Wednesday, April 2, 2025
4/2/2025
Albumin-Amended Antibody Drug Conjugate (A3DC) for Immunosuppression - PROJECT SUMMARY Immunosuppression is essential for treating various medical conditions, but current treatments often suffer from suboptimal effects and long-term lymphopenia and immune deficiency. Targeted depletion of programmed death-1-positive (PD-1+) cells presents a promising solution to these limitations. PD-1+ cells play a critical role in sustaining immune responses in contexts such as autoimmune diseases and organ transplantation. Consequently, depleting PD-1+ cells has been shown to effectively suppress immune responses. This strategy offers two key advantages: it is likely more potent because it targets both B and T effector cells, and it spares naïve cells (PD-1-) and lymphocyte repertoires, avoiding long-term immune deficiency and preserving immune protection. Therefore, developing suitable agents for PD-1+ cell depletion in clinical settings is a warranted effort. Previously, immunosuppression through PD-1+ cell depletion was achieved using immunotoxins, which are not ideal for chronic conditions requiring sustained immunosuppression. In our efforts to develop suitable agents, we engineered PD-1-specific antibody-drug conjugates (ADC) and depleting antibodies. Although effective in depleting PD-1+ cells, these agents failed to suppress autoimmunity in a type 1 diabetes (T1D) model, instead exacerbating auto-attacks and the progression of hyperglycemia. This paradoxical result may be attributed to the Fc component within the ADC and the depleting antibody, which can elicit proinflammatory, effector responses. Indeed, previous studies have shown that antibodies or ADCs designed for immunosuppression need have their Fc mutated or modified to minimize proinflammatory responses. Therefore, we posti that an Fc- devoid, PD-1-specific depleting agent might be ideal for achieving immunosuppression. Specifically, we suggest that a PD-1-specific Albumin-Amended Antibody Drug Conjugate (A3DC), with its Fc replaced by albumin, could effectively deplete PD-1+ cells. The PD-1 A3DC is built upon a scaffold protein comprising the single-chain variable fragment (scFv) of an anti-PD-1 antibody and albumin. The goal of this project is to generate PD-1 A3DCs and confirm their selective toxicity to PD-1+ cells and their immunosuppressive capability. Through preliminary studies, we have developed three scaffold proteins with varied domain configurations and demonstrated their binding and internalization by PD-1+ cells. Building on this progress, we aim to achieve our objectives through the following two aims: Aim 1: Determine and compare the toxicity of PD-1 A3DCs to PD-1+ cells. We plan to generate a library of 24 A3DCs and select three A3DCs from the library to be used in Aim 2, based on their binding with the neonatal Fc receptor and toxicity to PD-1+ cells. Aim 2: Determine and compare the immunosuppressive effect of PD-1 A3DCs in a mouse T1D model. The ultimate deliverable aim is to identify one or more A3DCs that deplete PD-1+ cells and suppress autoimmunity.
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