Safety and immunotoxicity assessment of immunomodulatory monoclonal antibodies

Abstract

Abbreviations: ADA, anti-drug antibody; ADCC, antibody-dependent cellular cytotoxicity; ADME, absorption, distribution, metabolism and excretion; APC, antigen-presenting cell; AS, ankylosing spondylitis; CAPS, cropyrin-associated periodic syndromes; CD, cluster of differentiation; CDC, complement-dependent cytotoxicity; CDR, complementarity-determining region; CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease; CRA, cytokine release assay; CrD, Crohn disease; CRS, cytokine release syndrome; CTLA-4, cytotoxic T lymphocyte antigen-4; DAMPs, damage-associated molecular patterns; DC, dendritic cell; DTH, delayed-type hypersensitivity; EBV, Epstein Barr virus; EFD-PPND, embryo-fetal development and peri-/ post-natal development; EMA, European Medicines Agency; EPAR, European Public Assessment Report; EPO, erythropoietin; ESG, Expert Scientific Group; FDA, Food and Drug Administration; FIH, first-in-human; GD, gestation day; GLP, good laboratory practice; HED, human equivalent dose; HHV-8, human herpes virus-8; HLA, human leukocyte antigen; HSA, human serum albumin; HSP, heat shock protein; HTLV-1, human T cell leukemia virus-1; ICH, International Conference on Harmonization; IHC, immunohistochemistry; KLH, keyhole limpet hemocyanin; LCV, lymphocryptovirus; LFA-1, leukocyte function antigen-1; LPS, lipopolysaccharide; mAb, monoclonal antibody; MABEL, minimum anticipated biological effect level; MHC, major histocompatibility comlex; MoA, mechanism of action; MRSD, maximum recommended starting dose; MS, multiple sclerosis; NCE, new chemical entity; NHP, non-human primate; NK, natural killer; NLR, nod-like receptor; NOAEL, no observed adverse effect level; PAD, pharmacologically-active dose; PAMPs, pathogen-associated molecular patterns; PEG-MGDF, pegylated megakaryocyte growth and development factor; PD, pharmacodynamic; PHA, phytohemaglutinin; PK, pharmacokinetic; PML, progressive multifocal leukoencephalopathy; PsA, psoriatic arthritis; RA, rheumatoid arthritis; RMP, risk management plan; RO, receptor occupancy; RSV, respiratory syncytial virus; SBA, summary basis of approval; SLE, systemic lupus erythromatosus; SPC, summary of product characteristics; SRBC, sheep red blood cell; TCR, tissue cross reactivity; TDAR, T cell-dependent antibody response; TLR, toll-like receptor; TT, tetanus toxoid; UC, ulcerative colitis; VLA-4, very late antigen-4Most therapeutic monoclonal antibodies (mAbs) licensed for human use or in clinical development are indicated for treatment of patients with cancer and inflammatory/autoimmune disease and as such, are designed to directly interact with the immune system. A major hurdle for the development and early clinical investigation of many of these immunomodulatory mAbs is their inherent risk for adverse immune-mediated drug reactions in humans such as infusion reactions, cytokine storms, immunosuppression and autoimmunity. A thorough understanding of the immunopharmacology of a mAb in humans and animals is required to both anticipate the clinical risk of adverse immunotoxic...

Measuring T-cell responses against LCV and CMV in cynomolgus macaques using ELISPOT: Potential application to non-clinical testing of immunomodulatory therapeutics

“…A number of immunosuppressive therapeutics are associated with increased rates of infections (Brennan et al, 2010;Major, 2010;Rychly & DiPiro, 2005), which can limit or prevent the use of these therapeutics and, therefore, limit the possible benefit to patients. A major challenge to the development of immunomodulatory therapeutics is that their liability to increase infection risk is often not known until large numbers of patients have been exposed in the clinic.…”

Monoclonal Antibodies: An Emerging Class of Therapeutics in Non Small Cell Lung Cancer

“…First, their range of targets is almost limitless. Second, they are unlikely to have unexpected side-effects [19,20]. Their high selectivity reduces the potential of non-mechanism-based toxicity and their bioconversion is well-defined.…”

“…Naked antibody-direct effects  Neutralizing infectious agents  Interfering with ligand-receptor interactions (antagonist activity)  Receptor cross-linking (agonist activity)  Sequestrating soluble mediators  Antibody as immunogens (anti-idiotype) peutic mAbs are generally safe [19,20]. Hence, preclinical and clinical trials tend to be very successful.…”

The Role of Anti-Drug Antibodies in the Pharmacokinetics, Disposition, Target Engagement, and Efficacy of a GITR Agonist Monoclonal Antibody in Mice

“…While modulation of costimulatory pathways have shown great preclinical potential as immunotherapies, immunerelated adverse events ranging from hyper-costimulation to cytokine dysregulation and immunogenicity have been observed (Chirino et al, 2004;Reuben et al, 2006;Suntharalingam et al, 2006;Brennan et al, 2010;Clarke 2010;Murphy et al, 2014). Ultimately, the administration of any biologic has the potential to generate anti-drug antibodies (ADAs) (Pepinsky et al, 2001;Shankar et al, 2006Shankar et al, , 2007Badylak and Gilbert 2008).…”