Oncology

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Affinity and receptor expression levels

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The leading challenge in therapeutic treatments for cancer is the accurate characterization of complex protein interactions under physiologically relevant conditions, consistent with the native protein and tumor environment. MDS overcomes these obstacles as an in-solution technology with the capacity to characterize interactions of drug candidates with their targets directly in cell lysates, lipid membranes, serum, or tissue homogenate.

Overview

Cancer is a global health problem accounting for one in six global deaths, necessitating the need for new treatment approaches. Current shifts focus on targeted tumor therapies and personalized treatment, demanding effective characterization of complex interactions under native conditions that mimic the cancer environment. Microfluidic Diffusional Sizing (MDS) overcomes these challenges by measuring in-solution interactions via size changes, compatible with complex matrices and complex targets such as membrane proteins. When measuring membrane protein interactions, MDS provides binding affinity, concentration, and receptor expression data, in addition to the physical size measurements to verify stability of therapeutics alone and in-complex. This understanding, notably receptor expression, expedites clinical advancement and generates patient-specific data for therapeutic efficiency.

Determine affinity and receptor expression levels of oncology relevant targets.

Figure 1. A simple membrane protein assay workflow using MDS to determine the binding affinity, concentration, and receptor expression level of an oncology relevant membrane protein and therapeutic binding partner.

Case Study

Recruitment of phospholipase Cγ1 to the non-structural membrane protein pK15 of Kaposi Sarcoma-associated herpesvirus promotes its Src-dependent phosphorylation.

Samarina et al., PLoS Pathogens. 17 (6), June 18, 2021. DOI:10.1371/journal.ppat.1009635.

Kaposi Sarcoma-associated herpesvirus (KSHV) causes three human malignancies, Kaposi Sarcoma (KS), Primary Effusion Lymphoma (PEL) and the plasma cell variant of multicentric Castleman’s Disease (MCD), as well as an inflammatory cytokine syndrome (KICS). In this publication, Samarina et al., uses MDS to determine the preferential binding region of pk15, a KSHV non-structural membrane protein, to phospholipase C gamma 1 (PLCγ1) by assessing binding affinity of native and pK15 mutants. pK15 is important in necessitating interaction with phospholipase C gamma 1 (PLCγ1) to initiate downstream signaling cascades contributing to KSHV pathogenic properties. Implementation of MDS confirmed the interaction site between pK15 and PLCγ1, offering insight into the function of PLCγ1 regulation by pK15. This also highlights a pivotal binding region that holds significance for potential therapeutic targeting.