Light Chain Bioscience (Switzerland)

ObjectiveSocioeconomic status (SES) and lifestyle activities (LA) are strongly related, and both are associated with dementia risk. We investigated the influence of SES and LA on brain atrophy and cognitive decline considering amyloid‐beta (Aβ) positron emission tomography and white matter hyperintensity (WMH) load.MethodsWe investigated 221 older adults (mean age, 67.1 ± 8.2 years) who underwent cognitive testing annually over a median follow‐up period of 3.4 years. Longitudinal T1‐weighted magnetic resonance imaging was available for 181 participants. Measures of SES and LA were collected using questionnaires and combined to SES and LA scores using a latent variable approach. We used linear mixed‐effects models to investigate if SES and LA are independently or interactively with Aβ and WMH load associated with decline in domains language, processing speed/attention, executive function, and episodic memory. Mediation models assessed whether these associations were explained by gray matter atrophy.ResultsSES and LA were associated with better cognitive performance at baseline, but were not associated with cognitive decline over time. In interaction with brain pathologies, higher LA reduced the detrimental effects of Aβ and WMH load on language decline, whereas higher SES reduced the detrimental effects of Aβ pathology on episodic memory decline. Individuals with low SES showed faster Aβ‐related gray matter atrophy, which mediated the association between Aβ and episodic memory decline but not language decline.InterpretationThese results suggest that multiple resilience mechanisms underlie the protective effects of SES and LA on cognitive decline. Interventions targeting SES‐related risk factors may be most effective when implemented early, before neurodegenerative changes begin. ANN NEUROL 2025;98:1222–1236

Abstract Background: The CEAxCD3 bispecific antibody (bsAb) NILK-2301 couples CEA (CEACAM5) on cancer cells and CD3 on T-cells inducing T-cell activation (signal 1) and tumor cell killing (TDCC). T-cell activation can be boosted by CEA-targeted CD28-costimulation (NILK-3301; signal 2). NILK-2401, carrying a fully effective IgG1 Fc, induces antibody-dependent phagocytosis (ADCP) and antibody-dependent cytotoxicity (ADCC) of tumor cells by co-targeting CEA and the innate immune checkpoint CD47 (“don’t eat me” signal). We present here next generation immunotherapy to overcome limited single class activity in CEA-expressing solid cancers. Methods: BsAbs were generated using LCB’s fully human κλ body platform. TDCC, ADCP, and ADCC with human PBMC or monocyte-derived macrophages were assessed using CEA+ colorectal (n=3), lung (n=2), and gastric (n=2) cancer lines. Combination activity of NILK-2401 + NILK-2301 (± NILK-3301) was assessed by flow cytometry. In vivo activity was tested in xenograft NOG or NSG/human PMBC-, HIS-, and hSIRPα/hCD47/hCD3/hCD28 transgenic mice. Safety data include binding to other CEACAMs, cytokine release in whole blood, erythrophagocytosis, platelet activation, exclusion of superagonism (NILK-3301), as well as PK- and tolerability in cynomolgus monkeys and Tg32-mice. Results: NILK-2301 induced dose-dependent killing of all tested cell lines, which was also visualized by live cell imaging. Combination of NILK-2301 (1 nM) + NILK-3301 vs. NILK-2301 alone (10 nM) increased TDCC (3-8-fold), T-cell activation (CD25, CD69, HLA-DR), cytokine secretion (interferon-γ, granzyme B, perforin), and CD4+/CD8+ T-cell proliferation. NILK-2401 blocked CD47-SIRPα interaction and induced ADCP/ADCC-mediated elimination of all cell lines. NILK-2301 + NILK-2401 treatment increased maximum activity (Emax) and reduced necessary dose of the T-cell bsAb to reach Emax. E.g., Emax of 30% killing (NILK-2301 alone) was increased in combination with NILK-2401 at 0.1/1/10 µg/mL to 40%, 80%, and 80%. In vivo, NILK-2301 (10 mg/kg IV, BIW) decreased tumor progression. NILK-2301/-3301 combination induced tumor regression in 8/8 mice. NILK-2401 delayed tumor growth vs. mean of control in 100% (15/15) of mice and prevented establishment of detectable tumors (>50mm3) in 53% (8/15). Results of double and quadruple transgenic mice, including triple bsAb combinations, will be presented at the meeting. No relevant safety signals were detected. Conclusions: NILK-2301 and NILK-2401 are active as single agents. Addition of NILK-2401 or NILK-3301 to NILK-2301 significantly increases activity, already at 10 -100x lower CEAxCD3 doses. GMP drug substance has been produced for NILK-2301 and NILK-2401. Generation of the clonal cell line for NILK-3301 clinical material production is ongoing. Citation Format: Anja Seckinger, Lise Nouveau, Sara Majocchi, Valéry Moine, Vanessa Buatois, Bruno Daubeuf, Franck Gueneau, Ulla Ravn, Krzysztof Masternak, Yves Poitevin, Emeline Rousset, Giovanni Magistrelli, Pauline Malinge, Limin Shang, Nicolas Fischer, Klaus Strein, Walter Ferlin, Dirk Hose. Combination of κλ bispecific antibodies targeting innate (CEAxCD47, NILK-2401) and adaptive immunity (CEAxCD3, NILK-2301 and CEAxCD28, NILK-3301) for next generation immunotherapy of CEA-expressing cancers. [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 5100.

Hexanucleotide G4C2 repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Dipeptide repeat proteins (DPRs) generated by translation of repeat-containing RNAs show toxic effects in vivo as well as in vitro and are key targets for therapeutic intervention. We generated human antibodies that bind DPRs with high affinity and specificity. Anti-GA antibodies engaged extra- and intra-cellular poly-GA and reduced aggregate formation in a poly-GA overexpressing human cell line. However, antibody treatment in human neuronal cultures synthesizing exogenous poly-GA resulted in the formation of large extracellular immune complexes and did not affect accumulation of intracellular poly-GA aggregates. Treatment with antibodies was also shown to directly alter the morphological and biochemical properties of poly-GA and to shift poly-GA/antibody complexes to more rapidly sedimenting ones. These alterations were not observed with poly-GP and have important implications for accurate measurement of poly-GA levels including the need to evaluate all centrifugation fractions and disrupt the interaction between treatment antibodies and poly-GA by denaturation. Targeting poly-GA and poly-GP in two mouse models expressing G4C2 repeats by systemic antibody delivery for up to 16 mo was well-tolerated and led to measurable brain penetration of antibodies. Long-term treatment with anti-GA antibodies produced improvement in an open-field movement test in aged C9orf72450 mice. However, chronic administration of anti-GA antibodies in AAV-(G4C2)149 mice was associated with increased levels of poly-GA detected by immunoassay and did not significantly reduce poly-GA aggregates or alleviate disease progression in this model.

Abstract Microbubbles (MBs) exhibit cavitation upon exposure to ultrasound (US), which creates opportunities to adopt them in new therapeutic approaches. The present study reports an efficient, translatable approach to precisely control the spaciotemporal delivery of therapeutic microRNAs (AmiR‐21 and miR‐100) and TK‐p53‐NTR triple therapeutic gene, co‐loaded in PLGA‐PEG‐PEI polymer nanoparticles (NPs) to tumor models of triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC) using US‐mediated targeted destruction of BR38 MBs. PLGA‐PEG‐PEI conjugated triblock co‐polymer NPs are synthesized and characterized for their physicochemical properties, and optimized for co‐loading of miRNAs and TK‐p53‐NTR. Quantitative in vivo imaging and ex vivo tissue analysis of 4T1 (TNBC) subcutaneous tumors in BALB/c mice reveal 19 ± 0.5% (p < 0.01) increase in delivery of miRNAs, and 48 ± 1.79% (p < 0.001) increase in delivery of TK‐p53‐NTR upon US treatment, which results to 48 ± 6.98% (p < 0.01) reduction in tumor growth as compared to contralateral tumors without US. This significantly increases the survival rate of animals as compared to pDNA control group. Similar treatment effects are observed in both TNBC and HCC tumor models. This novel combined therapeutic approach, entailing both miRNAs and suicide gene therapy has strong potential for future applications in cancer therapy.

Glycan-to-glycan binding was shown by biochemical and biophysical measurements to mediate xenogeneic self-recognition and adhesion in sponges, stage-specific cell compaction in mice embryos, and in vitro tumor cell adhesion in mammals. This intermolecular recognition process is accepted as the new paradigm accompanying high-affinity and low valent protein-to-protein and protein-to-glycan binding in cellular interactions. Glycan structures in sponges have novel species-specific sequences. Their common features are the large size >100 kD, polyvalency >100 repeats of the specific self-binding oligosaccharide, the presence of fucose, and sulfated and/or pyruvylated hexoses. These structural and functional properties, different from glycosaminoglycans, inspired their classification under the glyconectin name. The molecular mechanism underlying homophilic glyconectin-to-glyconectin binding relies on highly polyvalent, strong, and structure-specific interactions of small oligosaccharide motifs, possessing ultra-weak self-binding strength and affinity. Glyconectin localization at the glycocalyx outermost cell surface layer suggests their role in the initial recognition and adhesion event during the complex and multistep process. In mammals, Lex-to-Lex homophilic binding is structure-specific and has ultra-weak affinity. Cell adhesion is achieved through highly polyvalent interactions, enabled by clustering of small low valent structure in plasma membranes.

Genetic, clinical, biochemical and histochemical data indicate a crucial involvement of inflammation in Alzheimer's disease (AD), but harnessing the immune system to cure or prevent AD has so far proven difficult. Clarifying the cellular heterogeneity and signaling pathways associated with the presence of the AD hallmarks beta-amyloid and tau in the brain, would help to identify potential targets for therapy. While much attention has been so far devoted to microglia and their homeostatic phagocytic activity, additional cell types and immune functions might be affected in AD. Beyond microglia localized in the brain parenchyma, additional antigen-presenting cell (APC) types might be affected by beta-amyloid toxicity. Here, we investigated potential immunomodulatory properties of oligomeric species of beta-amyloid-peptide (Aβ) on microglia and putative APCs. We performed a comprehensive characterization of time- and pathology-dependent APC and T-cell alterations in a model of AD-like brain beta-amyloidosis, the APP-PS1-dE9 mouse model. We show that the deposition of first beta-amyloid plaques is accompanied by a significant reduction in MHC class II surface levels on brain APCs. Furthermore, taking advantage of customized in vitro systems and RNAseq, we demonstrate that a preparation containing various forms of oligomeric Aβ1-42 inhibits antigen presentation by altering the transcription of key immune mediators in dendritic cells. These results suggest that, beyond their neurotoxic effects, certain oligomeric Aβ forms can act as immunomodulatory agents on cerebral APCs and interfere with brain antigen presentation. Impaired brain immune surveillance might be one of the factors that facilitate Aβ and tau spreading in AD.

BackgroundPrimary hemophagocytic lymphohistiocytosis is a rare syndrome characterized by immune dysregulation and hyperinflammation. It typically manifests in infancy and is associated with high mortality.MethodsWe investigated the efficacy and safety of emapalumab (a human anti–interferon-γ antibody), administered with dexamethasone, in an open-label, single-group, phase 2–3 study involving patients who had received conventional therapy before enrollment (previously treated patients) and previously untreated patients who were 18 years of age or younger and had primary hemophagocytic lymphohistiocytosis. The patients could enter a long-term follow-up study until 1 year after allogeneic hematopoietic stem-cell transplantation or until 1 year after the last dose of emapalumab, if transplantation was not performed. The planned 8-week treatment period could be shortened or extended if needed according to the timing of transplantation. The primary efficacy end point was the overall response, which was assessed in the previously treated patients according to objective clinical and laboratory criteria.ResultsAt the cutoff date of July 20, 2017, a total of 34 patients (27 previously treated patients and 7 previously untreated patients) had received emapalumab; 26 patients completed the study. A total of 63% of the previously treated patients and 65% of the patients who received an emapalumab infusion had a response; these percentages were significantly higher than the prespecified null hypothesis of 40% (P=0.02 and P=0.005, respectively). In the previously treated group, 70% of the patients were able to proceed to transplantation, as were 65% of the patients who received emapalumab. At the last observation, 74% of the previously treated patients and 71% of the patients who received emapalumab were alive. Emapalumab was not associated with any organ toxicity. Severe infections developed in 10 patients during emapalumab treatment. Emapalumab was discontinued in 1 patient because of disseminated histoplasmosis.ConclusionsEmapalumab was an efficacious targeted therapy for patients with primary hemophagocytic lymphohistiocytosis. (Funded by NovImmune and the European Commission; NI-0501-04 and NI-0501-05 ClinicalTrials.gov numbers, NCT01818492 and NCT02069899.)