Immune checkpoint inhibition (ICI) has become a highly effective strategy for reversing cancer-induced immune suppression. Monoclonal antibodies (mAbs) targeting PD-1/PD-L1 are FDA-approved and increasingly used in clinical practice. However, preclinical mouse models have struggled to replicate the significant therapeutic responses and toxicities seen in patients. This discrepancy is largely due to commonly used models, which rely on fast-growing, ex vivo–cultured transplantable tumor cell lines implanted into young, naïve inbred mice. Another challenge arises from the repeated use of xenogeneic reagents in mice, such as rat or hamster mAbs against mouse antigens, which differ from the human or humanized mAbs applied clinically. Building on previous work showing that repeated administration of xenogeneic anti-PD-1 mAbs can trigger fatal hypersensitivity in some tumor-bearing mice, we compared these effects with those of a mouse-specific anti-PD-1 mAb. Treatment with a murine anti-mouse PD-1 (clone MuDX400) did not provoke lethal anaphylaxis in the 4T1 tumor model and demonstrated stronger antitumor activity across multiple models, likely because it avoided generating neutralizing antibodies against the therapeutic mAb, a problem observed with xenogeneic antibodies. These findings underscore the importance of using mouse-specific reagents in preclinical studies to more accurately reflect clinical outcomes, enabling proper assessment of long-term efficacy and toxicity while preventing xenogeneic immune responses that do not occur in patients. Moreover, this work provides a potential explanation for why preclinical murine studies have often failed to reproduce the clinical effectiveness and adverse effects of checkpoint inhibitors as single agents.
