Core D - Recombinant Antibody Core

CORE SUMMARY Core D is a new core in this renewal that will be used by all three Projects. Use of recombinant antibodies (rAbs) and novel bispecifics allows for precise control over and targeting of inhibitory receptors PD1 and LAG3 and provides invaluable insights into their synergy and roles in orchestrating immune responses across diverse cell types and diseases. Common rAbs and bispecifics will also facilitate comparison across the all Projects. AIM 1: To provide core antibody reagents. Core D will use a rigorous and efficient process to generate murinized IgG1-based rAbs specific for PD1 and LAG3 along with a PD1:LAG3 bispecific rAb, plus controls, for all Projects. Core D is optimizing a version of the bispecific that will selectively bind to only PD1+LAG3+ T cells using scFv yeast display affinity optimization system. AIM 2: To provide novel antibody tool reagents. Core D has the capacity and capability to generate innovative, high-risk/high-reward rAbs, bispecifics, and ADCs as needed for the Projects, with careful consideration mediated through Core A. Initially, we plan to develop 2 new rAb-based tools outlined in P2 and P3: [i] a cytolytic version of the PD1:LAG3 bispecific, achieved by mutating the IgG1 Fc or using an IgG1-IgA Fc fusion to broaden susceptibility to Fc receptor binding; and [ii] an antibody–drug conjugate (ADC) with IFNγ and/or IL2 attached to a PD1:LAG3 mono- and bi-specifics. These new tools will be generated, validated, and shipped to the Projects by Core D. IR-PPG Interactions: In addition to supporting all three Projects, Core D will also work with Core A to provide data access, facilitate production, monitor budget and core usage, and facilitate shipping to outside investigators once reagents are published, and Core C to consider additional, novel rAb tools.