Research on the effects of climate warming on ecological communities has focused on how temperature affects resource quantity. However, resource quality is also affected by warming, and changes in resource quality can have meaningful effects on the productivity of higher trophic levels. Aquatic communities in particular experience temperature‐mediated shifts in resource quality because the nutritional value of algae is highly sensitive to temperature. For example, the production of healthful omega‐3 polyunsaturated fatty acids (n‐3 PUFA) by algae often decreases with warming. Decreased levels of some algal PUFAs with warming have led to the hypothesis that global warming should lead to an overall decrease in productivity in aquatic communities. However, this hypothesis: (a) potentially oversimplifies the relationship between algal PUFAs and temperature, and (b) assumes that the nutritional requirements of consumers are not affected by temperature. Here, we test these assumptions using a freshwater community (Scenedesmus algae, Daphnia zooplankton, Chaoborus insects). Warming temperatures increased total algal PUFAs, but decreased algal cell size, resulting in no net effect of temperature on PUFA per algal cell. In contrast, quantities of algal neutral lipids decreased with warming. At the consumer level, Daphnia fed 12°C‐reared algae maintained higher population sizes than those fed 20°C or 28°C‐reared algae. However, the effect of algal food type diminished as Daphnia rearing temperature increased. The indirect effects of cold‐reared algae on the growth rate of Chaoborus predators were minor. These data highlight the importance of investigating the effects of temperature on both resource quality and on the nutritional needs of consumers. Our results suggest that at warmer temperatures, consumer nutritional requirements may be reduced. We caution against broad claims that the negative relationship between some algal PUFAs and temperature should result in overall declines in aquatic productivity with ongoing climate warming. A free Plain Language Summary can be found within the Supporting Information of this article.

Many T-cell engagers (TCE) and immuno-oncology biologics have limited efficacy in the clinic due to narrow therapeutic windows, checkpoint upregulation, and emergence of resistance mechanisms over time. The PROTECTTM (PROgrammed Tumor Engagement & Checkpoint/Costimulation Targeting) platform is designed to tackle these challenges by combining a masking domain that, when cleaved, provides additional immune-modulatory properties. The PROTECTTM mask consists of a PD1-PDL1 protein pair that sterically hinders CD3 binding in the periphery. The PD-L1 moiety is fused to the anti-CD3 antibody via a linker sequence containing a protease cleavage site. Once cleaved, the resultant molecule is a trispecific antibody providing TCE activity, checkpoint inhibition, and additional differentiated functionality. Previous studies employing pan T cell cytotoxicity assays showed the PROTECTTM mask increased the therapeutic window by 400-fold. We have now expanded our in vitro evaluation to include more relevant PBMC systems showing a greater expansion of the therapeutic window. In vivo treatment of established tumours with the unmasked trispecific results in complete and durable anti-tumour responses. Here we extend those in vivo studies (in context of established tumour models) to evaluate unmasking and pharmacokinetic properties. We further evaluated the unique and differentiated mechanism of action of the cleaved trispecific to not only enhance engagement of effector T-cells with tumor cells through avidity driven cis-engagement of a tumor associated antigen (TAA) and PD-L1 co-expressed on tumor cells, but to also enhance co-engagement of a TAA with effector T cells co-expressing PD-L1. In addition, the ability of the cleaved trispecific to bridge autologous T cells with DCs results in enhanced T cell activation and proliferation. Finally, TCR dependent signaling assays confirmed the ability of the cleaved trispecific to overcome PD1/PDL1 checkpoint activity. Taken together, the PROTECTTM platform integrates a masking and immune-modulatory technology that has the potential to widen the therapeutic window of CD3 engagers. Citation Format: Anna von Rossum, Genevieve Desjardins, Nichole Escalante, Wingkie Wong, Bryant Harbourne, Janessa Li, Begonia Silva Moreno, Prajwal Raghunatha, Richard Kunze, Madeline Fung, Florian Heinkel, Harsh Pratap, Kevin Haworth, Eric Escobar-Cabrera, Brandon Clavette, Surjit Dixit, Nina Weisser, Thomas Spreter von Kreudenstein. PROTECTTM, a novel trispecific antibody masking platform with integrated immune modulation displays unique activity and differentiated modes of action [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2926.