**Preface to "Monoclonal Antibody-Directed Therapy"**

The unparalleled specificity and high efficacy of monoclonal antibodies (mAbs) make them desirable modalities both as biological medicines and diagnosis tools. They are amongst the top-selling drugs globally and their market size continues to grow annually. There are over 100 mAb products on the market currently, but considering the thousands that are in clinical trials and the new advancements in this field, such as the development of biosimilars, their market share is expected to increase substantially in the near future. Developing an antibody therapeutic, however, is an onerous journey, as many degradation pathways can prevent this process occurring successfully. These roadblocks generally present themselves at every stage of drug development.

With the advancement of the field over recent years, different types of complex mAb formats have been developed, including full-size mAbs, antibody fragments, antibody-drug-conjugates (ADC) and bispecifics, but full-size mAbs by far still dominate the market. In addition, new approaches such as PEGylation or the hyperglycosylation of constant domains of mAbs and other forms of antibodies such as single domain antibodies (nanobodies) and antibody-targeted nanoparticles have also been frequently explored and they seem to be promising, but these products are yet to receive approvals and reach the market. New formulation and delivery strategies are also explored with novel additives and excipients that prevent protein aggregation.

The majority of biologics, in particular mAbs, are expensive due to the high costs associated with their development and manufacturing, and thus their similar follow-on counterparts—biosimilars—have become very attractive to many consumers because of their affordability. The development of biosimilars became possible for many blockbuster biologics owing to the loss of their patent protection and updates in regulatory guidelines.

Some of the antibody products are closely related to the reference product, but because they have superior characteristics compared to the former, they are called 'biobetters'. These next-generation therapeutics are not defined well at the moment, but perhaps some existing products such as ADCs, bispecifics, and PEGylated or hyperglycosylated versions of certain products can be called biobetters. Biobetters are expected to display improved efficacy/specificity, bind to more than one target or tackle some commonly observed physical–chemical developability issues such as protein aggregation. Advances in connecting the mechanisms influencing the disposition and pharmacokinetics of mAb products will continue to augment the discovery and development of antibody products. Immunogenicity, developability and parenteral delivery remain key spaces for the optimization of antibody products as therapeutic modalities.

These new developments and other advances, such as in silico methods employed to study and/or predict protein–protein interactions, require frequent updates in the literature and necessitate the publishing of books such as this one. Herein, Siniotis et al., provide a comprehensive overview of the challenges and opportunities in the development of therapeutic mAbs. The authors highlight milestones towards antibody engineered formats, including developments in computational approaches for the strategic design of antibodies with modulated functions and an extension into novel formulation technologies such as nanocarrier delivery systems for the potential to formulate for pulmonary delivery. This overview leads into several chapters of increased detailed discussions of various mAb and mAb-based therapeutics. Leung et al., provide a detailed review of antibody drug conjugates (ADCs), which comprise of a mAb conjugated to a small molecule payload via a chemical linker and are one of fastest growing next generation mAb-based therapeutic structures. The authors cover a balance of the immense potential of ADCs to provide the promising therapeutic options in areas of unmet need along with challenges in the field to date with emphasis on antibody conjugation, linker-payload chemistry, novel payload classes, absorption, distribution, metabolism, and excretion (ADME), and product developability. The work of Voynov and colleagues, further extends and emphasizes the therapeutic tractability and clinical success of T-cell engaging bispecific antibodies as an additional high potential mAb-based biologic designed with multiple functionalities. Hotinger and May expand on and stimulate thought around the more recent application of antibody therapeutics as another approach to combat bacterial based infections due to the striking rise in resistance to antibiotics. The last two chapters of the book discuss the pragmatic challenges and considerations with mAb and mAb-based therapy developability and drug-ability. The studies reported by Sharma and coworkers share methods leveraged to test the stability of the co-formulated antibodies that can support future efforts towards the formulation and characterization of multiple high-concentration antibodies for subcutaneous delivery. In the last chapter, Boune et al., detail the importance of the consideration of N-linked glycosylation variations, which can highly influence the desired therapeutic mAb pharmacokinetics and functional properties, thereby impacting their safety and efficacy profiles.

We strongly feel this is a timely commitment and would like to express our gratitude to researchers from both academia and industry for submitting their novel mAb therapy work for this issue in order to capture the new developments that have transpired, as well as covering established concepts in this exciting field. We would like to acknowledge the authors for contributing to this timely and excellent book and the editorial office of *Antibodies* for bringing it to fruition.

> **Veysel Kayser, Amita Datta-Mannan** *Editors*

*Review*
