High sensitivity
imaging tools could provide a more holistic view
of target antigen expression to improve the identification of patients
who might benefit from cancer immunotherapy. We developed for immunoPET
a novel recombinant human IgG1 (termed C4) that potently binds an
extracellular epitope on human and mouse PD-L1 and radiolabeled the
antibody with zirconium-89. Small animal PET/CT studies showed that 89Zr-C4 detected antigen levels on a patient derived xenograft
(PDX) established from a non-small-cell lung cancer (NSCLC) patient
before an 8-month response to anti-PD-1 and anti-CTLA4 therapy. Importantly,
the concentration of antigen is beneath the detection limit of previously
developed anti-PD-L1 radiotracers, including radiolabeled atezolizumab.
We also show that 89Zr-C4 can specifically detect antigen
in human NSCLC and prostate cancer models endogenously expressing
a broad range of PD-L1. 89Zr-C4 detects mouse PD-L1 expression
changes in immunocompetent mice, suggesting that endogenous PD-1/2
will not confound human imaging. Lastly, we found that 89Zr-C4 could detect acute changes in tumor expression of PD-L1 due
to standard of care chemotherapies. In summary, we present evidence
that low levels of PD-L1 in clinically relevant cancer models can
be imaged with immunoPET using a novel recombinant human antibody.
The pro-inflammatory cytokine interleukin (IL)-1β is a clinical target in many conditions involving dysregulation of the immune system; therapeutics that block IL-1β have been approved to treat diseases such as rheumatoid arthritis (RA), neonatal onset multisystem inflammatory diseases, cryopyrin-associated periodic syndromes, active systemic juvenile idiopathic arthritis. Here, we report the generation and engineering of a new fully human antibody that binds tightly to IL-1β with a neutralization potency more than 10 times higher than that of the marketed antibody canakinumab. After affinity maturation, the derived antibody shows a >30-fold increased affinity to human IL-1β compared with its parent antibody. This anti-human IL-1β IgG also cross-reacts with mouse and monkey IL-1β, hence facilitating preclinical development. In a number of mouse models, this antibody efficiently reduced or abolished signs of disease associated with IL-1β pathology. Due to its high affinity for the cytokine and its potency both in vitro and in vivo, we propose that this novel fully human anti-IL-1β monoclonal antibody is a promising therapeutic candidate and a potential alternative to the current therapeutic arsenal.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.