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Fine epitope mapping of the CD19 extracellular domain promotes design.

07:00 EST 8th November 2019 | BioPortfolio

Summary of "Fine epitope mapping of the CD19 extracellular domain promotes design."

The B cell surface protein CD19 is present throughout the cell life cycle and uniformly expressed in leukemias making it a target for chimeric antigen receptor engineered immune cell therapy. Identifying the sequence dependence of CD19 binding to antibodies empowers fundamental study and more tailored development of CD19-targeted therapeutics. To identify the antibody-binding epitopes on CD19, we screened a comprehensive single-site saturation mutation library of the human CD19 extracellular domain to identify mutations detrimental to binding FMC63 - the dominant CD19 antibody used in chimeric antigen receptor development - as well as 4G7-2E3 and 3B10, which have been used in various CD19 research and development. All three antibodies had partially overlapping, yet distinct, epitopes near the published epitope of antibody B43. The FMC63 conformational epitope spans spatially adjacent, but genetically distant, loops in exons 3 and 4. The 3B10 epitope is a linear peptide sequence that binds CD19 with 440 pM affinity. Along with their primary goal of epitope mapping, the mutational tolerance data also empowered additional CD19 variant design and analysis. A designed CD19 variant with all N-linked glycosylation sites removed successfully bound antibody in the yeast display context, which provides a lead for aglycosylated applications. Screening for thermally stable variants identified mutations to guide further CD19 stabilization for fusion protein applications and revealed evolutionary affinity-stability tradeoffs. These fundamental insights into CD19 sequence-function relationships enhance understanding of antibody-mediated CD19-targeted therapeutics.

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This article was published in the following journal.

Name: Biochemistry
ISSN: 1520-4995
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Medical and Biotech [MESH] Definitions

Methods used for studying the interactions of antibodies with specific regions of protein antigens. Important applications of epitope mapping are found within the area of immunochemistry.

A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere.

A discoidin domain receptor for FIBRILLAR COLLAGEN that functions in a variety of cellular processes. For example, it regulates cell attachment to the EXTRACELLULAR MATRIX, remodeling of the extracellular matrix, CELL MIGRATION; CELL DIFFERENTIATION; CELL PROLIFERATION; and CELL SURVIVAL.

An approach, process, or methodology which emphasizes credible evidence and the best available scientific knowledge, judiciously integrated to achieve the best possible outcomes in structural design. For example, the design of a new OUTPATIENT CLINIC might incorporate a review of published research on outpatient clinic design, decisions on similar past projects, along with interviews with staff and consumers.

Using fine needles (finer than 22-gauge) to remove tissue or fluid specimens from the living body for examination in the pathology laboratory and for disease diagnosis.

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