GNUV201, a novel human/mouse cross-reactive and low pH-selective anti-PD-1 monoclonal antibody for cancer immunotherapy.

BACKGROUND: Several PD-1 antibodies approved as anti-cancer therapies work by blocking the interaction of PD-1 with its ligand PD-L1, thus restoring anti-cancer T cell activities. These PD-1 antibodies lack inter-species cross-reactivity, necessitating surrogate antibodies for preclinical studies, which may limit the predictability and translatability of the studies. RESULTS: To overcome this limitation, we have developed an inter-species cross-reactive PD-1 antibody, GNUV201, by utilizing an enhanced diversity mouse platform (SHINE MOUSE™). GNUV201 equally binds to human PD-1 and mouse PD-1, equally inhibits the binding of human PD-1/PD-L1 and mouse PD-1/PD-L1, and effectively suppresses tumor growth in syngeneic mouse models. The epitope of GNUV201 mapped to the "FG loop" of hPD-1, distinct from those of Keytruda® ("C'D loop") and Opdivo® (N-term). Notably, the structural feature where the protruding epitope loop fits into GNUV201's binding pocket supports the enhanced binding affinity due to slower dissociation (8.7 times slower than Keytruda®). Furthermore, GNUV201 shows a stronger binding affinity at pH 6.0 (5.6 times strong than at pH 7.4), which mimics the hypoxic and acidic tumor microenvironment (TME). This phenomenon is not observed with marketed antibodies (Keytruda®, Opdivo®), implying that GNUV201 achieves more selective binding to and better occupancy on PD-1 in the TME. CONCLUSIONS: In summary, GNUV201 exhibited enhanced affinity for PD-1 with slow dissociation and preferential binding in TME-mimicking low pH. Human/monkey/mouse inter-species cross-reactivity of GNUV201 could enable more predictable and translatable efficacy and toxicity preclinical studies. These results suggest that GNUV201 could be an ideal antibody candidate for anti-cancer drug development.

ABDGAN: Arbitrary Time Blur Decomposition Using Critic-Guided TripleGAN.

Recent studies have proposed methods for extracting latent sharp frames from a single blurred image. However, these methods still suffer from limitations in restoring satisfactory images. In addition, most existing methods are limited to decomposing a blurred image into sharp frames with a fixed frame rate. To address these problems, we present an Arbitrary Time Blur Decomposition Triple Generative Adversarial Network (ABDGAN) that restores sharp frames with flexible frame rates. Our framework plays a min-max game consisting of a generator, a discriminator, and a time-code predictor. The generator serves as a time-conditional deblurring network, while the discriminator and the label predictor provide feedback to the generator on producing realistic and sharp image depending on given time code. To provide adequate feedback for the generator, we propose a critic-guided (CG) loss by collaboration of the discriminator and time-code predictor. We also propose a pairwise order-consistency (POC) loss to ensure that each pixel in a predicted image consistently corresponds to the same ground-truth frame. Extensive experiments show that our method outperforms previously reported methods in both qualitative and quantitative evaluations. Compared to the best competitor, the proposed ABDGAN improves PSNR, SSIM, and LPIPS on the GoPro test set by 16.67%, 9.16%, and 36.61%, respectively. For the B-Aist++ test set, our method shows improvements of 6.99%, 2.38%, and 17.05% in PSNR, SSIM, and LPIPS, respectively, compared to the best competitive method.

Biocatalysis enables the scalable conversion of biobased furans into various furfurylamines.

Biobased furans have emerged as chemical building blocks for the development of materials because of their diverse scaffolds and as they can be directly prepared from sugars. However, selective, efficient, and cost-effective scalable conversion of biobased furans remains elusive. Here, we report a robust transaminase (TA) from Shimia marina (SMTA) that enables the scalable amination of biobased furanaldehydes with high activity and broad substrate specificity. Crystallographic and mutagenesis analyses provide mechanistic insights and a structural basis for understanding SMTA, which enables a higher substrate conversion. The enzymatic cascade process established in this study allows one-pot synthesis of 2,5-bis(aminomethyl)furan (BAMF) and 5-(aminomethyl)furan-2-carboxylic acid from 5-hydroxymethylfurfural. The biosynthesis of various furfurylamines, including a one-pot cascade reaction for BAMF generation using whole cells, demonstrates their practical application in the pharmaceutical and polymer industries.