Monoclonal Antibodies: From Benchtop to Bedside

Keywords::

• effective dosing
• imaging
• personalized medicine
• species scaling
• target delivery

A quick review of US FDA-approved monoclonal antibodies through the public-accessible Drugs@FDA webpage revealed that six monoclonal antibodies received approval between 2009 and 2010, and that the monoclonal antibody products approved so far are largely indicated for cancers, autoimmune diseases, organ transplantations or for imaging and diagnosis [101]. Monoclonal antibodies, designed to specifically recognize a unique epitope on a particular antigen, possess a unique array of characteristics that render them versatile. Monoclonal antibodies consisting of amino acids have numerous functional groups available for chemical conjugation. Indeed, chemical conjugation of monoclonal antibodies with different types of molecules has been applied to increase their in vivo stability or delivery efficiency. This approach has also been used to create monoclonal antibody vectors for delivery of cytotoxic drugs to cancer cells or to carry radioactive isotopes or fluorescent imaging probes for medical imaging and disease diagnosis. Certolizumab pegol, for example, consists of an approximately 40 kDa polyethylene glycol conjugated to a recombinant, humanized antibody Fab´ fragment to increase the metabolism stability and circulating half-life of the antibody fragment. Gemtuzumab ozogamicin, for instance, is a conjugate of a monoclonal antibody and the cytotoxic anticancer antibiotic ozogamicin. These existing approaches are continuously being expanded for the development of new molecules for medical use. Use of monoclonal antibodies as carriers of small-molecule drugs or molecular-imaging probes is an active research area. To gain an understanding of the R&D activity in this area, PubMed is a useful source of knowledge and a database. Keywords of ‘antibody drug conjugate‘ on PubMed yielded 143 publications, while keywords of ‘monoclonal antibodies‘ and ‘imaging‘ yielded 657 publications, when the search was limited to the past 2 years. Conjugates of monoclonal antibodies with imaging probes provide the much-needed detection and staging of tumors for the treatment of various cancers while conjugates of monoclonal antibodies with cytotoxic drugs provide targeted therapy to maximize the success of eradicating tumor cells or treating other diseases. Efficiency of conjugation as well as the yield and stability of a monoclonal antibody conjugate depends on the nature of monoclonal antibodies and the type of cytotoxic payloads or probes to be conjugated. These issues will be elaborated in two articles in this issue, aiming to provide readers with insights into the challenges and successes in this area of research [1,2]. The technical challenges encountered, the scientific methods used to overcome difficulties, and the optimal outcomes achieved in both applications will offer a stimulating and educational contrast and comparison.

The market size of monoclonal antibodies is expected to reach approximately US$70 billion by 2015 [3,102]. In 2008 and 2009, 193 monoclonal antibodies were under clinical development. A PubMed search offered a glimpse of research activities on developing monoclonal antibodies for treating diseases. When limited to 2010, key words of ‘monoclonal antibodies‘ and ‘Phase III‘ yielded 346 publications, and 229 publications when the word ‘cancer‘ was added. Adding the word ‘autoimmune‘ yielded eight publications, while adding ‘transplant‘ to the search yielded 16 publications. Key words of ‘monoclonal antibodies‘ and ‘Phase II‘ yielded 402 publications. Replacing ‘Phase II‘ with ‘Phase I‘ yielded 372 publications. Since clinical trials are time consuming, this crude survey roughly reflects the recent clinical trials involving monoclonal antibodies. When the word ‘preclinical‘ was combined with monoclonal antibodies, 475 publications were found in the past 2 years. In short, extensive efforts and resources are being devoted to developing monoclonal antibodies for treating diseases. Owing to the nature of their chemical composition and molecular sizes, monoclonal antibodies have their own set of problems and challenges during development. Monoclonal antibodies, large in size, have limited permeation through tissues and cell membranes, and are usually developed to target the surface antigen on a cell membrane and are administered by injection. Owing to their proteinous nature, monoclonal antibodies can cause immunogenicity, other undesirable or severe immunological responses and induction of neutralizing antibodies. Therefore, first-in-human dose-finding studies need to be carefully planned out and executed with all preclinical information and data being considered to project the likely therapeutic window.

The results of dose-finding studies will affect the dose(s) chosen for late-stage clinical trials. Therefore, when designing the first-in-human studies, scaling up the preclinical doses in animal models to define the dose(s) to be studied in humans, a whole array of factors need to be considered so that adequate doses are selected and can be studied effectively in healthy subjects or a targeted population. The development team would need interspecies scaling of pharmacological effects, pharmacokinetics and pharmacodynamics to design doses for the first-in-human studies. A successful interspecies scaling method hinges on an understanding of the similarity and difference between species in the disposition mechanism and pharmacodynamic effects of a monoclonal antibody, and on adequate projection of immunogenicity responses and tolerability in humans. The pharmacokinetic characteristics of a monoclonal antibody, without adequate pharmacodynamic responses, only provide somewhat limited in vivo kinetic data, since pharmacokinetic data reflect only exposure at the macroscopic level without shedding light on what transpires at the microscopic cellular level. Disappointingly, for a good majority of products, pharmacodynamic parameters are not readily validated or available for correlation with clinical outcomes, so ultimately pharmacokinetics are the only parameters available for linking dose to clinical efficacy. As a result, interspecies scaling of pharmacokinetics is frequently the only path enabling a decision on the doses for first-in-human studies. Since the results of first-in-human studies will be used for planning and designing the subsequent Phase II and III trials, the stake of accurate interspecies scaling of pharmacokinetics is high. To provide readers with the most efficient methodologies for pharmacokinetic interspecies scaling and related drawbacks, one article is devoted to this subject [4]. When designing the dose-finding studies of monoclonal antibody therapy for solid tumors, one would need to ensure that, in addition to considering those factors aforementioned, adequate diffusion and permeation of monoclonal antibodies into the interior of a solid tumor is achieved, since it is a prerequisite for effective killing of tumor cells embedded in solid tumors. The size, shape and type of solid tumors will affect the efficiency of monoclonal antibodies in killing solid tumor cells, and their clinical efficacy. Theoretical approaches and experimental studies have been used to model and investigate the effectiveness of delivering monoclonal antibodies into solid tumors to eradicate the tumor cells inside. One article comprehensively discusses dose selection for clinical trials and elaborates on the methods and approaches used to clinically define the most effective dose(s) for treating solid tumors with monoclonal antibodies, using a minimum number of clinical trials [5].

Valid correlation of drug levels in human body fluids with the clinical efficacy end points for monoclonal antibodies relies on validated bioanalytical methods that offer adequate precision and accuracy. Owing to the issues of immunogenicity and neutralizing monoclonal antibodies, development and validation of bioanalytical methods is the foremost requirement for our confidence in the consistency of in vitro measurement quality and in vivo clinical results. An article on bioanalytical methods surely brings much needed pieces of the puzzle along with the two articles on interspecies scaling and dose selection to provide a comprehensive coverage of what goes into the early stages of developing a monoclonal antibody [6]. Another factor to consider in the early development of monoclonal antibodies is the impact of delivering formulations on their bioavailability. Subcutaneous injection is frequently used for administration of monoclonal antibodies, only second to intravenous injection. However, this mode of injection does not achieve complete bioavailability, partly due to binding of monoclonal antibodies to subcutaneous tissues. Physicochemical characteristics of subcutaneous formulations that affect the extent of interactions between a monoclonal antibody with subcutaneous tissues can play a crucial role in its subcutaneous bioavailability.

Last but not least, is the topic of personalized medicine for this therapy class. An article in this issue provides an overview of the safety profiles of approved monoclonal antibodies and their related immunoglobulin-containing fusion proteins [7]. Pharmacogenomic information pertinent to the association of patients‘ genomics with their differential clinical outcomes (efficacy and safety) is highlighted. Current, consistent and controversial findings in pharmacogenomic associations with clinical efficacy or safety of monoclonal antibodies or immunoglobulin-containing fusion proteins are summarized along with the successes achieved and challenges ahead in delivery of this class of molecules for maximizing personalized medicine. Medical utility of monoclonal antibodies is only limited by our imagination. It is expected that efficient and accurate delivery strategies and technologies will continuously evolve to unveil the ever-broadening medical benefits of monoclonal antibodies.

Disclaimer

The views expressed are those of the author and do not necessarily reflect the official policy of the US FDA. No official endorsement is intended or should be inferred.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.