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Background Despite the survival benefits observed with immune checkpoint blockade (ICB) treatment—programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1), many patients with cancer have not benefited from these agents because of impaired antigen presentation and other resistance mechanisms. To overcome resistance to checkpoint therapy, we designed bispecific antibodies (BsAbs) targeting CD89 and tumor antigens. We demonstrated their immunomodulatory efficacy as a separate treatment strategy or combined with immune checkpoint inhibitors.Methods We have previously generated a heterodimeric one-arm IgG1 Fc-based bispecific antibody. For animal efficacy studies, murine tumors in a humanized transgenic mice model were used to determine the effects of CD89-bispecific antibodies on antigen presentation and immune cell recruitment. The efficacy of the CD89 bispecific antibody against tumors resistant to pembrolizumab was evaluated in double-transgenic mice.Results BsAbs targeting CD89 on tumor-associated macrophages (TAMs) increased the ratio of M1:M2 and activated the antigen presentation, leading to increased cytotoxic T cell-mediated tumor regression. CD89-BsAbs also potentiated a combinational antitumor effect with PD-1/PD-L1 inhibitors and overcame the ICB resistance by augmenting cytotoxic T-cell infiltration and reshaping tumor immune microenvironment. In an hCD89/hPD-1 double transgenic mouse model engrafted with pembrolizumab-resistant B16-HER2 tumor cells, the HER2-CD89 bispecific antibody potently inhibited tumor growth.Conclusions CD89 BsAbs targeting tumor antigens and TAMs controlled tumor growth in animal models by improving antigen presentation and T-cell infiltration. Our results suggest a general strategy for overcoming resistance to ICB.

Introduction The infrapatellar fat pad (IPFP) is commonly resected during total knee arthroplasty (TKA) for better exposure. However, our previous studies have suggested that IPFP size was protective against, while IPFP signal intensity alteration was detrimental on knee symptoms and structural abnormalities. We hypothesise that an IPFP with normal qualities, rather than abnormal qualities, should be preserved during TKA. The aim of this study is to compare, over a 1-year period, the postoperative clinical outcomes of IPFP preservation versus resection after TKA in patients with normal or abnormal IPFP signal intensity alteration on MRI.Methods and analysis Three hundred and sixty people with end-stage knee osteoarthritis and on the waiting list for TKA will be recruited and identified as normal IPFP quality (signal intensity alteration score ≤1) or abnormal IPFP quality (signal intensity alteration score ≥2). Patients in each hospital will then be randomly allocated to IPFP resection group or preservation group. The primary outcomes are the summed score of self-reported Knee Injury and Osteoarthritis Outcome Score (KOOS), KOOS subscales assessing function in daily activities and function in sport and recreation. Secondary endpoints will be included: KOOS subscales (pain, symptoms and quality of life), Knee Society Score, 100 mm Visual Analogue Scale (VAS) Pain, timed up-and-go test, patellar tendon shortening, 100 mm VAS self-reported efficacy of reduced pain and increased quality of life, and Insall-Salvati index assessed on plain X-ray. Adverse events will be recorded. Intention-to-treat analyses will be used.Ethics and dissemination The study is approved by the local Medical Ethics Committee (Zhujiang Hospital Ethics Committee, reference number 2017-GJGBK-001) and will be conducted according to the principle of the Declaration of Helsinki (64th, 2013) and the Good Clinical Practice standard, and in compliance with the Medical Research Involving Human Subjects Act . Data will be published in peer-reviewed journals and presented at conferences, both nationally and internationally.Trial registration number This trial was registered at Clinicaltrial.gov website on 19 October 2018 with identify number NCT03763448.

Objective: To describe the associations between infrapatellar fat pad (IPFP) signal intensity alteration at baseline and knee symptoms and structural changes in older adults.Methods: A total of 874 subjects (mean 62.1 years, 50.1% female) selected randomly from local community were studied at baseline and 770 were followed up (only 357 had MRI at follow-up) over 2.6 years. T1-weighted or T2-weighted fat suppressed MRI was used to assess IPFP signal intensity alteration (0-3), cartilage volume, cartilage defects and bone marrow lesions (BMLs) at baseline and 2.6 years later. Knee pain was assessed by self-administered Western Ontario and McMaster Osteoarthritis Index questionnaire. Radiographic osteoarthritis (OA) was assessed.Results: In cross-sectional analyses, IPFP signal intensity alteration was significantly and positively associated with total knee pain as well as knee cartilage defects, BMLs and knee radiographic OA and negatively associated with patellar cartilage volume after adjustment for age, sex, body mass index and/or radiographic OA. Longitudinally, baseline signal intensity alteration within IPFP was significantly and positively associated with increases in knee pain when going upstairs/downstairs as well as increases in tibiofemoral cartilage defects and BMLs, and negatively associated with change in lateral tibial cartilage volume in multivariable analyses.Conclusions: IPFP signal intensity alteration at baseline was associated with knee structural abnormalities and clinical symptoms cross-sectionally and longitudinally in older adults, suggesting that it may serve as an important imaging biomarker in knee OA. [ABSTRACT FROM AUTHOR]