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Preclinical and clinical safety of monoclonal antibodies

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Owing to their unique specificity, monoclonal antibodies have provided a novel approach to the treatment of human diseases. Several types of antibodies against a diverse array of pharmacological targets have been marketed and many more are currently in clinical trials. Factors related to antigen expression, target pharmacology, and antibody effector functions can contribute to the adverse event profiles observed with monoclonal antibodies. Effective translation of information gained from preclinical research and safety studies into clinical development is a crucial step for successful development of monoclonal antibodies.

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Overview of antibody function and safety

Therapeutic monoclonal antibodies (mAbs) generally exhibit exclusive specificity for the target antigen. This unique characteristic discriminates mAbs from other therapeutic modalities such as small molecule drugs. Hence, it is not surprising that the pharmacology of the target antigen, mAb construct, and mAb isotype determine not only pharmacokinetics (PK) and pharmacodynamics (PD) but also the safety profiles. Factors influencing the PK and PD of mAbs have been discussed previously 1, 2, 3.

Toxicity related to mAb pharmacology

Some of the toxicities observed with antibodies are primarily an extension of the pharmacological response. For example, immunosuppressive and anti-angiogenic mAbs exhibit clear mechanism-based toxicity profiles (Table 1). Bevacizumab is the first monoclonal antibody with the ability to inhibit angiogenesis by blocking the actions of VEGF. Angiogenesis is the process of formation of new blood vessels from pre-existing blood vessels and is of crucial importance in embryonic development, wound

Preclinical safety studies of monoclonal antibodies

Monoclonal antibodies are generally safe and well tolerated, and the toxicities observed with this class of biologics are usually clinically manageable. The antigen-related toxicities are often predictable from preclinical studies if the antibody cross-reacts with the target antigen in the relevant animal models.

Estimating of the safe starting dose in clinical trials for therapeutic mAbs

The primary objectives of the Phase 1 clinical trails are the assessment of safety, pharmacokinetics, and pharmacodynamics [56]. In general, the selection of the first-human dose is guided by considerations of preclinical pharmacology, pharmacodynamics, pharmacokinetics, and toxicology. When feasible, attempts are made to scale up all the preclinical information with inclusion of translational assumptions in order to select an initial clinical dose that avoids toxicity.

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Future prospects

Therapeutic monoclonal antibodies provide a unique and novel opportunity for the treatment of many human diseases. With the advancement of new technologies and the diversity in the novel therapeutic targets, many new opportunities for the clinical development of mAb-based therapeutics should arise. Many examples exist of successful transitions from preclinical to clinical development that have been greatly facilitated by preclinical safety and pharmacology data. As the unfortunate incidence

Acknowledgement

The authors would like to thank James Liu for his contributions and assistance in preparation of the manuscript.

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