Immunogenicity in nonclinical species is common; however, the management of immunogenicity in addition to loss of exposure, and infusion reactions in sub chronic and chronic studies can be more than challenging. In pilot and 4-week repeat dose toxicology studies of a mAb to a soluble immunomodulatory target, there was evidence of immunogenicity based on increased drug clearance on Day 28 compared to Day 1, especially at lower dose levels. This information was used to select higher dose levels for the 26-week chronic study. When infusion reactions occurred at all dose levels in the 26-week chronic study after repeat dosing, interim analyses (TK) and additional endpoints (complement activation and cytokines) were added to the study design to determine if immunogenicity or a direct test article-effect was causing the observed adverse toxicity. An ADA assay was being developed but was not readily available. The study then proceeded with an immunogenicity management plan for animals with infusion reactions, appropriate representation of animals in terminal and recovery groups, the terminal necropsy date was adjusted, and immunohistochemistry for the detection of immune complexes was added as a study endpoint. A weight of evidence approach, in the absence of ADA data, was then used to define the NOAEL to support the ongoing clinical program.