Enhanced delivery of antibodies across the blood-brain barrier via TEMs with inherent receptor-mediated phagocytosis.

BACKGROUND: The near impermeability of the blood-brain barrier (BBB) and the unique neuroimmune environment of the CNS prevents the effective use of antibodies in neurological diseases. Delivery of biotherapeutics to the brain can be enabled through receptor-mediated transcytosis via proteins such as the transferrin receptor, although limitations such as the ability to use Fc-mediated effector function to clear pathogenic targets can introduce safety liabilities. Hence, novel delivery approaches with alternative clearance mechanisms are warranted. METHODS: Binders that optimized transport across the BBB, known as transcytosis-enabling modules (TEMs), were identified using a combination of antibody discovery techniques and pharmacokinetic analyses. Functional activity of TEMs were subsequently evaluated by imaging for the ability of myeloid cells to phagocytose target proteins and cells. FINDINGS: We demonstrated significantly enhanced brain exposure of therapeutic antibodies using optimal transferrin receptor or CD98 TEMs. We found that these modules also mediated efficient clearance of tau aggregates and HER2+ tumor cells via a non-classical phagocytosis mechanism through direct engagement of myeloid cells. This mode of clearance potentially avoids the known drawbacks of FcγR-mediated antibody mechanisms in the brain such as the neurotoxic release of proinflammatory cytokines and immune cell exhaustion. CONCLUSIONS: Our study reports a new brain delivery platform that harnesses receptor-mediated transcytosis to maximize brain uptake and uses a non-classical phagocytosis mechanism to efficiently clear pathologic proteins and cells. We believe these findings will transform therapeutic approaches to treat CNS diseases. FUNDING: This research was funded by Janssen, Pharmaceutical Companies of Johnson & Johnson.

Innate and Innate-Like Cells: The Future of Chimeric Antigen Receptor (CAR) Cell Therapy.

Conventional αß CAR-T cell-based approaches have revolutionized the field of cancer immunotherapy, but hurdles remain, especially for solid tumors. Novel strategies in conjunction with alternative cell types are therefore required for effective CAR-based therapies. In this respect, innate and innate-like cells with unique immune properties, such as natural killer (NK) cells, NKT cells, γδ T cells, and macrophages, are promising alternatives to αß CAR-T adoptive therapy. We review the applicability of these cells in the context of CAR therapy, focusing on therapies under development, the advantages of these approaches relative to conventional CAR-T cells, and their potential in allogeneic therapies. We also discuss the inherent limitations of these cell types and approaches, and outline numerous strategies to overcome the associated obstacles.

Responsiveness of Serum C-Reactive Protein, Interleukin-17A, and Interleukin-17F Levels to Ustekinumab in Psoriatic Arthritis: Lessons From Two Phase III, Multicenter, Double-Blind, Placebo-Controlled Trials.

OBJECTIVE: To evaluate the associations of C-reactive protein (CRP) and circulating Th17-associated cytokine levels with psoriatic arthritis (PsA) disease activity and therapeutic response to ustekinumab. METHODS: Interleukin-17A (IL-17A), IL-17F, IL-23, and CRP concentrations were measured in serum samples collected as part of the 2 PSUMMIT phase III studies of ustekinumab in PsA (n = 927). In post hoc analyses, relationships of IL-17A, IL-17F, and CRP levels at baseline, week 4, and week 24 with baseline skin and joint disease activity and response to therapy were evaluated using generalized linear models and Pearson's product-moment correlation tests. RESULTS: Baseline serum levels of IL-17A and IL-17F were positively correlated with baseline skin disease scores (r = 0.39-0.62). IL-23 levels were correlated with skin disease scores to a lesser extent (r = 0.26-0.31). No significant correlations were observed between these cytokine or CRP levels and baseline joint disease activity. There was no significant association of baseline levels of IL-17A, IL-17F, IL-23, or CRP with therapeutic response to ustekinumab in either the skin or joints. Significant reductions from baseline in levels of IL-17A, IL-17F, and CRP were seen in patients treated with ustekinumab compared to those treated with placebo. Ustekinumab-treated patients in whom 75% improvement in the Psoriasis Area and Severity Index score or 20% improvement according to the American College of Rheumatology criteria was achieved after 24 weeks of treatment had greater reductions in CRP level (geometric mean decreases of 51-58% versus 32-33%; P < 0.05), but not IL-17A or IL-17F levels, than nonresponders. CONCLUSION: Baseline serum IL-23/IL-17 levels correlated with skin, but not joint, disease activity, suggesting tissue-specific variation. However, neither baseline Th17-associated cytokine levels nor CRP level were predictive of therapeutic response to ustekinumab in the skin or joints, despite rapid reductions in their levels following ustekinumab therapy.

CC-chemokine ligand 2 inhibition in idiopathic pulmonary fibrosis: a phase 2 trial of carlumab.

The objective of this study was to determine the safety and efficacy of carlumab in the treatment of idiopathic pulmonary fibrosis (IPF).A phase 2, randomised, double-blind placebo-controlled dose-ranging study was conducted in patients with IPF (n=126). Patients were randomised to carlumab (1 mg·kg(-1), 5 mg·kg(-1), or 15 mg·kg(-1)) or placebo every 4 weeks. The primary endpoint was the rate of percentage change in forced vital capacity (FVC). Secondary endpoints were time to disease progression, absolute change in FVC, relative change in diffusing capacity of the lung for carbon monoxide (DLCO), and St George's Respiratory Questionnaire (SGRQ) total score.Due to a pre-planned, unfavourable interim benefit-risk analysis, dosing was suspended. The rate of percentage change in FVC showed no treatment effect (placebo -0.582%, 1 mg·kg(-1) -0.533%, 5 mg·kg(-1) -0.799% and 15 mg·kg(-1) -0.470%; p=0.261). All active treatment groups showed a greater decline in FVC (1 mg·kg(-1) -290 mL, 5 mg·kg(-1) -370 mL and 15 mg·kg(-1) -320 mL) compared with placebo (-130 mL). No effect on disease progression, DLCO, infection rates or mortality was observed. SGRQ scores showed a nonsignificant trend toward worsening with active treatment. Unexpectedly, free CC-chemokine ligand 2 levels were elevated above baseline at both 24 and 52 weeks. A higher proportion of patients with one or more serious adverse events was observed in the 5 mg·kg(-1) group (53.1%) compared with 1 mg·kg(-1) (15.2%), 15 mg·kg(-1) (21.9%) and placebo (46.4%), although no unexpected serious adverse events were noted.Although dosing was stopped prematurely, it is unlikely that carlumab provides benefit to IPF patients.