The breakthrough by Kohler and Milstein in the 70’s permitted the deliberate production of antigen specific antibodies, opening the era of hybridoma monoclonal antibodies. Since then, monoclonal antibodies have greatly contributed to biological research and more recently, provided significant clinical value. The approaches for generating a therapeutic antibody have been varied.

Monoclonal antibodies are generally obtained in mice and are thus structurally mouse proteins (or murine). Initially, murine antibodies directed towards human protein targets were injected into patients. However, this procedure gave rise to immune rejection via a human anti-mouse antibody (HAMA) response eventually neutralizing the efficacy of therapeutic antibodies.

Because of the generation of HAMA and of other related unwanted side effects, the V regions (antigen-specific) of mouse antibodies were subsequently linked to (figure 2) a human H and L constant region framework (= chimeric), or, alternatively, the sequences of the murine CDRs grafted onto a human constant "backbone" (= humanized). While both strategies generate antibodies containing less murine derived sequences, both can still generate unwanted anti-mouse antibody responses (HAMA), often with neutralizing effect on the antibody.

New technologies have evolved permitting the creation of fully human antibodies still endowed with the exquisite specificity for a given therapeutic target. The transgenic mouse approach is one alternative, in which mouse antibody gene expression is replaced by fully human antibody gene expression.

NovImmune uses two different technologies in house: the UltiMAb system developed by Medarex to obtain fully human therapeutic monoclonal antibodies using transgenic mice and the selection of fully human antibodies displayed on bacteriophages (small viruses of bacterias). This is referred to as antibody display selection.

Figure 2 - Various Types of Therapeutic Antibodies