By Kenneth J. Olivier Jr., Sara A. Hurvitz
Providing sensible and confirmed strategies for antibody-drug conjugate (ADC) drug discovery luck in oncology, this ebook is helping readers enhance the drug security and healing efficacy of ADCs to kill distinct tumor cells.
• Discusses the fundamentals, drug supply suggestions, pharmacology and toxicology, and regulatory approval strategies
• Covers the behavior and layout of oncology scientific trials and using ADCs for tumor imaging
• Includes case reviews of ADCs in oncology drug development
• Features contributions from highly-regarded specialists at the frontlines of ADC learn and development
Read or Download Antibody-Drug Conjugates: Fundamentals, Drug Development, and Clinical Outcomes to Target Cancer PDF
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Extra resources for Antibody-Drug Conjugates: Fundamentals, Drug Development, and Clinical Outcomes to Target Cancer
Such dosing comparisons can be approximated in units of mg/kg, given that mouse and human each have approximately similar ratios of plasma volume to body weight, 40 to 43 mL/kg . Although one also needs to take into account potential differences in pharmacokinetic properties of the ADC between mouse and human, as well as any differences in normal tissue antigen expression in the case of antibodies that do not cross-react with the mouse antigen which can result in differences in antigen-mediated clearance, assessment of anti-tumor activity in units of mg/kg may offer valuable initial insight into the potential of an ADC for development.
There are a variety of other site-specific conjugation approaches that are being evaluated in the research laboratory [53, 59, 60]; however, a detailed description of these approaches is beyond the scope of this chapter and is about “typical” ADCs at this time. 0 has a molecular mass that is about 2% greater than that of the corresponding “naked” antibody moiety. Ideally, the biochemical parameters of an ADC should be broadly similar to those of its nonmodified antibody moiety, behaving mostly as intact monomeric molecules upon size-exclusion chromatography, with very little aggregate present [56, 61].
Thus, the lack of cytotoxicity of these potent microtubule-acting compounds toward nondividing, or only slowly dividing, normal cells may contribute to the tolerability of ADCs made using them as payloads. 3 Linker Chemistries An optimal linker should be sufficiently stable in circulation in the bloodstream to take advantage of the pharmacokinetic properties of the antibody moiety (the long half-life), yet should allow efficient release of an active cytotoxic compound within the tumor cell. Linkers used in typical ADCs can be characterized as either cleavable or noncleavable.