mechanism of action
The feasibility of using albumin to facilitate the delivery of molecules specifically to the sentinel lymph nodes is well established. Surgeons routinely administer albumin-binding fluorescent dyes to melanoma and breast cancer patients to visualize the drainage of lymphatic vessels into sentinel lymph nodes to guide the surgical procedures and increase the accuracy of assessments for potential metastases. These dyes are too small to efficiently accumulate in lymphatics independently but bind tightly with endogenous albumin in the interstitial fluid at the injection site, which then chaperones the dyes through the lymphatics into the lymph node. We utilize similar mechanistic principles to facilitate transport and delivery of our therapeutic AMP constructs to the lymph nodes. Once delivered to the lymph nodes, our immunomodulatory payload is transferred to APCs.
In order to facilitate the generation of antigen-specific T cells, APCs must deliver three critical signals to the T cell. The first signal involves antigenic peptides, derived from APC protein-processing pathways, presented in the context of the appropriate major histocompatibility complex, or MHC, molecules. Upon encountering an AMP-peptide in the lymph node, APCs engulf and process the AMP construct into antigenic fragments, with APC activity facilitated by activation of certain pathways of the innate immune system, such as TLRs. These fragments then associate with major histocompatibility complex class I or class II, MHC class I or MHC class II, structures, which in turn activate the adaptive immune system’s response cascade. The MHC class I peptide antigen complex engages with the T cell receptor, facilitated by the CD8 co-receptor and co-stimulatory ligands, which increase APC interaction with the T cell.
The second signal involves the APC expressing positive costimulatory molecules, principally, CD40, CD80 and CD86. Conformational changes related to the CD80 receptor of the APC binding with the CD28 co-receptor on the T cell trigger the activity of CD8+ T cells. At the same time the MHC class II antigen complex, along with the coordination of CD4+ T cells, stimulates B cells to produce antibodies directed towards specific epitopes. APCs typically present peptides derived from exogenous protein through the MHC class II pathway, but can also, when appropriately activated, efficiently cross present exogenous antigen through the MHC class I pathway, resulting in enhanced CD8+ T cell activation. Cross presentation is critical for generating a CD8+ T cell mediated immune response to viruses and tumors. In the presence of sufficient negative co-stimulatory signals, or the lack of sufficient positive co-stimulation, the interaction between APCs and T cells can lead to tolerization, dysfunction, or death of the T cells rather than activation and expansion. Our AMP therapeutics are designed to avoid this occurrence, through the inclusion of an adjuvant that is intended to enhance the co-stimulatory function of the APCs.
The third signal collectively refers to the cytokine microenvironment of the immune synapse where the priming interaction between APCs and T cells is occurring. This cytokine combination determines the differentiation and fitness of the downstream T cell response. Our AMP platform may be able to leverage the concentration of critical immune cells present in the lymph nodes to efficiently activate DCs, which in turn drive and sustain these critical three critical signals to orchestrate the adaptive immune response.
The therapeutic utility of both CAR-T and CPIs requires sufficient tumor-specific T cells, particularly CD8+ T cells, in coordination with sufficient co-stimulatory molecules in the tumor microenvironment, or TME, to activate and sustain a targeted immune response. Patients whose tumors remain resistant to infiltration by T cells represent a significant unmet medical need. Our technology may have the capability to facilitate T cell expansion, activation, maturation, trafficking, functionality and persistence required for effective CPI therapy. These characteristics may be essential to treatments that are both efficacious and durable.