Format-tuning of in vivo-launched bispecific T cell engager enhances efficacy against renal cell carcinoma.

BACKGROUND: Advanced clear cell renal cell carcinoma (ccRCC) is a prevalent kidney cancer for which long-term survival rates are abysmal, though immunotherapies are showing potential. Not yet clinically vetted are bispecific T cell engagers (BTEs) that activate T cell-mediated cancer killing through intercellular synapsing. Multiple BTE formats exist, however, with limited cross-characterizations to help optimize new drug design. Here, we developed BTEs to treat ccRCC by targeting carbonic anhydrase 9 (CA9) while characterizing the persistent BTE (PBTE) format and comparing it to a new format, the persistent multivalent T cell engager (PMTE). These antibody therapies against ccRCC are developed as both recombinant and synthetic DNA (synDNA) medicines. METHODS: Antibody formatting effects on binding kinetics were assessed by flow cytometry and intercellular synaptic strength assays while potency was tested using T-cell activation and cytotoxicity assays. Mouse models were used to study antibody plasma and tumor pharmacokinetics, as well as antitumor efficacy as both recombinant and synDNA medicines. Specifically, three models using ccRCC cell line xenografts and human donor T cells in immunodeficient mice were used to support this study. RESULTS: Compared with a first-generation BTE, we show that the PBTE reduced avidity, intercellular synaptic strength, cytotoxic potency by as much as 33-fold, and ultimately efficacy against ccRCC tumors in vivo. However, compared with the PBTE, we demonstrate that the PMTE improved cell avidity, restored intercellular synapses, augmented cytotoxic potency by 40-fold, improved tumor distribution pharmacokinetics by 2-fold, and recovered synDNA efficacy in mouse tumor models by 20-fold. All the while, the PMTE displayed a desirable half-life of 4 days in mice compared with the conventional BTE's 2 hours. CONCLUSIONS: With impressive efficacy, the CA9-targeted PMTE is a promising new therapy for advanced ccRCC, which can be effectively delivered through synDNA. The highly potent PMTE format itself is a promising new tool for future applications in the multispecific antibody space.

Insights into the Slow Uptake of Residential Lead Paint Remediation Funds: A Lancaster, Pennsylvania, Case Study.

Lead poisoning is a preventable condition that continues to affect thousands of children each year. Given that local governments and municipalities are eligible to apply for federal funds to perform lead remediation in low-income family homes, we sought to understand how lead poisoning knowledge levels may affect the uptake of these funds. We recruited and conducted 28 in-depth, semi-structured interviews with community members from Lancaster County in the state of Pennsylvania in the USA. We audio-recorded and transcribed each interview, and analyzed each transcript for salient themes. The interviewed participants displayed a varying degree of knowledge about lead and lead poisoning. Most of the participants were unaware of the lead paint remediation funds. Participants learned about lead from various sources, such as social media, and personal experiences with lead poisoning appeared to enhance knowledge. Some participants assumed lead poisoning prevention would be addressed by other stakeholders if necessary, including healthcare professionals and landlords. The results of this study suggest that in order to increase the timely uptake of the remediation funds, community-based organizations should design interventions that aim to increase awareness and knowledge about lead poisoning and lead poisoning prevention. These interventions should be tailored for different audiences including community members, healthcare professionals, and landlords.