in clinical and preclinical settings, demonstrating superior efficacy in eliminating target cells compared to conventional depleting antibodies. Notably, bikes excel in eliminating target cells with modest antigen expression that is similar to the case of PD-1. Our innovative approach involves developing and utilizing anti-PD-1 bikes (PD-1 bikes) designed to bridge NK cells to PD-1+ cells, activate NK cells, and redirect their cytotoxicity towards PD-1+ cells. We hypothesize that PD-1 bikes have the potential to efficiently deplete primary PD-1+ cells and, consequently, mitigate disease progression in mouse models of ADS. We have successfully produced and characterized an anti-human PD-1 bike that targets the activating NK cell receptor CD16. This bike effectively initiates NK cell- mediated depletion of PD-1+ cells. These preliminary results underscore the rationale and feasibility of using bikes to deplete PD-1+ cells and alleviate ADS. To test our hypothesis, we will undertake the following two aims: aim 1: characterization and functional comparison of mouse PD-1 bikes. Aim 2: establishment of the efficacy and safety advantages of mouse PD-1 bikes.