Proteomics - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 422

8.9.1 Toxicity of Natural Substances
It is irrational to assume that all compounds of natural origin are safe and free from
fatal toxicities. The biological system will deal with such compounds as if they were
xenobiotics only. Some primary information can be gathered by studying in vivo effi-
cacy and biodistribution in suitable animal models.
8.9.2 Reasons for Studying Protein and Peptide Toxicity
The toxicity profile of proteins and peptides has to be thoroughly established, as
these data must be furnished to confirm the intrinsic safety of the clinical formulation
and to maintain the stability, safety, and efficacy of a product during the manufactur-
ing process. These data must also be furnished for USFDA approval.
An overview of toxicity study design for proteins and peptides is outlined as fol-
lows: the first step involves providing a rationale for undertaking the study, followed
by selection of a suitable animal species. Animal models will be subjected to the
study of pathological changes and toxicological changes following protein therapy.
The basic tenets covered are composed of cytopathology versus histopathological
changes; histochemical screening; elucidation of tissue injury and finding the cause
of death, if applicable; antibody specificity and cross-reactivity screening; generic
toxicities; immunogenicity; idiopathic toxicities; screening of genetically engineered
protein derivatives and recombinant products; amplification and induction systems;
and finally, formulation and process effects.
The extensive use of proteins in diagnostics and therapeutics has made it imper-
ative to undertake comprehensive nonclinical and clinical toxicological studies.
However, the old classical methods may not suffice to mitigate the toxicological
profile of proteins and peptides that have been studied in the last two decades. The
toxicological study protocols and plans must be intelligently devised through critical
selection. Conventional toxicological testing supplemented with sophisticated inter-
pretation will facilitate expanding the scope and vision of preclinical researchers in
establishing the safety and efficacy of new protein-based pharmaceuticals. Hence, the
most pressing need is to develop, establish, validate, and promote the safe, rational,
and efficacious use of proteins in therapeutics.
8.10 Conclusion
Proteomic studies have facilitated elucidation of the physiological and pharmacologi-
cal role of proteins in a biological system. Major breakthroughs have opened new
gateways for using proteins in diagnostics in the form of biomarkers or therapeutics
as in the use of monoclonal antibodies in cancer. Today's scientists realize the role
of proteins as potential pharmaceuticals. However, some basic issues are associated
with proteins: size, structure, high molecular weight, biological barriers to efficacious
protein absorption in vivo , and lability as well as their vulnerability to various exo-
geneous and endogeneous physicochemical factors have rendered proteins challeng-
ing candidates for formulation. At this stage, current belief holds that pharmaceutical