Challenges and approaches for the development of safer immunomodulatory biologics.

Immunomodulatory biologics, which render their therapeutic effects by modulating or harnessing immune responses, have proven their therapeutic utility in several complex conditions including cancer and autoimmune diseases. However, unwanted adverse reactions--including serious infections, malignancy, cytokine release syndrome, anaphylaxis and hypersensitivity as well as immunogenicity--pose a challenge to the development of new (and safer) immunomodulatory biologics. In this article, we assess the safety issues associated with immunomodulatory biologics and discuss the current approaches for predicting and mitigating adverse reactions associated with their use. We also outline how these approaches can inform the development of safer immunomodulatory biologics.

Considerations regarding nonhuman primate use in safety assessment of biopharmaceuticals.

Selection of a pharmacologically responsive species can represent a major challenge in designing nonclinical safety assessment programs for many biopharmaceuticals (eg, monoclonal antibodies (mAbs)). Frequently, the only relevant species for nonclinical testing of mAbs is the non-human primate (NHP). This situation, coupled with a rapidly increasing number of mAb drugs in development, has resulted in a significant increase in the number of NHPs used in nonclinical safety assessment. Apart from ethical considerations related to responsible animal use, there is a clear need for more efficient and innovative approaches to drug discovery and development; these factors drive the need to investigate alternative approaches and strategies for the safety assessment. This review summarizes important scientific and regulatory perspectives derived from presentations and audience discussions in an educational forum at the 2010 annual American College of Toxicology meeting regarding opportunities for employing alternative approaches to minimize NHP use in mAb drug development.

Carcinogenicity assessments of biotechnology-derived pharmaceuticals: a review of approved molecules and best practice recommendations.

An important safety consideration for developing new therapeutics is assessing the potential that the therapy will increase the risk of cancer. For biotherapeutics, traditional two-year rodent bioassays are often not scientifically applicable or feasible. This paper is a collaborative effort of industry toxicologists to review past and current practice regarding carcinogenicity assessments of biotherapeutics and to provide recommendations. Publicly available information on eighty marketed protein biotherapeutics was reviewed. In this review, no assessments related to carcinogenicity or tumor growth promotion were identified for fifty-one of the eighty molecules. For the twenty-nine biotherapeutics in which assessments related to carcinogenicity were identified, various experimental approaches were employed. This review also discusses several key principles to aid in the assessment of carcinogenic potential, including (1) careful consideration of mechanism of action to identify theoretical risks, (2) careful investigation of existing data for indications of proliferative or immunosuppressive potential, and (3) characterization of any proliferative or immunosuppressive signals detected. Traditional two-year carcinogenicity assays should not be considered as the default method for assessing the carcinogenicity potential of biotherapeutics. If experimentation is considered warranted, it should be hypothesis driven and may include a variety of experimental models. Ultimately, it is important that preclinical data provide useful guidance in product labeling.

Expression and function of erythropoietin receptors in tumors: implications for the use of erythropoiesis-stimulating agents in cancer patients.

Safety concerns surrounding the use of recombinant human erythropoietin (Epo) to treat anemia in cancer patients were raised after 2 recent clinical studies reported a worse survival outcome in patients who received epoetin alpha or epoetin beta compared with patients who received placebo. Although those findings contrasted with previous clinical studies, which demonstrated no difference in survival for cancer patients who received erythropoiesis-stimulating agents (ESAs), some investigators have suggested a potential role for ESAs in promoting tumor growth through 1) stimulation of Epo receptors (EpoR) expressed in tumors, 2) stimulation and formation of tumor vessels, and/or 3) enhanced tumor oxygenation. The first and second hypotheses appeared to be supported by some EpoR expression and ESA in vitro studies. However, these conclusions have been challenged because of poor specificity of EpoR-detection methodologies, conflicting data from different groups, and the lack of correlation between in vitro data and in vivo findings in animal tumor models. For this report, the authors reviewed the biology of EpoR in erythropoiesis and compared and contrasted the reported findings on the role of ESAs and EpoR in tumors.

Prolonged treatment of human osteoarthritic chondrocytes with insulin-like growth factor-I stimulates proteoglycan synthesis but not proteoglycan matrix accumulation in alginate cultures.

OBJECTIVE: To determine the level of anabolic response when chondrocytes isolated from human osteoarthritic cartilage are stimulated with 2 doses of insulin-like growth factor-I (IGF-I) for extended culture periods. METHODS: Human chondrocytes were isolated from knee cartilage removed at the time of joint replacement surgery for osteoarthritis (OA). The cells were cultured in alginate beads under serum-free conditions and treated with 100 ng/ml or 1000 ng/ml of human recombinant IGF-I. Response was measured during culture periods of 1 to 28 days by determining the level of radiolabeled sulfate incorporated into alcian blue precipitable material and by measuring the level of total proteoglycan accumulation using the dimethylmethylene blue (DMB) assay. For the latter assay, cultures treated with osteogenic protein-1 (OP-1) were used for comparison to IGF-I. Results were normalized to cell numbers using DNA measurements. RESULTS: The level of IGF-I stimulated sulfate incorporation relative to untreated controls increased with time in culture, with a peak response occurring between days 7 and 14 of culture. There was no significant difference between the 2 IGF-I doses. Despite the stimulation of sulfate incorporation, the DMB assay did not reveal a significant accumulation of proteoglycans in the cell-associated and further-removed matrix with either dose of IGF-I in cultures carried out to 21 days. In contrast, compared to controls, OP-1 at 100 ng/ml stimulated a 3-fold increase in matrix proteoglycan at day 21 of culture. CONCLUSION: Prolonged IGF-I treatment of human OA chondrocytes in serum-free alginate cultures stimulated sulfate incorporation without significant accumulation of a proteoglycan matrix in longterm cultures. However, significant proteoglycan accumulation was seen in cultures treated with OP-1, suggesting it is a better stimulator of proteoglycan production by OA chondrocytes.