Printed From:

Last update: November 2018

The study of antibodies has been a focal point in biology and medicine since the early 1900s. However, it was the discovery of hybridoma technologies by Milstein and Kohler in 1975 that was the catalyst for the significant advances in the field and the development of the modern therapeutic monoclonal antibodies (mAbs) available today.1

Historical aspects

The first concept of using antibodies as therapeutics came over 100 years ago, when in the 1890’s Hoechst introduced the first immunobiological therapeutic to treat diphtheria1. This was followed by early characterisation and standardisation of anti-serum therapies by Paul Ehrlich for which he was awarded the Nobel Prize1.

Many years later, the commercial path was paved by Genentech and Eli Lilly who produce the first recombinant therapeutic mAb, the human insulin product Humulin, which was approved in 1982 and was soon followed by a wide range of mAbs for use in many different therapeutic areas including oncology, haematology, rheumatology and cardiology.1,2

Developments in molecular biology antibody engineering in the early 1990s led to the development of the chimeric, humanised and fully human mAbs available today.2

Antibody structure

Antibodies, also known as immunoglobulins (Igs) are B-cell produced molecules composed of four polypeptide chains, two copies of a heavy chain and two copies of a light chain. These chains come together to form a characteristic Y shape1,2. There are five isotypes which are distinguished by differences in their heavy chains: isotypes IgM, IgD, IgG, IgE and IgA.

IgG is the most abundant antibody in humans and typically functions in the immune response. IgG's are the most common class of Ig isotypes used as the structural basis for the production of therapeutic antibodies.2

Chimeric, humanised and fully human mAbs

The creation of chimeric, humanised and fully human mAbs was a major breakthrough in the field as humanisation has led to significant and beneficial reductions in immunogenicity.2

Chimeric mAbs are created by fusing the murine variable domains (responsible for binding to the target) with human constant domains2,3. Humanised mAbs are created by replacing the hyper-variable loops of a fully human antibody with the hyper-variable loops of the murine antibody of interest3. Fully human mAbs are created by replacing the entire mouse antibody genome with that from a human using transgenic hybridoma technology2.

Monoclonal antibody: an International Non-proprietary Name (INN) comprise a ‘mab’ suffix preceded by a sub-stem indicating the antibody type, e.g., chimeric (-xi-), humanized (-zu-), or human (-u-).4

Developing a fully human mAb using transgenic hybridoma mouse technology

Generation of fully human therapeutic mAbs was made possible by the development of transgenic mouse platforms which involves:2

  1. Antibody heavy- and light-chains within mice embryonic stem (ES) cells undergoing gene-targeted deletion,
  2. Crossbreeding results in mice incapable of producing mouse antibodies,
  3. Yeast artificial chromosomes containing either human heavy- or light-chain DNA are introduced into ES cells,
  4. Crossbreeding of mice derived from ES cells results in transgenic mice that produce both human and mouse antibodies,
  5. Mice incapable of producing mouse antibodies are crossbred with transgenic mice resulting in a mouse expressing fully human antibodies; a XenoMouse,
  6. Antibody-producing B cells isolated from the spleen of the XenoMouse are used to produce hybridomas (B cells are fused with an immortal cell line),
  7. Fully human mAbs are produced and purified.


Therapeutic mAbs – mechanism of action

Antibodies mediate their actions by various types of direct and indirect effects. Direct effects are conferred by binding with cell surface receptors, membrane bound proteins, growth factors or circulating proteins. Most therapeutic mAbs use the variable regions to produce a direct effect on target biology2. Indirect effects occur when antibodies bind to targeted cells and recruit other cells with the capacity of antibody dependent cellular cytotoxicity, promote activation of a cellular death cascade or are conjugated to drugs toxins or radioisotopes2. Praluent has a direct effect by binding to PCSK9 and inhibiting binding to LDLR.

mAbs - a growing therapeutic class

Since the commercialisation of the first therapeutic mAb in 1986, this class of biopharmaceuticals has grown significantly and, at the current rate of approval — around 4 new products per year — it is predicted approximately 70 therapeutic mAbs will available to treat disease by 2020.5


  • Zhiqiang A. ed. Therapeutic monoclonal antibodies. From Bench to bedside. Hoboken: Whiley. 2010.
  • Foltz IN, et al. Evolution and emergence of therapeutic monoclonal antibodies: what cardiologists need to know. Circulation. 2013; 127:2222-30
  • Chames P, et al. Therapeutic antibodies: successes, limitations and hopes for the future. Br J Pharmacol. 2009; 157:220–233
  • Jones TD, et al. The INNs and outs of antibody nonproprietary names. MAbs. 2016; 8:1-9.
  • Ecker DE, et al. The therapeutic monoclonal antibody market. MAbs. 2015; 7:9-14.