The Synergistic Potential of Combining PD-1/PD-L1 Immune Checkpoint Inhibitors with NOD2 Agonists in Alzheimer’s Disease Treatment

Abstract

Our research over the past decade has compellingly demonstrated the potential of Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) receptor agonists in Alzheimer’s disease (AD) treatment. These agonists facilitate the conversation of pro-inflammatory monocytes into patrolling monocytes, leading to the efficient clearance of amyloid-β (Aβ) in the AD-affected cerebrovascular system. This approach surpasses the efficacy of targeting Aβ formation, marking a significant shift in therapeutic strategies. Simultaneously, inhibitors of PD-1/PD-L1 immune check point or glycogen synthase kinase 3 beta (GSK3β), which modulates PD-1, have emerged as potent AD treatment modalities. PD-1 inhibitor exhibits a profound potential in monocytes’ recruitment to the AD-afflicted brain. Recent evidence suggests that an integrated approach, combining the modulation of NOD2 and PD-1, could yield superior outcomes. This innovative combinatorial therapeutic approach leverages the potential of MDP to act as a catalyst for the conversion of inflammatory monocytes into patrolling monocytes, with the subsequent recruitment of these patrolling monocytes into the brain being stimulated by the PD-1 inhibitor. These therapeutic interventions are currently under preclinical investigation by pharmaceutical entities, underscoring the promise they hold. This research advocates for the modulation, rather than suppression, of the innate immune system as a promising pharmacological strategy in AD.

Soluble PD-L1 reprograms blood monocytes to prevent cerebral edema and facilitate recovery after ischemic stroke

“…It is important to note that the effects of PD-1 signaling on monocytes appears to be disease-dependent as there is evidence that PD-1 blockade augments the influx of monocytes into the brain in Alzheimer’s disease (AD) models ( Rosenzweig et al, 2019 ; Baruch et al, 2016 ; Ghareghani and Rivest, 2023 ). In this context, intraperitoneal injection of anti-PD-L1 antibody increased trafficking of Ly6C hi CD45 hi CD11b+ cells from the periphery into the brain ( Rosenzweig et al, 2019 ; Baruch et al, 2016 ) mediated by CCR2 signaling ( Ben-Yehuda et al, 2021 ).…”

PD-1/PD-L1 Inhibitors for Alzheimer’s Pathology: A Literature Review

“…There is also an interesting synergistic potential between PD-1 inhibitors and NOD2 ( nucleotide-binding oligomerization domain-containing protein 2) agonists. 33 With activation from MDP (muramyl dipeptide), NOD2 facilitates pro-inflammatory monocytes into being converted to patrolling monocytes, which show superior abilities to phagocytose and clear Aβ. 34 This "best of both worlds" approach allows for both the clearance of Aβ and also minimizing inflammation.…”

Alzheimer’s Disease: Novel Targets and Investigational Drugs for Disease Modification

“…IBC-Ab002 is a humanized IgG1 antibody that inhibits programmed death ligand (PD-1), evoking the immune response. PD-1 inhibitors facilitate the conversion of proinflammatory monocytes to patrolling monocytes, reducing Aβ protein in the brain and enhancing cognition [ 50 , 51 ]. Nonclinical observations of the utility of these agents have not been confirmed in human clinical trials.…”