Anti-PDCD1 monoclonal antibody, clone MIH4

Background: Gene expression profiling distinguishes the absence or presence of moderate to severe grades of -acute cellular rejection in cardiac allograft recipients using,I 20-gene classifier. We explored the hypothesis that the rejection classifier also differentiates various forms of mild rejection and we performed sub-analyses based on time post-transplant and confirmatory pathology interpretations. Methods: A post hoc analysis of 265 CARGO study patients and 714 clinical encounters focused on the correlation of rejection classifier- derived gene expression (GE) scores for blood samples accompanying endomyocardial biopsies. Biopsy grades assigned by a study center pathologist (center) were re-interpreted by three pathologists (panel) in a blinded manner. Results: Mean GE scores not only differentiated Grades >= 3A from Grade 0 (p < 0.00001, center or panel), but also from Grades 1A or 2 (P < 0.05, center or panel), based on mild rejection sub-groups defined by the ISHLT 1990 grading system. In contrast, mean GE scores for Grades 1B and >= 3A were indistinguishable, using either center or panel interpretation. Sub-group analyses of encounters from 2 to 6 months or >6 months post-transplant showed similar results for the classifier's ability to discriminate moderate to severe rejection from Grades 1A and 2 mild rejection, but indistinguishable mean GE scores for Grades >= 3A and the Grade 1B sub-group. Of the classifier's 11 informative genes, expression of MIR and WDR40 showed statistically significant increases for both Grade 1B and Grade :3A rejection, while expression of PDCD1. or SEMA7A showed similar directional patterns without achieving statistical significance. Conclusions: These data demonstrate that GE scores discriminate moderate to severe rejection from Grades 1A and 2 mild rejection. However, a sub-group of mild rejection cases, defined as Grade 113 according to the 1990 grading system, share a molecular signature more consistent with moderate to severe rejection. The clinical relevance of these data remains to be defined. J Heart Lung Transplant 2007; 26:1270 - 80. Copyright (c) 2007 by the International Society for Heart and Lung Transplantation.

Emerging immune therapy, such as with the anti-programmed cell death-1 (anti-PD-1) monoclonal antibody nivolumab, has shown efficacy in tumor suppression. Patients with terminal cancer suffer from cancer pain as a result of bone metastasis and bone destruction, but how PD-1 blockade affects bone cancer pain remains unknown. Here, we report that mice lacking Pdcd1 (Pd1(-/-)) demonstrated remarkable protection against bone destruction induced by femoral inoculation of Lewis lung cancer cells. Compared with WT mice, Pd1(-/-) mice exhibited increased baseline pain sensitivity, but the development of bone cancer pain was compromised in Pd1(-/-) mice. Consistently, these beneficial effects in Pd1(-/-) mice were recapitulated by repeated i.v. applications of nivolumab in WT mice, even though nivolumab initially increased mechanical and thermal pain. Notably, PD-1 deficiency or nivolumab treatment inhibited osteoclastogenesis without altering tumor burden. PD-L1 and CCL2 are upregulated within the local tumor microenvironment, and PD-L1 promoted RANKL-induced osteoclastogenesis through JNK activation and CCL2 secretion. Bone cancer upregulated CCR2 in primary sensory neurons, and CCR2 antagonism effectively reduced bone cancer pain. Our findings suggest that, despite a transient increase in pain sensitivity following each treatment, anti-PD-1 immunotherapy could produce long-term benefits in preventing bone destruction and alleviating bone cancer pain by suppressing osteoclastogenesis.