A bispecific antibody AP203 targeting PD-L1 and CD137 exerts potent antitumor activity without toxicity.

BACKGROUND: Bispecific antibody has garnered considerable attention in the recent years due to its impressive preliminary efficacy in hematological malignancies. For solid tumors, however, the main hindrance is the suppressive tumor microenvironment, which effectively impedes the activation of infiltrating T cells. Herein, we designed a bispecific antibody AP203 with high binding affinity to PD-L1 and CD137 and assessed its safety and anti-tumor efficacy, as well as explored the mechanism of action. METHODS: The optimal antibody binders against PD-L1 and CD137 were screened from the OmniMab phagemid library. The binding affinity of the constructed AP203 were evaluated using enzyme-linked immunosorbent assay (ELISA) and biolayer interferometry (BLI). T-cell stimulatory capacity was assessed using the allogeneic mixed lymphocyte reaction (MLR), antigen-specific recall response, and coculture with PD-L1-expressing cells. In vivo antitumor efficacy was evaluated using two models of tumor-xenografted humanized mice with profiling of tumor infiltrating lymphocytes (TILs). The possible toxicity of AP203 was examined using in vitro cytokine release assay by human PBMCs. RESULTS: AP203, which simultaneously targeted PD-L1 and costimulatory CD137, elicit superior agonistic effects over parental antibodies alone or in combination in terms of T cell activation, enhanced memory recall responses, and overcoming Treg-mediated immunosuppression (P < 0.05). The agonistic activity of AP203 was further demonstrated PD-L1-dependent by coculturing T cells with PD-L1-expressing cells. In vivo animal studies using immunodeficient or immunocompetent mice both showed a dose-related antitumor efficacy superior to parental antibodies in combination (P < 0.05). Correspondingly, AP203 significantly increased tumor infiltrating CD8 + T cells, while decreased CD4 + T cells, as well as Treg cells (P < 0.05), resulting in a dose-dependent increase in the CD8 + /CD4 + ratio. Moreover, either soluble or immobilized AP203 did not induce the production of inflammatory cytokines by human PBMCs. CONCLUSIONS: AP203 exerts potent antitumor activity not only by blocking PD-1/PD-L1 inhibitory signaling, but also by activating CD137 costimulatory signaling in effector T cells that consequently counteracts Treg-mediated immunosuppression. Based on promising preclinical results, AP203 should be a suitable candidate for clinical treatment of solid tumors.

Fully human chitinase-3 like-1 monoclonal antibody inhibits tumor growth, fibrosis, angiogenesis, and immune cell remodeling in lung, pancreatic, and colorectal cancers.

Considering the limited efficacy of current therapies in lung, colorectal, and pancreatic cancers, innovative combination treatments with diverse mechanisms of action are needed to improve patients' outcomes. Chitinase-3 like-1 protein (CHI3L1) emerges as a versatile factor with significant implications in various diseases, particularly cancers, fostering an immunosuppressive tumor microenvironment for cancer progression. Therefore, pre-clinical validation is imperative to fully realize its potential in cancer treatment. We developed phage display-derived fully human monoclonal CHI3L1 neutralizing antibodies (nAbs) and verified the nAbs-antigen binding affinity and specificity in lung, pancreatic and colorectal cancer cell lines. Tumor growth signals, proliferation and migration ability were all reduced by CHI3L1 nAbs in vitro. Orthotopic or subcutaneous tumor mice model and humanized mouse model were established for characterizing the anti-tumor properties of two CHI3L1 nAb leads. Importantly, CHI3L1 nAbs not only inhibited tumor growth but also mitigated fibrosis, angiogenesis, and restored immunostimulatory functions of immune cells in pancreatic, lung, and colorectal tumor mice models. Mechanistically, CHI3L1 nAbs directly suppressed the activation of pancreatic stellate cells and the transformation of macrophages into myofibroblasts, thereby attenuating fibrosis. These findings strongly support the therapeutic potential of CHI3L1 nAbs in overcoming clinical challenges, including the failure of gemcitabine in pancreatic cancer.

An optical wavefront sensor based on a double layer microlens array.

In order to determine light aberrations, Shack-Hartmann optical wavefront sensors make use of microlens arrays (MLA) to divide the incident light into small parts and focus them onto image planes. In this paper, we present the design and fabrication of long focal length MLA with various shapes and arrangements based on a double layer structure for optical wavefront sensing applications. A longer focal length MLA could provide high sensitivity in determining the average slope across each microlens under a given wavefront, and spatial resolution of a wavefront sensor is increased by numbers of microlenses across a detector. In order to extend focal length, we used polydimethysiloxane (PDMS) above MLA on a glass substrate. Because of small refractive index difference between PDMS and MLA interface (UV-resin), the incident light is less refracted and focused in further distance. Other specific focal lengths could also be realized by modifying the refractive index difference without changing the MLA size. Thus, the wavefront sensor could be improved with better sensitivity and higher spatial resolution.

Thin autofocus camera module by a large-stroke micromachined deformable mirror.

The conventional auto-focus and zoom image systems were made by a set of motor-moved lenses. Because of mechanical moving parts, it is not easy to miniaturize their sizes. In this paper, we propose a thin autofocus system using a large stroke MEMS (micro-electro-mechanical systems) deformable mirror which has the potential to downscale the size and to minimize chromatic aberration. The large stroke MEMS deformable mirror is made by a polyimide membrane that has a maximum 12 microm displacement over a 3 mm aperture. The module size is 5.4 mm thick in optical design layout and 6.7 mm after packaging. This autofocus system is designed with the f-number=4.13, on-axis MTF=0.28 at full frequency of 230 cycles/mm, and incident light within+/-26 degree. The position of clear image can vary from 4 cm to 50 cm achieved by controlling the surface curvature of the MEMS deformable mirror.

Reliability of a MEMS Actuator Improved by Spring Corner Designs and Reshaped Driving Waveforms.

In this paper, we report spring corner designs and driving waveforms to improve the reliability for a MEMS (Micro-Electro-Mechanical System) actuator. In order to prevent the stiction problems, no stopper or damping absorber is adopted. Therefore, an actuator could travel long distance by electromagnetic force without any object in moving path to absorb excess momentum. Due to long displacement and large mass, springs of MEMS actuators tend to crack from weak points with high stress concentration and this situation degrades reliability performance. Stress distribution over different spring designs were simulated and a serpentine spring with circular and wide corner design was chosen due to its low stress concentration. This design has smaller stress concentration versus displacement. Furthermore, the resonant frequencies are removed from the driving waveform based on the analysis of discrete Fourier transfer function. The reshaped waveform not only shortens actuator switching time, but also ensures that the spring is in a small displacement region without overshooting so that the maximum stress is kept below 200 MPa. The experimental results show that the MEMS device designed by theses principles can survive 500 g (gravity acceleration) shock test and pass 150 million switching cycles without failure.