Preclinical characterization of ISB 1342, a CD38 × CD3 T-cell engager for relapsed/refractory multiple myeloma.

Although treatment of multiple myeloma (MM) with daratumumab significantly extends the patient's lifespan, resistance to therapy is inevitable. ISB 1342 was designed to target MM cells from patients with relapsed/refractory MM (r/r MM) displaying lower sensitivity to daratumumab. ISB 1342 is a bispecific antibody with a high-affinity Fab binding to CD38 on tumor cells on a different epitope than daratumumab and a detuned scFv domain affinity binding to CD3ε on T cells, to mitigate the risk of life-threatening cytokine release syndrome, using the Bispecific Engagement by Antibodies based on the TCR (BEAT) platform. In vitro, ISB 1342 efficiently killed cell lines with different levels of CD38, including those with a lower sensitivity to daratumumab. In a killing assay where multiple modes of action were enabled, ISB 1342 showed higher cytotoxicity toward MM cells compared with daratumumab. This activity was retained when used in sequential or concomitant combinations with daratumumab. The efficacy of ISB 1342 was maintained in daratumumab-treated bone marrow patient samples showing lower sensitivity to daratumumab. ISB 1342 induced complete tumor control in 2 therapeutic mouse models, unlike daratumumab. Finally, in cynomolgus monkeys, ISB 1342 displayed an acceptable toxicology profile. These data suggest that ISB 1342 may be an option in patients with r/r MM refractory to prior anti-CD38 bivalent monoclonal antibody therapies. It is currently being developed in a phase 1 clinical study.

Lyme disease bacterium does not affect attraction to rodent odour in the tick vector.

BACKGROUND: Vector-borne pathogens experience a conflict of interest when the arthropod vector chooses a vertebrate host that is incompetent for pathogen transmission. The qualitative manipulation hypothesis suggests that vector-borne pathogens can resolve this conflict in their favour by manipulating the host choice behaviour of the arthropod vector. METHODS: European Lyme disease is a model system for studying this conflict because Ixodes ricinus is a generalist tick species that vectors Borrelia pathogens that are specialized on different classes of vertebrate hosts. Avian specialists like B. garinii cannot survive in rodent reservoir hosts and vice versa for rodent specialists like B. afzelii. The present study tested whether Borrelia genospecies influenced the attraction of field-collected I. ricinus nymphs to rodent odours. RESULTS: Nymphs were significantly attracted to questing perches that had been scented with mouse odours. However, there was no difference in questing behaviour between nymphs infected with rodent- versus bird-specialized Borrelia genospecies. CONCLUSION: Our study suggests that the tick, and not the pathogen, controls the early stages of host choice behaviour.

Serological signature of tick-borne pathogens in Scandinavian brown bears over two decades.

BACKGROUND: Anthropogenic disturbances are changing the geographic distribution of ticks and tick-borne diseases. Over the last few decades, the tick Ixodes ricinus has expanded its range and abundance considerably in northern Europe. Concurrently, the incidence of tick-borne diseases, such as Lyme borreliosis and tick-borne encephalitis, has increased in the human populations of the Scandinavian countries. METHODS: Wildlife populations can serve as sentinels for changes in the distribution of tick-borne diseases. We used serum samples from a long-term study on the Scandinavian brown bear, Ursus arctos, and standard immunological methods to test whether exposure to Borrelia burgdorferi sensu lato, the causative agent of Lyme borreliosis, and tick-borne encephalitis virus (TBEV) had increased over time. Bears had been sampled over a period of 18 years (1995-2012) from a southern area, where Ixodes ricinus ticks are present, and a northern area where ticks are uncommon or absent. RESULTS: Bears had high levels of IgG antibodies against B. burgdorferi sensu lato but not TBEV. Bears at the southern area had higher values of anti-Borrelia IgG antibodies than bears at the northern area. Over the duration of the study, the value of anti-Borrelia IgG antibodies increased in the southern area but not the northern area. Anti-Borrelia IgG antibodies increased with the age of the bear but declined in the oldest age classes. CONCLUSIONS: Our study is consistent with the view that ticks and tick-borne pathogens are expanding their abundance and prevalence in Scandinavia. Long-term serological monitoring of large mammals can provide insight into how anthropogenic disturbances are changing the distribution of ticks and tick-borne diseases.