TCR-mimic antibody-drug conjugates targeting intracellular tumor-specific mutant antigen KRAS G12V mutation

Limited clinical application of antibody-drug conjugates(ADCs)targeting tumor associated antigens(TAAs)is usually caused by on-target off-tumor side effect.Tumor-specific mutant antigens(TSMAs)only expressed in tumor cells which are ideal targets for ADCs.In addition,intracellular somatic mutant proteins can be presented on the cell surface by human leukocyte antigen class I(HLA I)molecules forming tumor-specific peptide/HLA I complexes.KRAS G12 V mutation frequently occurred in varied cancer and was verified as a promising target for cancer therapy.In this study,we generated two TCR-mimic antibodydrug conjugates(TCRm-ADCs),2E8-MMAE and 2 A5-MMAE,targeting KRAS G12 V/HLAA*0201 complex,which mediated specific antitumor activity in vitro and in vivo without obvious toxicity.Our findings are the first time validate the strategy of TCRm-ADCs targeting intracellular TSMAs,which improves the safety of antibody-based drugs and provides novel strategy for precision medicine in cancer therapy.

Anti-human leukocyte antigens and anti-major histocompatibility complex class I-related chain A antibody expression in kidney transplantation during a four-year follow-up

Background Humoral immunity is an important factor for long-term survival of renal allograft. Here we performed a four-year follow-up to explore the clinical significance of monitoring anti-human leukocyte antigens （HLA） and anti-major histocompatibility complex class I-related chain A （MICA） antibody expression after kidney transplantation. Methods We obtained serial serum samples from 84 kidney transplant patients over a four-year period. All patients were followed up at least 6 months after transplantation and had at least two follow-up points. Anti-HLA and anti-MICA antibody titres and serum creatinine （SCr） levels were evaluated at each follow-up. Patients were divided into 4 groups： HLA（＋） MICA（-）, HLA（-）MICA（＋）, HLA（＋）MICA（＋） and HLA（-）MICA（-）. The impact of post-transplant antibody level on kidney allograft function was evaluated. Results Antibodies were detected in 38.1% （32/84） of the renal allograft recipients. HLA, MICA and HLA＋MICA expression was observed in 18.89%, 14.44% and 5.93% of the recipients respectively. The most frequent anti-HLA and anti-MICA specific antibodies identified were All, A24, A29, A32, A33, A80; B7, B13, B37; DR17, DR12, DR18, DR52, DR53, DR1, DR4, DR9, DR51; DQ7, DQ4, DQ8, DQ2, DQ9, DQ5, DQ6 and MICA02, MICA18, MICA19, MICA07, MICA27. As the time after transplantation elapsed, more recipients developed de novo antibody expression. Total 11.91% （10/84） of the recipients had de novo antibody expression during the follow up. The average level of SCr and the percentage of recipients with abnormal allograft function were significantly higher in recipients with anti-HLA and/or anti- MICA antibody expression than those without. The appearance of anti-HLA and anti-MICA antibody expression always preceded the increase in SCr value. Conclusions Anti-HLA and anti-MICA antibody expression has predictive value for early and late allograft dysfunction. The presence of donor specific antibody is detrimental to graft function and graft survival.

Association of human leukocyte antigen-DR-DQ-DP haplotypes with the risk of hepatitis B virus-related hepatocellular carcinoma

Aim:Genetic polymorphisms of human leukocyte antigen(HLA)class II molecules are associated with chronic hepatitis B virus(HBV)infection.We aimed to investigate the impacts of HLA-II haplotypes on viral evolution and the risks of HBV-caused liver diseases.Methods:HLA-DR-DQ-DP haplotypes were estimated in 1210 healthy controls,296 HBV clearance subjects,301 asymptomatic hepatitis B surface antigen carriers,770 chronic hepatitis B patients,443 HBV-related liver cirrhosis(LC)patients,and 1037 HBV-related hepatocellular carcinoma(HCC)patients.HBV mutations were determined by sequencing.The associations of HLA-DR-DQ-DP haplotypes with viral mutations and the risks of liver diseases were assessed by multivariate logistic regression.Results:Compared to HBV-free subjects,the haplotypes CCAACG,CCGACG,TCAATA,and TCGATA were associated with decreased HCC risk,with an odds ratio(OR)[95%confidence interval(CI)]of 0.62(0.40-0.95),0.60(0.39-0.92),0.73(0.54-0.98),and 0.58(0.42-0.78),respectively.CCAACG,CCGACG,and TCAATA were significantly associated with decreased frequencies of the HCC-risk HBV mutations:preS1 deletion,APOBECsignature HBV mutations in the core promoter and preS regions,A51C/T,G104C/T,and G146C/T.TCGATA and TTAACG were associated with increased LC risk,with an OR(95%CI)of 1.54(1.03-2.30)and 2.23(1.50-3.33),respectively.However,TCGATA and TTAACG were not consistently associated with the cirrhosis-risk HBV mutations.Conclusion:CCAACG,CCGACG,and TCAATA are inversely associated with HCC risk,possibly because they are involved in creating an immune microenvironment attenuating the generation of HCC-risk HBV mutations.TCGATA and TTAACG might predispose the polarity of immunity towards Th17 isotype related to LC.

Association of defective HLA-Ⅰ expression with antigen processing machinery and their association with clinicopathological characteristics in Kazak patients with esophageal cancer

Background It has been confirmed that defective expression of human leukocyte antigen class Ⅰ （HLA-Ⅰ） molecules can contribute to the immune evasion of cancer cells in some types of cancer. The aim of this study was to examine the expression of HLA class Ⅰ antigen and the antigen-processing machinery （APM） components in esophageal squamous cell carcinoma （ESCC） and their role in high risk human papillomavirus （HPV） infection, and to analyze their association with histopathological characteristics in the Kazak ethnic group.Methods A total of 50 formalin-fixed, paraffin-embedded ESCC lesions were collected from the First Affiliated Hospital of Xinjiang Medical University, China. The expression levels of HLA-Ⅰ antigen and APM components were determined by immunohistochemistry; the HPV DNA were detected using polymerase chain reaction （PCR）.Results A high frequency of down-regulation or loss of expression of HLA and APM components were found in esophageal cancer in Kazak people. HLA-Ⅰ, TAP1, CNX, LMP7, Erp57, Tapasin and ERAP1 were down-regulated in 68%,44%, 48%, 40%, 52%, 32% and 20% of ESCC lesions then, respectively. The loss of expression of HLA-Ⅰ antigen was significantly correlated with part of the APM components and positively correlated with high risk HPV16 infection. TAP1,CNX, LMP7, Erp57 and Tapasin loss were significantly associated with tumor grading, lymph node metastasis and depth of invasion （P〈0.05）.Conclusion Our results suggest that APM component defects are a mechanism underlying HLA-Ⅰ antigen down-regulation in ESCC lesions, and indicate that the loss expression of HLA-Ⅰ and APM components will become an important marker of ESCC and analysis of HLA-Ⅰ and APM component expression can provide useful prognostic information for patients with ESCC from the Kazak ethnic group.