Antibody Engineering for Creating Novel Biopharmaceutical Products
Antibodies (Ab), or immunoglobulins (Ig), are naturally occurring proteins found in great abundance in our bodies. They are used by the immune system to identify and subdue antigens, or foreign substances that are found in the body which may cause disease or infection. Antibody engineering is a powerful resource for creating novel biopharmaceuticals.
The most basic unit of an antibody is called an immunoglobulin monomer, which include two heavy chains and two light chain forms. Antibodies can be composed of multiple Ig monomer units. Each unit forms a Y-shape, which is composed of two fragment antigen-binding (Fab) regions, and a fragment crystallizable (Fc) region. The tip of each Fab region contains a paratope or binding site, which acts as a lock into which a specific key, or epitope of an antigen (e.g., of a bacteria, or virus) binds to. The Fc region is responsible for the effector functions, the interactions between the antibody molecule and other parts of the immune system, such as complement, and cells that express Fc receptors.
Each binding site is shaped by variable domains from a light and heavy chain (VH and VL), in the form of three loops per variable domain type. These loops are called the complementarity determining regions (CDRs), as they are the most important determining factor when binding (or complementarity to antigens. The remaining areas within the variable domains are referred to as framework regions (FR). These regions create a framework that presents the CDRs at the binding surface of the antibody, allowing them to contact the antigen.
Both heavy and light chains of an Ig unit are comprised of multiple domains, each of which is encoded by their own distinct gene segments, or subgenes. Light chains are composed of a single variable and a single constant domain (VL and CL), each of which is encoded by a separate gene, joined by a distinct joining (JL) region. Heavy chains are approximately twice the size of light chains and are translated from four main genes; VH, CH1, CH2 and CH3. There is an additional joining region between VH and CH1, that is analogous to the light chain, however this region has not only a JH gene involved but also a selection of 1 or more small genes referred to as diversity of D genes or regions. In addition, there is an additional region between CH1 and CH2 that encodes the hinge between the Fab (comprised of VL/CL and VH/CH1 ) and the Fc (CH2 and CH3).
The tremendous diversity of both specificity and function found in immunglobulins is due in large part to the dozens of different VH and VL genes encoded by the chromosomes of each individual, but also to the diversity of the constant regions, which encode 2 types of light chain (k and l), in addition to 9 or more heavy chains (a1, a1, g1, g2, g3, g4, d, e and m)
Comparing relative sequencing patterns and their utilization among humans, mice, and other species also provide important predictive data for antibody engineering projects. The highly complex and modular function of antibodies lends a great deal of detail and flexibility for their application in targeting antigens through novel biopharmaceuticals.
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