Periodic Table of Antibodies

Any format that contains an Fc domain and any antigen-binding portion of an antibody (e.g., Fab, scFv or domain antibody) is classified as an Fc containing antibody.

Any format that contains any antigen-binding portion of an antibody (e.g., Fab, scFv or domain antibody) but not an Fc domain is classified as an antibody fragment.

Any format that contains an Fc domain but no antigen-binding portion of an antibody (e.g., Fab, scFv or domain antibody) is classified as an Fc fusion protein.

Number of different epitopes to which a molecule can bind. As demonstrated in our Periodic Table, there are many different ways of creating multispecific antibodies. Learn more about our approach to engineering bispecific and trispecific antibodies here.

For the sake of our Periodic Table, Fc fusion proteins have been classed as having a specificity. For example, an IgG fused to PD1 will have a specificity of two. The first specificity comes from the IgG and the second from PD1.

Antibody valency refers to the number of antigenic determinants that an individual antibody molecule can bind. For the purpose of our Periodic Table, the valency value is calculated as the total valency of the format. For formats with multiple specificities, this is a combination of all the antigen-binding portions of the molecule. For clarity with multispecific formats, an additional value is given in parenthesis representing the breakdown of valencies for the different specificities. For instance, 4 (2:1:1) would represent a trispecific format with two binding sites to antigen A, one binding site to antigen B, and one binding site to antigen C.

Although people often refer to affinity as being the critical determinant of how tightly an antibody binds to its cognate antigen, it must also be appreciated that valency is a critical, and often underappreciated, component. Affinity measures the strength of interaction between an antigen (epitope) and an antibody’s antigen-binding site (paratope). It is defined by the same basic thermodynamic principles that govern any reversible biomolecular interaction. Avidity gives a measure of the overall strength of an antibody-antigen complex. It is dependent on three major parameters: i) affinity of the antibody for the epitope; ii) valency of both the antibody and antigen; iii) structural arrangement of the parts that interact. Careful consideration to each of these components must be taken to achieve the optimal binding characteristics for any given antibody-antigen pairing.

Although in many cases it is assumed that tighter binding is better this is not always the case. For instance, in the field of T-cell recruitment via CD3ε engagement it is becoming increasingly apparent that there is an optimal affinity and avidity for CD3ε which balances potency and side-effects (Bortoletto et al 2002; Leong et al 2017; Wu and Cheung 2018).

In simple terms, the half-life of a drug is a pharmacokinetic parameter that is defined as the time it takes for the concentration of the drug in the plasma to decrease by 50%. The half-life of a biologic is affected by a number of factors, including molecular size, charge, FcRn recycling, receptor mediated endocytosis (RME), and stability.

In our Periodic Table, we have kept the half-life definition quite simple and ignored target-mediated effects. In this simplistic view, the half-life of the formats is determined exclusively by their molecular size and whether they bind to FcRn. Molecules with a size lower than the renal filtration limit of 70 kDa have been defined as having a short half-life (typically hours in humans). Molecules with a size above the renal filtration limit but without the ability to bind to FcRn have been defined as having a moderate half-life (typically days in humans). Molecules with a size above the renal filtration limit and the ability to bind to FcRn have been defined as having a long half-life (typically weeks in humans).

It should be noted that a range of different strategies can be taken to enhance the half-life of a biologic, including:

• Fusion to an Fc domain. This provides the FcRn binding capability of the IgG Fc domain as well as increases the size of the protein.
• Fusion to albumin. This provides the FcRn binding capability of serum albumin as well as increases the size of the protein.
• Fusion to an albumin-binding domain. By incorporating an antibody or antibody-like domain targeted at albumin, the resulting fusion protein can piggy-back onto albumin and thus gain a half-life extension.
• Conjugation to polymers. Chemical conjugation to polymers (e.g., PEGylation) or genetic fusion to biological equivalents (e.g., PASylation or HESylation) significantly increases the hydrodynamic radius of a protein and can significantly enhance half-life through prevention of renal filtration.

For more information on technologies to extend serum half-life, we recommend this 2016 review by Ronald Kontermann.

Manufacturability encompasses a range of properties such as expression titer, aggregation, long-term stability and solubility. It would be a mammoth task to measure and quantify each of these properties for all the formats shown in our Periodic Table. It must also be appreciated that the manufacturability of a format can change dramatically depending on the specific sequences (e.g., variable domains) that are incorporated into the format. However, to give an approximate guide to the potential manufacturability of each format, we have assigned a value based on in-house expression titers. All formats have been ranked based on titer and then given a score out of 10, with 10 being the most manufacturable and 1 the least.

For fun, we decided to assign an ingenuity score to each of the formats in our Periodic Table. This is an arbitrary number but represents our feelings about how ingenious the antibody engineering behind the format is. All formats are scored out of 5 with a higher number representing a greater level of ingenuity. Native formats, such as IgG and IgM, have a score of 1 as no real level of protein engineering was required to create them.