Graduate Research Talk: ASAP-MMP: An Antibody Sequence Analysis Pipeline to Identify Design Features by Targeting Matric Metalloprotieinase

Abstract

Matrix metalloproteinases (MMPs) are a family of zinc-dependent enzymes that play numerous roles in normal physiology and development, but under pathological conditions, disregulated MMP activity can facilitate cancer progression and undesired inflammation. Biological inhibitors of MMPs in the form of antibodies offer an appealing method for disrupting MMP enzyme activity, as antibodies are capable of potently, specifically inhibiting individual MMPs in ways that traditional small molecules cannot. The key challenge in establishing antibody-based inhibition as a general strategy for interfering with the pathologic functions of MMPs is the lack of fundamental information relating the amino acid sequences of inhibitory antibodies to their unique properties as binder or inhibitors.

We present an Antibody Sequence Analysis Pipeline (ASAP-MMP) for identifying features common to MMP-targeting antibodies. From sequences in both MMP-targeting and reference datasets, this pipeline extracts germline, CDR canonical structure, isoelectric point and frequent positional motifs features and support several analyses to identify features and feature value that are significantly overrepresented using a comparative approach. Our results show that identities of the heavy chain germline and canonical structure of CDR-H2 region of MMP-targeting antibodies are very distinct from the reference dataset, suggesting that these unique characteristics are key in generating antibodies that target MMPs. This pipeline forms the basis for a broader range of analysis for the identification of antibody features that alter the biological functions of their targets.