Search

Alzheimer’s disease (AD) is the seventh leading cause of death globally with an estimated 6.5 million Americans aged 65 and above living with Alzheimer’s dementia in 2022 and at a projected national cost of $321 billion. AD is characterized by a progressive and irreversible neurodegenerative dysfunction with clinical symptoms such as deterioration in cognition and memory loss. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a multi-site, public-private global research initiative that supports both investigation and development of treatments that slow or terminate AD progression. The study included 60 participants, comprising 30 AD and 30 control cohorts respectively. All participants were from the ADNI 1 group with a recorded Functional Activities Questionnaire (FAQ.) and Neuropsychiatric Inventory Questionnaire (NPI-Q) score. Gray matter volumetric alterations detected from magnetic resonance image (MRI) scans have been validated as a crucial AD biomarker.Cortical atrophy was quantified by measuring the volume and surface area of the cortex across the whole brain using an automated pipeline in MIMICS. A stepwise multivariate regression analysis was conducted to investigate the correlation between the participants’ measured cortical volume and surface area with other potential factors that may influence their susceptibility to developing Alzheimer’s disease. The results of the study showed both part volume and surface area generic model fit to be statistically significant at (p = 0.0004) and (p = 0.011) respectively. While the age weighting showed overall significant difference in both part surface area and volume measured by MIMICS at (P = 0.019) and (P = 0.0075), the age group 65 -70 years appear most significant at (P< 0.001). In addition, the performance metrics conducted to evaluate the capability of the model showed an accuracy of 0.68. The study demonstrates the promising utility of voxel-based morphometry using MIMICS, though developing the automated pipeline currently in place, may help improve the accuracy and correlation indices through its use. The results of the study provide further evidence of brain atrophy in the pathophysiology of Alzheimer’s disease and highlight the potential of MRI morphometry for the development of AD biomarkers.

Antibodies have been widely used as reagents, homing devices, diagnostics and as therapeutic agents against different targets in clinic and research. Recently a number of monoclonal antibodies and their drug conjugates have been approved as therapeutic agents. While these molecules have great potential in various applications and therapeutics, extensive use of full length antibodies has been hampered by the high cost of production, large molecular weight and limited ability to penetrate tumor tissues. These limitations have led to the research for antibody alternatives with lower molecular weight, similar binding and affinity properties but without the lengthy and complicate process of generating antibodies. Some examples of these efforts include minibodies, fragment antigen binding (FAB), ScFv, and synthetic antibody mimics. Although these antibody alternatives have low molecular weight, as compared to the antibody, they are either derived from full size antibodies or by a long and tedious in vitro screening process. Therefore, a rational design of molecules that mimic antibody binding is a logical first step for the development of antibody alternatives. In this study, a novel approach to design antibody mimics without involving massive experimental screening was developed. The design was developed by mapping and identifying EGFR epitope region where Cetuximab CDR binds and modifying sequences using knob-socket computational model. The binding of antibody mimics were first analyzed by using MOE to obtain the binding energy, total and preserved interactions as compared to the interactions between EGFR and Cetuximab. Further, the designed antibody mimics were used to form a peptide drug conjugate (PDC). Antibody mimics were found to specifically bind and internalized by EGFR overexpressing cell lines with three to four folds higher than control cells. Antibody mimics showed binding in nanomolar range with Pep11 with binding affinity (K D ) of 252nM as shown by SPR studies. EGFR phosphorylation studies also showed that antibody mimics were able to inhibit the binding of EGF to the EGFR in a similar fashion as Cetuximab. Specific binding, affinity and functional activity of the antibody mimics demonstrated that these peptides were able to mimic all the three important characteristics of antibodies. Peptide drug conjugate (PDC) was found to be around 10 fold more potent as compared to the drug itself towards EGFR overexpressed cancer cells. PDC also showed more than 100 fold low potency against control cells. These studies demonstrated that a rational design of molecules to mimic the antibody characteristics is feasible. The antibody mimics were also successfully applied and used as targeting moiety to design peptide drug conjugates for efficient targeted drug delivery system than antibody drug conjugates.