Antibody-based immunotherapies for the targeting of the PD-L1 protein in cancer and Alzheimer's disease

Immunotherapy has emerged as a powerful and versatile therapeutic strategy, showing substantial promise in the treatment of a wide range of diseases. To date, a range of immunotherapeutic modalities has been developed to harness the body’s immune system to combat disease, including cell therapies, cytokine therapies, vaccines, viro-immunotherapies, monoclonal antibodies, and immune checkpoint inhibitors. Among this broad spectrum of therapeutics, immune checkpoint inhibitors targeting coinhibitory receptors like PD-L1 have gained significant traction for their ability to reinvigorate the body’s immune response to disease.

Despite notable progress and promise in certain patient populations, immunotherapies continue to face challenges, as their efficacy remains inconsistent and varies significantly across individuals and disease states. Herein, we aimed to address key obstacles limiting the broader application of immune checkpoint inhibitors, with a particular focus on PD-L1-targeting therapies in cancer. Specifically, antibody-based strategies were developed and evaluated to overcome the different resistance mechanisms of tumors to PD-L1 blockade, including lactic acid production by tumor cells, which hinder PD-L1 antibody binding, and the immunosuppressive microenvironment of immune-cold tumors. Proposed approaches include a combination therapy of an inhibitor of a lactic acid transporter expressed on tumor cells with a PD-L1-antibody-drug conjugate, as well as a bispecific antibody that binds to PD-L1 and an immunogen capable of eliciting an immune response within the tumor microenvironment. To support the translational relevance of these strategies, we have established humanized PD-L1 mice and a human PD-L1-expressing murine breast cancer cell line, E0771^hPD-L1.

These cancer-focused approaches were subsequently extended to the treatment of neurodegenerative diseases by adapting the antibody platform to design a disease-modifying, antibody-based immunotherapy for Alzheimer’s disease. To address two key pathological factors for enhanced disease intervention, a bispecific antibody was designed and tested in humanized PD-L1 Alzheimer’s disease model mice. This antibody binds to PD-L1 and amyloid-beta, a pathogenic peptide implicated in Alzheimer’s disease pathology. In parallel, the immune system’s role in Alzheimer’s disease pathology was investigated, with particular attention to the expression of PD-L1 on microglial cells in the disease-affected brain.

Collectively, this thesis presents antibody-based immunotherapies for the targeting of the PD-L1 protein in cancer and Alzheimer’s disease, as well as research tools that may facilitate future translational research in immunotherapy development. All together, these studies aim to advance the clinical potential and broaden the applicability of immunotherapy across diverse patient populations and health conditions, ultimately improving patient outcomes and supporting healthier aging.