Glossary

ADCC

Antibody-dependent cell-mediated cytotoxicity: target cell-killing that is mediated by effector cells of the immune system (e.g. natural killer cells, macrophages and neutrophils) and which requires the target cell being marked by an antibody. Antibodies bind antigens on target cells with their antigen-binding site and then recruit effector cells with their Fc domain.

antibody

A glycoprotein produced by B-cells that is used by the immune system to identify and neutralize foreign targets such as bacteria and viruses. Antibodies, which are also referred to as immunoglobulins, bind with high specificity to their target antigen. Antibodies that specifically bind to disease targets are widely used as therapeutics in humans in a wide variety of indications, including cancer, auto-immune diseases and infectious diseases.

antigen

Any substance to which antibodies specifically bind.

antigen-binding site

Synonym for paratope. The region of an antibody that binds to antigens, which is formed by determinants in the variable domains of the heavy and/or light chains.

bispecificity

Ability of an antibody to bind two different epitopes.

CDC

Complement-dependent cytotoxicity: target cell killing that is mediated by the complement system. CDC can be induced via different routes. Antibodies may induce complement activation by the classical route after binding their antigen on cells. Initiation of complement activation involves the binding of complement factor C1q to specific motifs within the CH2 domain of antibodies, triggering activation of the complement cascade.

CH

Constant domain of the antibody heavy chain. Each heavy chain of an antibody molecule has three constant domains (CH1-3).

CL

Constant domain of the antibody light chain.

controlled Fab-arm exchange

The in vitro post-production process employed by the DuoBody platform in which IgG1 half-molecules recombine with other IgG1 half-molecules to generate bispecific IgG1 antibodies. This unidirectional reaction only takes place under tailored reaction conditions in vitro with IgG1 antibodies containing single matched point-mutations in the CH3 domains and forms the basis of the DuoBody technology (see Figure 3). Although this process was originally developed as an IgG1-based platform, controlled Fab-arm exchange can be extended to other IgG subclasses to suit particular applications.

covalent interaction

A strong chemical bond that involves the sharing of pairs of electrons between two atoms.

disulphide bonds

Covalent bond between cysteine residues in proteins. These links are also called S-S-bonds or disulfide bridges. DuoBody technology provides a specific solution for controlled breaking (reduction) and reformation (oxidation) of such bonds resulting in the stable heavy-light chain pairing between IgG1 half molecule in bispecific antibodies (i.e. DuoBody molecule).

epitope

Binding site of an antibody on an antigen.

Fab

Fragment antigen binding: Antibody region that comprises the complete light chain and the variable (VH) and first constant (CH1) domain of the heavy chain. This fragment contains the antigen-binding site of the antibody and each antibody contains two Fab-regions.

Fab-arm exchange

A physiological process that results in the reassortment of human IgG4 half-molecules. This process occurs naturally in vivo and can be mimicked in vitro. As a functional consequence of this process,  Fab arms containing antigen-binding sites are exchanged between antibody molecules leading to novel binding combinations in the newly formed, bispecific  antibody. The DuoBody® technology is based on this naturally occurring process for generating bispecificity.

Fc domain

Fragment crystallizable domain, involving the CH2 and CH3 domains. This part of the molecule mediates the effector functions of immunoglobulins, including ADCC and CDC.

Fc-effector functions

The immune system’s cellular (e.g. ADCC) and humoral (e.g. CDC) effector systems, which are triggered by the interactions of the Fc-domain of antibodies with Fc receptors on effector cells or the complement factor C1q.

heavy chain

Large polypeptide subunit of immunoglobulins.

hinge region

The region between the CH1 and CH2 domains of the heavy chain, which is highly flexible. Disulphide bonds in the hinge region are part of the interactions between two heavy chains in an IgG molecule.

human immunoglobulin G (IgG)

A certain subclass of immunoglobulin or antibody (see definition of antibody). IgG and in particular the IgG1 subclass is the antibody class that is most commonly used for antibody therapeutics.

IgG half-molecule

Half of the complete IgG antibody, consisting of one heavy chain attached to one light chain (see Figure 1).

light chain

Small polypeptide subunit of immunoglobulins.

monospecificity

Ability of an antibody to recognize only one specific epitope.

non-covalent interaction

A type of chemical bond that does not involve the sharing of pairs of electrons, but rather involves electromagnetic or hydrophobic interactions.

parental antibodies

Monospecific antibodies containing matched single mutations with different specificity from which a bispecific antibody is generated in the process of controlled Fab-arm exchange (see Figure 3).

post-production process

Refers to the controlled Fab-arm exchange process that takes place after the separate production of the two parental IgG1 monoclonal antibodies, each containing single matched mutations in the third constant (CH3) domain (see Figure 3).

tumor heterogeneity

Describes the fact that a remarkable variability of cell phenotypes is apparent within tumors, including clinically relevant phenotypes such as the ability to survive therapy. Bispecific antibodies can be directed to therapeutically target different cell phenotypes within one tumor.

VH

Variable domain of the heavy chain.

VL

Variable domain of the light chain.

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