General Processes

Quantification of protein expression is important when considering the translation of a candidate protein biomarker. If there are changes in posttransla-

tional modification of the biomarker, it would be preferable to be able to quantify levels of both protein expression and posttranslational modification, utilizing technologies such as ligand-binding assays (LBA), enzymatic assays, liquid chromatography-mass spectrometry (LC-MS) in multiple-reaction mode (MRM-LC-MS), protein assay, and real-time polymerase chain reaction (RT-PCR) genomics. LBAs can be performed in high throughput at a relatively low cost per samples, which is most advantageous for application through phases of characterization and qualification development of a novel bio-marker. Therefore, LBAs have been widely used for protein biomarker quantification and will be the typical method for discussion in this chapter.

The developmental processes of a novel biomarker and a new chemical drug entity are intertwined (Lee et al., 2003, 2007). Biomarker development may happen concurrently with the development of a single or multiple drug candidates, a refined new chemical or biological entity, or for extended indications and/or additional mechanisms. The progress of a potential biomarker does not always coincide with or parallel that of a new drug candidate development. To utilize and integrate information from development of drugs in therapeutic programs and the development of relevant putative biomarkers, a detailed work plan can be prepared for the novel biomarker and the study objectives identified in the corresponding study protocols of each drug candidate. Innovative companies often organize biomarker work groups to facilitate timely input and communication among therapeutic areas and supporting teams.

As depicted in Figure 2, novel target (BMKa) and/or proximal biomarkers (BMKb) of a specific mechanism can be used for multiple drug candidates to prove the mechanism of action by drug intervention during the exploratory and demonstration phases. If the circulatory biomarkers are reflecting their actions in the target cells/organs, measurements of blood levels of the target and/or proximal biomarkers can be included during clinical trials for further characterization purposes. In addition, distal biomarkers (BMKi,j) of a specific disease indication that have been used for other drug compounds can be applied for a new drug of a different mechanism toward the same indication. In general, distal biomarkers are closer to the disease symptom magnification for efficacy and off-target indirect effects, while the target and proximal bio-markers are closer to the direct exposure effect. Thus, the establishment of PD relationships to pharmacokinetics (PK) is usually simpler for the target or proximal biomarkers, while linkage to a clinical outcome may be shown more readily by distal biomarkers. PK-PD modeling is used to correlate the doseexposure effects. PK- PD modeling based on various mechanisms of action, direct and indirect drug effects, and reactions of biological cascades has been developed (Mager et al., 2003). For proof of biology, the biochemical coverage of biomarkers from target hit to distal to clinical outcome would provide a thorough understanding of drug effect and characterization of a novel bio-marker, whether it is a target, proximal, or distal. Additionally, off-target negative effects should be monitored carefully by toxicity biomarkers (BMKt). Such information is vital in the selection of lead candidates and appropriate dose ranges for clinical trials (FDA, 2004).

Specific target pathway

On-target biomarker

Specific target pathway

BMKa'

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