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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.
This article was published in the following journal.
V-domain immunoglobulin (Ig) suppressor of T cell activation (VISTA) is an immune checkpoint protein that inhibits the T cell response against cancer. Similar to PD-1 and CTLA-4, a blockade of VISTA...
Chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated clinical success in treatment of B-cell hematologic cancers. In this study, we compared human Transferrin epitope tagged CAR-T cel...
Guertu virus (GTV) is a tick-borne phleboviruses (TBPVs) which belongs to the genus Banyangvirus in the family of Phenuiviridae. In vitro and in vivo studies of GTV demonstrated that it was able to in...
CD19-targeted chimeric antigen receptor (CAR) T-cells (CAR19s) show remarkable efficacy in the treatment of relapsed/refractory acute lymphocytic leukemia and Non-Hodgkin lymphoma. However, the use of...
The production of broadly neutralizing antibodies (bNAbs) is a major goal in the development of an HIV-1 vaccine. The membrane-proximal external region (MPER) of gp41, which plays a critical role in t...
In the conventional treatment options, B cell leukemia could be treated with chemotherapy drugs or HSCT. But chemotherapy could barely cured leukemia. And HSCT is often limited by lacking ...
The purpose of this study is to infusion CD19 CAR-T cells to the patients with relapsed and refractory CD19+ B cell leukemia, to assess the safety and feasibility of this strategy. The CAR...
This Phase II study is to evaluate the efficacy and safety of a CD19-targeting humanized selective CAR-T (CD19 hsCAR-T) in refractory/relapsed CD19+ B-ALL leukemia patients who have no ava...
This study aims to evaluate the safety, efficacy and duration of response of CD19 Chimeric Antigen Receptor (CAR) redirected allogeneic γδT-cells in patients with high risk, relapsed CD1...
This study aims to evaluate the safety, efficacy and duration of response of CD19 Chimeric Antigen Receptor (CAR) redirected autologous T-cells in patients with high risk, relapsed CD19+ h...
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.
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...
An antibody is a protein produced by the body's immune system when it detects harmful substances, called antigens. Examples of antigens include microorganisms (such as bacteria, fungi, parasites, and viruses) and chemicals. Antibodies may be produc...