Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody.
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ABSTRACT:
SUBMITTER: Roshanbin S
PROVIDER: S-EPMC9318263 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Penetrating traumatic brain injury (pTBI) has been difficult to model in small laboratory animals, such as rats or mice. Previously, we have established a non-fatal, rat model for pTBI using a modified air-rifle that accelerates a pellet, which hits a small probe that then penetrates the experimental animal's brain. Knockout and transgenic strains of mice offer attractive tools to study biological reactions induced by TBI. Hence, in the present study, we adapted and modified our model to be used with mice. The technical characterization of the impact device included depth and speed of impact, as well as dimensions of the temporary cavity formed in a brain surrogate material after impact. Biologically, we have focused on three distinct levels of severity (mild, moderate, and severe), and characterized the acute phase response to injury in terms of tissue destruction, neural degeneration, and gliosis. Functional outcome was assessed by measuring bodyweight and motor performance on rotarod. The results showed that this model is capable of reproducing major morphological and neurological changes of pTBI; as such, we recommend its utilization in research studies aiming to unravel the biological events underlying injury and regeneration after pTBI.
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Project description:Brain-directed immunotherapy is a promising strategy to target amyloid-β (Aβ) deposits in Alzheimer's disease (AD). In the present study, we compared the therapeutic efficacy of the Aβ protofibril targeting antibody RmAb158 with its bispecific variant RmAb158-scFv8D3, which enters the brain by transferrin receptor-mediated transcytosis. AppNL-G-F knock-in mice received RmAb158, RmAb158-scFv8D3, or PBS in three treatment regimens. First, to assess the acute therapeutic effect, a single antibody dose was given to 5 months old AppNL-G-F mice, with evaluation after 3 days. Second, to assess the antibodies' ability to halt the progression of Aβ pathology, 3 months old AppNL-G-F mice received three doses during a week, with evaluation after 2 months. Reduction of RmAb158-scFv8D3 immunogenicity was explored by introducing mutations in the antibody or by depletion of CD4+ T cells. Third, to study the effects of chronic treatment, 7-month-old AppNL-G-F mice were CD4+ T cell depleted and treated with weekly antibody injections for 8 weeks, including a final diagnostic dose of [125I]RmAb158-scFv8D3, to determine its brain uptake ex vivo. Soluble Aβ aggregates and total Aβ42 were quantified with ELISA and immunostaining. Neither RmAb158-scFv8D3 nor RmAb158 reduced soluble Aβ protofibrils or insoluble Aβ1-42 after a single injection treatment. After three successive injections, Aβ1-42 was reduced in mice treated with RmAb158, with a similar trend in RmAb158-scFv8D3-treated mice. Bispecific antibody immunogenicity was somewhat reduced by directed mutations, but CD4+ T cell depletion was used for long-term therapy. CD4+ T cell-depleted mice, chronically treated with RmAb158-scFv8D3, showed a dose-dependent increase in blood concentration of the diagnostic [125I]RmAb158-scFv8D3, while concentration was low in plasma and brain. Chronic treatment did not affect soluble Aβ aggregates, but a reduction in total Aβ42 was seen in the cortex of mice treated with both antibodies. Both RmAb158 and its bispecific variant RmAb158-scFv8D3 achieved positive effects of long-term treatment. Despite its ability to efficiently enter the brain, the benefit of using the bispecific antibody in chronic treatment was limited by its reduced plasma exposure, which may be a result of interactions with TfR or the immune system. Future research will focus in new antibody formats to further improve Aβ immunotherapy.
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Project description:Single-cell mRNA sequencing of anti-PD-1 GITR-L bispecific antibody treated CT26 mouse tumor model infiltrating leukocytes
2021-12-20 | GSE190105 | GEO
Project description:PD-L1-blocking antibodies produce significant clinical benefit in selected cancer patients by reactivating functionally-impaired antigen-experienced anticancer T cells. However, the efficacy of current PD-L1-blocking antibodies is potentially reduced by 'on-target/off-tumor' binding to PD-L1 widely expressed on normal cells. This lack of tumor selectivity may induce a generalized activation of all antigen-experienced T cells which may explain the frequent occurrence of autoimmune-related adverse events during and after treatment. To address these issues, we constructed a bispecific antibody (bsAb), designated PD-L1xEGFR, to direct PD-L1-blockade to EGFR-expressing cancer cells and to more selectively reactivate anticancer T cells. Indeed, the IC50 of PD-L1xEGFR for blocking PD-L1 on EGFR+ cancer cells was ?140 fold lower compared to that of the analogous PD-L1-blocking bsAb PD-L1xMock with irrelevant target antigen specificity. Importantly, activation status, IFN-? production, and oncolytic activity of anti-CD3xanti-EpCAM-redirected T cells was enhanced when cocultured with EGFR-expressing carcinoma cells. Similarly, the capacity of PD-L1xEGFR to promote proliferation and IFN-? production by CMVpp65-directed CD8+ effector T cells was enhanced when cocultured with EGFR-expressing CMVpp65-transfected cancer cells. In contrast, the clinically-used PD-L1-blocking antibody MEDI4736 (durvalumab) promoted T cell activation indiscriminate of EGFR expression on cancer cells. Additionally, in mice xenografted with EGFR-expressing cancer cells 111In-PD-L1xEGFR showed a significantly higher tumor uptake compared to 111In-PD-L1xMock. In conclusion, PD-L1xEGFR blocks the PD-1/PD-L1 immune checkpoint in an EGFR-directed manner, thereby promoting the selective reactivation of anticancer T cells. This novel targeted approach may be useful to enhance efficacy and safety of PD-1/PD-L1 checkpoint blockade in EGFR-overexpressing malignancies.
| S-EPMC6136863 | biostudies-other
Project description:BackgroundTransferrin receptor (TfR1) mediated enhanced brain delivery of antibodies have been studied extensively in preclinical settings. However, the brain pharmacokinetics, i.e. brain entry, distribution and elimination are still not fully understood for this class of antibodies. The overall aim of the study was to compare the brain pharmacokinetics of two BBB-penetrating bispecific antibodies of different size (210 vs 58 kDa). Specifically, we wanted to investigate if the faster systemic clearance of the smaller non-IgG antibody di-scFv3D6-8D3, in comparison with the IgG-based bispecific antibody mAb3D6-scFv8D3, was also reflected in the brain.MethodsWild-type (C57/Bl6) mice were injected with 125I-iodinated ([125I]) mAb3D6-scFv8D3 (n = 46) or [125I]di-scFv3D6-8D3 (n = 32) and euthanized 2, 4, 6, 8, 10, 12, 16, or 24 h post injection. Ex vivo radioactivity in whole blood, peripheral organs and brain was measured by γ-counting. Ex vivo autoradiography and nuclear track emulsion were performed on brain sections to investigate brain and parenchymal distribution. Capillary depletion was carried out at 2, 6, and 24 h after injection of [125I]mAb3D6-scFv8D3 (n = 12) or [125I]di-scFv3D6-8D3 (n = 12), to estimate the relative levels of radiolabelled antibody in brain capillaries versus brain parenchyma. In vitro binding kinetics for [125I]mAb3D6-scFv8D3 or [125I]di-scFv3D6-8D3 to murine TfR were determined by LigandTracer.Results[125I]di-scFv3D6-8D3 showed faster elimination from blood, lower brain Cmax, and Tmax, a larger parenchymal-to-capillary concentration ratio, and a net elimination from brain at an earlier time point after injection compared with the larger [125I]mAb3D6-scFv8D3. However, the elimination rate from brain did not differ between the antibodies. The study also indicated that [125I]di-scFv3D6-8D3 displayed lower avidity than [125I]mAb3D6-scFv8D3 towards TfR1 in vitro and potentially in vivo, at least at the BBB.ConclusionA smaller size and lower TfR1 avidity are likely important for fast parenchymal delivery, while elimination of brain-associated bispecific antibodies may not be dependent on these characteristics.
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Project description:The programmed cell death 1 (PD-1) signaling pathway, a key player in immune checkpoint regulation, has become a focal point in cancer immunotherapy. In the context of cancer, upregulated PD-L1 on tumor cells can result in T cell exhaustion and immune evasion, fostering tumor progression. The advent of PD-1/PD-L1 inhibitor has demonstrated clinical success by unleashing T cells from exhaustion. Nevertheless, challenges such as resistance and adverse effects have spurred the exploration of innovative strategies, with bispecific antibodies (BsAbs) emerging as a promising frontier. BsAbs offer a multifaceted approach to cancer immunotherapy by simultaneously targeting PD-L1 and other immune regulatory molecules. We focus on recent advancements in PD-1/PD-L1 therapy with a particular emphasis on the development and potential of BsAbs, especially in the context of solid tumors. Various BsAb products targeting PD-1 signaling are discussed, highlighting their unique mechanisms of action and therapeutic potential. Noteworthy examples include anti-TGFβ × PD-L1, anti-CD47 × PD-L1, anti-VEGF × PD-L1, anti-4-1BB × PD-L1, anti-LAG-3 × PD-L1, and anti-PD-1 × CTLA-4 BsAbs. Besides, we summarize ongoing clinical studies evaluating the efficacy and safety of these innovative BsAb agents. By unraveling the intricacies of the tumor microenvironment and harnessing the synergistic effects of anti-PD-1/PD-L1 BsAbs, there exists the potential to elevate the precision and efficacy of cancer immunotherapy, ultimately enabling the development of personalized treatment strategies tailored to individual patient profiles.
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Project description:Anti-programmed cell death-1 (PD-1)/PD-ligand-1 (PD-L1) treatments are effective in a fraction of patients with advanced malignancies. However, the majority of patients do not respond to it. Resistance to cancer immunotherapy can be mediated by additional immune checkpoints. We hypothesized that co-targeting of PD-L1 and lymphocyte-activation gene 3 (LAG-3) could provide an alternative therapeutic approach. Here, we developed IBI323, a dual blockade bispecific antibody targeting PD-L1 and LAG-3. We assessed the binding affinity, blocking activity, cell bridging effect, and immunomodulation function of IBI323 using in vitro assays. We also evaluated, in two humanized mouse models, anti-tumor effects and antitumor T cell immunity induced by IBI323. IBI323 bound to PD-L1 and LAG-3 with similar potency as its parental antibodies and blocked the interaction of PD-1/PD-L1, CD80/PD-L1, and LAG-3/MHC-II. Moreover, IBI323 mediated the bridging of PD-L1+ cells and LAG-3+ cells and demonstrated superior immune stimulatory activity compared to each parent antibody in mixed leukocyte reaction. In PD-L1/LAG-3 double knock-in mice bearing human PD-L1 knock-in MC38 tumors, IBI323 showed stronger anti-tumor activity compared to each parental antibody. The better antitumor response correlated with increased tumor-specific CD8+ and CD4+ T cells. IBI323 also induced stronger anti-tumor effect against established A375 tumors compared with combination in mice reconstituted with human immune cells. Collectively, these data demonstrated that IBI323 preserved the blockade activities of parental antibodies while processing a novel cell bridging function. Based on the encouraging preclinical results, IBI323 has significant value in further clinical development.
| S-EPMC8237984 | biostudies-literature
Project description:Abstract Background Immune checkpoint inhibitors (ICI) PD-1/PD-L1 antibody are key drugs for the treatment of cancer. Bispecific antibody is one of the strategies aimed to meet the clinical needs for cancer patients who are resistant to or refractory from ICI treatment. TIM-3, one of the next generation of ICI targets, co-expressed on exhausted T cells with PD-1. It is also expressed by innate immune populations, including NK and DC. Dual blocking PD-1 and TIM-3 not only on T cells but also on DC, NK cells may achieve better clinical benefit for patients who are resistant to or refractory from ICI treatment. Method A bivalent TIM-3 and PD-1 bispecific antibody (Bis5) was developed, a series of in vitro and in vivo efficacy, preclinical pharmacokinetic and toxicity studies were conducted. A Phase I, multicenter, open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and preliminary efficacy of Bis5 in patients with advanced and/or metastatic solid tumors is ongoing in China. Results Bis5 showed affinity of 5-8 nM to both TIM-3 and PD-1, with better cell activity than TIM-3 and PD-1 mAb combination to activated T cell as well as NK and DC, over the other clinical stage reference BsAb. In huPD-1/TIM-3 double knock in mice-CT26 tumor model, Bis5 showed significant tumor inhibition activity and doubled the survival rate, while neither PD-1 mAb, TIM-3 mAb nor PD-1 and TIM-3 antibody combination showed activity. The highest non-severe toxicity dose (HNSTD) was 200mg/kg in monkeys. Nine cohorts (0.001-15 mg/kg) are planned to be enrolled sequentially in the dose escalation part in the Phase I study, as of April 2023, seven cohorts enrollment have completed. No dose limiting toxicity was observed, and the optimal effective dose was not reached. No TRAE higher than grade 2 was observed. The TRAE with ≥10% Incidence was anemia. SD >4 or 2 months were shown in the suboptimal dose levels in NSCLC and CRC (0.3mg/kg, 1mg/kg). The Part 2 dose expansion will further characterize the safety profile and preliminary tumor response in several cohorts including NSCLC, CRC, ESCC etc. Conclusion Bis5 showed good preclinical efficacy and safety profile, its clinical performance is expected. Clinical trial information: NCT05357651.
| S-EPMC10370444 | biostudies-literature
Project description:BackgroundAlthough ɑ-synuclein (ɑ-syn) spreading in age-related neurodegenerative diseases such as Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) has been extensively investigated, the role of aging in the manifestation of disease remains unclear.MethodsWe explored the role of aging and inflammation in the pathogenesis of synucleinopathies in a mouse model of DLB/PD initiated by intrastriatal injection of ɑ-syn preformed fibrils (pff).ResultsWe found that aged mice showed more extensive accumulation of ɑ-syn in selected brain regions and behavioral deficits that were associated with greater infiltration of T cells and microgliosis. Microglial inflammatory gene expression induced by ɑ-syn-pff injection in young mice had hallmarks of aged microglia, indicating that enhanced age-associated pathologies may result from inflammatory synergy between aging and the effects of ɑ-syn aggregation. Based on the transcriptomics analysis projected from Ingenuity Pathway Analysis, we found a network that included colony stimulating factor 2 (CSF2), LPS related genes, TNFɑ and poly rl:rC-RNA as common regulators.ConclusionsWe propose that aging related inflammation (eg: CSF2) influences outcomes of pathological spreading of ɑ-syn and suggest that targeting neuro-immune responses might be important in developing treatments for DLB/PD.
| S-EPMC9447339 | biostudies-literature
Project description:AbstractT-cell bispecific antibodies (T-BsAbs) such as blinatumomab hold great promise for cancer immunotherapy. A better understanding of the in vivo immune response induced by T-BsAbs is crucial to improving their efficacy and safety profile. However, such efforts are hindered by the limitations of current preclinical models. To address this, we developed a syngeneic murine model with humanized CD3 and target antigen (CD20). This model enables the development of disseminated leukemia with a high tumor burden, which mirrors clinical findings in human patients with relapsed/refractory acute lymphoblastic leukemia. Treatment of this model with T-BsAbs results in cytokine release syndrome, with cytokine profiles and levels reflecting observations made in human patients. This model also faithfully recapitulates the dynamics of T-cell activation seen in human patients, including the temporary disappearance of T cells from the bloodstream. During this phase, T cells are sequestered in secondary lymphoid organs and undergo activation. Clinical correlative studies that rely primarily on peripheral blood samples are likely to overlook this critical activation stage, leading to a substantial underestimation of the extent of T-cell activation. Furthermore, we demonstrate that surface expression of the T-BsAb target antigen by leukemia cells triggers a swift immune response, promoting their own rejection. Humanizing the target antigen in the recipient mice is crucial to facilitate tolerance induction and successful establishment of high tumor burden. Our findings underscore the importance of meticulously optimized syngeneic murine models for investigating T-BsAb-induced immune responses and for translational research aimed at improving efficacy and safety.
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