We report here the discovery and optimization of a novel T cell retargeting anti-GUCY2C x anti-CD3ε bispecific antibody for the treatment of solid tumors. Using a combination of hybridoma, phage ...display and rational design protein engineering, we have developed a fully humanized and manufacturable CD3 bispecific antibody that demonstrates favorable pharmacokinetic properties and potent in vivo efficacy. Anti-GUCY2C and anti-CD3ε antibodies derived from mouse hybridomas were first humanized into well-behaved human variable region frameworks with full retention of binding and T-cell mediated cytotoxic activity. To address potential manufacturability concerns, multiple approaches were taken in parallel to optimize and de-risk the two antibody variable regions. These approaches included structure-guided rational mutagenesis and phage display-based optimization, focusing on improving stability, reducing polyreactivity and self-association potential, removing chemical liabilities and proteolytic cleavage sites, and de-risking immunogenicity. Employing rapid library construction methods as well as automated phage display and high-throughput protein production workflows enabled efficient generation of an optimized bispecific antibody with desirable manufacturability properties, high stability, and low nonspecific binding. Proteolytic cleavage and deamidation in complementarity-determining regions were also successfully addressed. Collectively, these improvements translated to a molecule with potent single-agent in vivo efficacy in a tumor cell line adoptive transfer model and a cynomolgus monkey pharmacokinetic profile (half-life>4.5 days) suitable for clinical development. Clinical evaluation of PF-07062119 is ongoing.
As the only directly imaged multiple planet system, HR 8799 provides a unique opportunity to study the physical properties of several planets in parallel. In this paper, we image all four of the HR ...8799 planets at H-band and 3.3 microns with the new LBT adaptive optics system, PISCES, and LBTI/LMIRCam. Our images offer an unprecedented view of the system, allowing us to obtain H and 3.3$ micron photometry of the innermost planet (for the first time) and put strong upper-limits on the presence of a hypothetical fifth companion. We find that all four planets are unexpectedly bright at 3.3 microns compared to the equilibrium chemistry models used for field brown dwarfs, which predict that planets should be faint at 3.3 microns due to CH4 opacity. We attempt to model the planets with thick-cloudy, non-equilibrium chemistry atmospheres, but find that removing CH4 to fit the 3.3 micron photometry increases the predicted L' (3.8 microns) flux enough that it is inconsistent with observations. In an effort to fit the SED of the HR 8799 planets, we construct mixtures of cloudy atmospheres, which are intended to represent planets covered by clouds of varying opacity. In this scenario, regions with low opacity look hot and bright, while regions with high opacity look faint, similar to the patchy cloud structures on Jupiter and L/T transition brown-dwarfs. Our mixed cloud models reproduce all of the available data, but self-consistent models are still necessary to demonstrate their viability.
We report on the performance of a vector apodizing phase plate coronagraph that operates over a wavelength range of 2-5 mu m. and is installed in MagAO/Clio2 at the 6.5 m Magellan Clay telescope at ...Las Campanas Observatory, Chile. The coronagraph manipulates the phase in the pupil to produce three beams yielding two coronagraphic point-spread functions (PSFs) and one faint leakage PSF. The phase pattern is imposed through the inherently achromatic geometric phase, enabled by liquid crystal technology and polarization techniques. The coronagraphic optic is manufactured using a direct-write technique for precise control of the liquid crystal pattern. and multitwist retarders for achromatization. By integrating a linear phase ramp to the coronagraphic phase pattern, two separated coronagraphic PSFs are created with a single pupil-plane optic, which makes it robust and easy to install in existing telescopes. The two coronagraphic PSFs contain a 180 degrees dark hole on each side of a star, and these complementary copies of the star are used to correct the seeing halo close to the star. To characterize the coronagraph, we collected a data set of a bright (m(L) = 0-1) nearby star with similar to 1.5 hr of observing time. By rotating and optimally scaling one PSF. and subtracting it from the other PSF, we see a contrast improvement by 1.46 magnitudes at 3.5 lambda/D. With regular angular differential imaging at 3.9 mu m, the MagAO vector apodizing phase plate coronagraph delivers a 5 sigma Delta mag contrast of 8.3 (= 10(-3.3)) at 2 lambda/D and 12.2 (= 10(-4.8)) at 3.5 lambda/D.
The next generation of extremely large telescopes (ELTs) have the potential to image habitable rocky planets, if suitably optimized. This will require the development of fast high order "extreme" ...adaptive optics systems for the ELTs. Located near the excellent site of the future GMT, the Magellan AO system (MagAO) is an ideal on-sky testbed for high contrast imaging development. Here we discuss planned upgrades to MagAO. These include improvements in WFS sampling (enabling correction of more modes) and an increase in speed to 2000 Hz, as well as an H2RG detector upgrade for the Clio infrared camera. This NSF funded project, MagAO-2K, is planned to be on-sky in November 2016 and will significantly improve the performance of MagAO at short wavelengths. Finally, we describe MagAO-X, a visible-wavelength extreme-AO "afterburner" system under development. MagAO-X will deliver Strehl ratios of over 80% in the optical and is optimized for visible light coronagraphy.
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