The golden age of engineered therapeutic antibodies

Since the first approval of monoclonal antibodies more than 25 years ago, the field has seen the emergence of engineered antibodies, e.g. Fc-engineered antibodies, antibody drug conjugates (ADCs) and bispecific antibodies (bsAbs). Notably, as of today, 13 ADCs and 17 bsAbs have been approved by health authorities and already account for more than US$10bn and US$8bn in global sales, respectively.

It is important to note that bsAbs are increasingly being applied for the treatment of diseases beyond oncology. Based on the recent therapeutic progress, ADCs and bsAbs represent the fastest growing class of therapeutic antibodies in (pre-)clinical development and have been a major driver of deal-making in the biopharmaceutical industry in the past years. Interestingly, the first bispecific antibodies approved, catumxomab and blinatumomab, were originally developed by academic start-ups in Munich, Germany.

ADCs and bsAbs continue to be an attractive area of research for innovative biotech companies due to the availability of technologies allowing a comparably rapid identification and optimisation of development candidates, the progress made with the manufacturing of complex molecules, and the generally favourable clinical development success rates for therapeutic antibodies.

BsAbs are particularly attractive from a conceptual point of view, as they allow the mediation of completely novel mechanisms of action for the therapy of various diseases that cannot be achieved with conventional monospecific antibodies. This includes, for example, the recruitment and engagement of immune cell subsets for tumour cell killing, e.g., with T-cell engagers, mimicking of blood coagulation factors, dual-targeted bispecific ADCs with selectivity for defined cancer types, cis-targeting of T-cell subsets with dual checkpoint inhibitors or cytokines, degradation of cell surface proteins, transport of antibodies across the blood-brain-barrier, triggering of cytokine receptors with cytokine mimetics or activation mechanisms that can switch bsAbs on/off in the tumour microenvironment to prevent undesired peripheral toxicities, and many more.

It is amazing to see how researchers after 50 years of antibody engineering continue to come up with novel and ingenious solutions to tackle therapeutic challenges and to observe how novel methods like single-cell sequencing, proteomics, cryo-EM, machine learning and artificial intelligence help to further accelerate therapeutic innovation. Given all this progress and the diversity of ideas pursued in biotech companies and biopharmaceutical industry, I firmly believe that the golden age of engineered antibodies and their use for synthetic ­biology is only about to start. Their potential is beyond our imagination.

Author:
Dr Christian Klein, CXO in residence and drug hunter at the early-stage VC specialist Curie.Bio, has 22 years of industry experience in the field of therapeutic antibodies, co-authored 220 publications and is co-inventor of 240 patent families. The biochemist joined Roche pRED in 2002 and co-led teams pioneering the development of CrossMabs, 2+1 TCBs, 4-1BB/CD28 costimulators and PD1-cis immunocytokines. He contributed to 32 clinical NMEs for Roche of which four are approved and to numerous collaborations with biotech companies.

This article was originally published in European Biotechnology Magazine Winter 2024.