PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer.

High-grade serous ovarian cancers (HGSOC) represent the most common subtype of ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 antigen-binding fragments (Fabs) with the anti-CD3 scFv. In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mg/kg. Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles to support its use as a treatment for high-grade serous ovarian cancers.

Temporal and Isoform-Specific Expression of CTBP2 Is Evolutionarily Conserved Between the Developing Chick and Human Retina.

Complex transcriptional gene regulation allows for multifaceted isoform production during retinogenesis, and novel isoforms transcribed from a single locus can have unlimited potential to code for diverse proteins with different functions. In this study, we explored the CTBP2/RIBEYE gene locus and its unique repertoire of transcripts that are conserved among vertebrates. We studied the transcriptional coregulator (CTBP2) and ribbon synapse-specific structural protein (RIBEYE) in the chicken retina by performing comprehensive histochemical and sequencing analyses to pinpoint cell and developmental stage-specific expression of CTBP2/RIBEYE in the developing chicken retina. We demonstrated that CTBP2 is widely expressed in retinal progenitors beginning in early retinogenesis but becomes limited to GABAergic amacrine cells in the mature retina. Inversely, RIBEYE is initially epigenetically silenced in progenitors and later expressed in photoreceptor and bipolar cells where they localize to ribbon synapses. Finally, we compared CTBP2/RIBEYE regulation in the developing human retina using a pluripotent stem cell derived retinal organoid culture system. These analyses demonstrate that similar regulation of the CTBP2/RIBEYE locus during chick and human retinal development is regulated by different members of the K50 homeodomain transcription factor family.

Comparison of 36 assisted reproduction laboratories monitoring environmental conditions and instrument parameters using the same quality-control application.

RESEARCH QUESTION: Assisted reproduction laboratories record instrument performance periodically. No standardized guidelines have been produced for this activity despite mandatory auditing systems in several countries. This study of 36 laboratories in 12 different countries was conducted to assess differences and similarities between quality assurance programmes using an adaptable cloud-based quality-control app for instrument monitoring. DESIGN: A total of 36 deidentified IVF laboratories that subscribed to the same quality-assurance application were studied. Data were evaluated based on instrument types allocated to 10 domains: incubators, gas tanks, warming surfaces, refrigerators and freezers, cryo-storage, environment, water purification, peripheral equipment, checklists and miscellaneous. RESULTS: The incubator domain constituted the greatest proportion of parameters (35%), followed by surface warming instruments at 15%. Most incubator O2 readings were monitored between 4.5 and 5.5%, and between 5.5 and 6.5% for CO2. The altitude of the laboratory was poorly correlated with the CO2 setting. Incubator display and measured values of gases and temperature by built-in sensors vary considerably compared with third-party sensors. A quality-control diligence score or mean average data points was calculated for each laboratory. This score is independent of number of instruments or laboratory size. Higher scores were associated with laboratories in countries with government regulations and mandatory auditing systems. CONCLUSIONS: Major differences exist in instrument monitoring practices among laboratories. Although incubator monitoring is the largest domain, many other sensitive instruments are diligently monitored by most laboratories. International standardization and guidelines are needed.