PD-1 BiKE: Targeting and Depleting PD-1 Positive Cells for Autoimmune Disease Treatment

PROJECT SUMMARY
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.

Grant Number: 1R21AI185716-01A1
NIH Institute/Center: NIH
Principal Investigator: Mingnan Chen