Multiparatopic antibodies induce targeted downregulation of programmed death-ligand 1.

Programmed death-ligand 1 (PD-L1) drives inhibition of antigen-specific T cell responses through engagement of its receptor programmed death-1 (PD-1) on activated T cells. Overexpression of these immune checkpoint proteins in the tumor microenvironment has motivated the design of targeted antibodies that disrupt this interaction. Despite clinical success of these antibodies, response rates remain low, necessitating novel approaches to enhance performance. Here, we report the development of antibody fusion proteins that block immune checkpoint pathways through a distinct mechanism targeting molecular trafficking. By engaging multiple receptor epitopes on PD-L1, our engineered multiparatopic antibodies induce rapid clustering, internalization, and degradation in an epitope- and topology-dependent manner. The complementary mechanisms of ligand blockade and receptor downregulation led to more durable immune cell activation and dramatically reduced PD-L1 availability in mouse tumors. Collectively, these multiparatopic antibodies offer mechanistic insight into immune checkpoint protein trafficking and how it may be manipulated to reprogram immune outcomes.

Kloss gibbon (Hylobates klossii) behavior facilitates the avoidance of human predation in the Peleonan forest, Siberut Island, Indonesia.

Kloss gibbons (Hylobates klossii) are endemic to the Mentawai Islands in Indonesia and have been subject to human predation for more than 2000 years in the absence of any other significant predators. We investigate the behavior of Kloss gibbons that may be attributed to avoiding human predation. We observed Kloss gibbons in the Peleonan forest in the north of Siberut Island, the northernmost of the Mentawai island chain, over 18 months in 2007 and 2008, and collected data on their singing behavior, the number of individuals present during different conditions and their responses to humans. We examine behaviors that may reduce the risk of predation by humans during singing (the most conspicuous gibbon behavior), daily non-singing activities and encounters with humans. The individual risk of being stalked by hunters is reduced by singing in same-sex choruses and the risk of successful capture by hunters during singing is reduced by singing less often during daylight hours and by leaving the location of male pre-dawn singing before full light (reducing the visual signal to hunters). Groups in the Peleonan also fission during non-singing daily activity and rarely engage in play or grooming, enhancing the crypticity of their monochromatic black pelage in the canopy. We also observed a coordinated response to the presence of humans, wherein one adult individual acted as a "decoy" by approaching and distracting human observers, while other group members fled silently in multiple directions. "Decoy" behavior occurred on 31% of 96 encounters with unhabituated Kloss gibbons that detected our presence. "Decoy" individuals may put themselves at risk to increase the survival of related immatures (and adult females with infants) who have a greater risk of predation. We argue that, in combination, these behaviors are an evolved response to a long history of predation by humans.

Singing by male and female Kloss gibbons (Hylobates klossii) in the Peleonan Forest, Siberut Island, Indonesia.

Kloss gibbons (Hylobates klossii) are endemic to the Mentawai Islands in Indonesia and are one of only two gibbon species in which mated pairs do not sing duets. This is the first long-term study of the factors influencing the singing activity of Kloss gibbons within a northern Siberut Island population and follows two previous studies in central Siberut nearly 30 years ago. We collected data on the presence/absence of male and female singing within the study area on 198 days and within a focal group on 47 days. Rainfall during the time period in which they normally sing inhibits singing in both males and females. Our study supports the hypothesis that male and female songs function in intrasexual resource defence, as singing is associated with singing by same-sex neighbours, and same-sex choruses are more likely to occur after one or more days of silence (from that sex), suggesting there is pressure for individuals to communicate with same-sex neighbours regularly. Singing was not coordinated within a mated pair, suggesting that vocal coordination of the pair has been lost with the loss of the duet and that Kloss gibbon songs do not convey information to neighbours about the strength of the pair bond. On days when males sang predawn, females were more likely to sing after dawn and earlier in the morning. Additionally, the number of groups singing in female choruses was positively associated with the number of males that had sung in the predawn male chorus. We suggest that female songs have an intersexual territory defence as well as an intrasexual function.

Social dynamics modify behavioural development in captive white-cheeked (Nomascus leucogenys) and silvery (Hylobates moloch) gibbons.

Behavioural development was quantified in one family group of silvery gibbons (Hylobates moloch) and one of white-cheeked gibbons (Nomascus leucogenys) over 11 months during 2005 and 2008 at the Perth Zoo. Levels of locomotion, solo play and play solicitation peaked by 5 years of age but continued solo and social play in older immatures suggested that social development continued until at least 7 years of age. Mature offspring responded to play solicitations from younger siblings. The transition to sub-adulthood was marked by the presence of spatial peripheralisation from the parents, and coincided with aggression from the father to a sub-adult male. After the birth of a new infant, the male sub-adult stayed closer to his mother (and the infant) but not to his father; his juvenile brother was closer to both parents. Within-family observations of behaviour that is difficult to observe in the wild but can be observed in captivity contributes to our understanding of family dynamics in gibbons. Observations of these captive groups suggest that sub-adult peripheralisation may be influenced by family social dynamics as well as by local ecology, and that older offspring are responsive to the development of younger siblings.