Effect of CA125/MUC16 on complement-dependent cytotoxicity (CDC) of farletuzumab and other CDC-mediating antibodies via inhibition of antibody-C1q binding.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23082-e23082 ◽  
Author(s):  
J Bradford Kline ◽  
Shawn Fernando ◽  
Stephen Harley ◽  
Luigi Grasso ◽  
Nicholas C Nicolaides
Keyword(s):  
Immune Responses ◽  
Cell Lines ◽  
Folate Receptor ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Recurrent Ovarian Cancer ◽  
Cellular Cytotoxicity ◽  
Host Immune Responses ◽  
Investigational Agent ◽  
Functional Assays

e23082 Background: Human cancers employ a number of mechanisms to evade host immune responses. Here we report the effects of the tumor-shed antigen CA125 on suppressing complement-dependent cellular cytotoxicity (CDC). This finding relates to a prespecified subgroup analysis of an 1100 patient Ph3 clinical trial testing the investigational agent farletuzumab, a monoclonal antibody (mAb) to folate receptor alpha, plus standard-of-care chemotherapy in patients with recurrent ovarian cancer. In this study, patients with low levels of CA125 (no greater than 3X the upper limit of normal) treated with farletuzumab compared to placebo demonstrated improvements in both progression free survival (HR 0.49, p = 0.0028) and overall survival (HR 0.44, p = 0.0108). Farletuzumab’s pharmacologic activity is mediated in part through antibody dependent cellular cytotoxicity (ADCC) and CDC. Here we show that CA125 inhibits IgG1- and IgM-mediated CDC by suppressing antibody interaction with the C1q complement-initiating protein. Methods: Functional assays employing cell lines expressing antibody-specific antigens were used to measure CDC activity. CA125 isolates from various patients and cell lines were used to monitor CA125 effects on complement function. ELISA assays were used to measure the effects of CA125 inhibition on C1q-antibody interaction. Results: Functional assays showed that CA125 suppressed antibody-mediated CDC in a dose dependent fashion. Molecular studies revealed that this suppression is caused by CA125 binding to antibody, leading to suppression of antibody-C1q interaction. Conclusions: Here we demonstrate that CA125 can elicit immunosuppression by perturbing the interaction of tumor targeting antibodies and the C1q complement-initiating protein. This effect is through a direct binding of CA125 to antibody. These findings provide new insights into the potential biological mechanisms by which tumors produce tumor shed antigens like CA125 to suppress host immune responses such as CDC. This finding has important clinical applications for the development of therapeutics utilizing complement-mediated mechanisms.

Effect of the tumor-shed antigen CA125 on humoral immune responses of IgG1, IgG3, and IgM-type antibodies.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 15-15
Author(s):  
J Bradford Kline
Keyword(s):  
Ovarian Cancer ◽  
Immune Responses ◽  
Folate Receptor ◽  
Standard Of Care ◽  
Serum Levels ◽  
Serum Samples ◽  
Host Immune Responses ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Platinum Sensitive

15 Background: Human cancers employ a number of mechanisms to evade host immune responses. Here we report the effects of CA125 on suppressing humoral immune responses of naturally occurring and therapeutic antibodies (Abs). These data stem from prespecified subgroup analysis of a Ph3 trial testing farletuzumab, a monoclonal Ab (mAb) to folate receptor alpha, plus standard-of-care carboplatin-taxane (CT) chemotherapy in patients with recurrent platinum-sensitive ovarian cancer. Patients with low CA125 serum levels treated with farletuzumab plus CT demonstrated improvements in PFS (HR 0.49, p = 0.0028) and OS (HR 0.44, p = 0.0108) compared to placebo plus CT. Farletuzumab utilizes Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) with the aim to kill target bound tumor cells. These functions were analyzed in patient samples to determine if CA125 negatively impacts mAb-mediated humoral responses. Methods: Molecular and cell based assays tested the effects of CA125 on humoral immune activity mediated by mAbs on ovarian cancer patient serum samples. Results: Here we show that CA125 inhibits ADCC and CDC by directly binding to a subset of mAbs and perturbing engagement with Fc-γ activating receptors CD16a and CD32a and the C1q complement initiating protein. The effects occur via CA125 binding to the mAb variable domain, which alters the structure of the CH2 motif leading to suppressed binding by CD16a/CD32a and C1q. The lack of inhibition by the high affinity CD64a Fc-γ receptor as well as lack of FcRn inhibition suggests a conformational change occurs within the CH2 motif that perturbs the binding of low affinity CD16a, CD32a and C1q proteins. The effect appears to involve a subset of Abs composed of IgG1, IgG3 and IgM isotypes. Conclusions: CA125 has an immunosuppressive effect on Ab-mediated humor immunity in a subset of tested Abs of varied isotypes including IgG1, IgG3, and IgM. The effects have implications in monitoring therapeutic mAbs that may be negatively affected by CA125 binding as well as potential implications for identifying patients who may be at risk for developing certain types of cancer, including ovarian.

A regimen of weekly nab-paclitaxel with weekly carboplatin in recurrent ovarian cancer: A retrospective analysis.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15516-e15516
Author(s):  
Amit Rauthan ◽  
Poonam Patil ◽  
S. P. Somashekhar ◽  
Shabber Zaveri
Keyword(s):  
Ovarian Cancer ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Complete Response ◽  
Recurrent Ovarian Cancer ◽  
Hypersensitivity Reactions ◽  
Free Survival ◽  
Platinum Resistant ◽  
Number Of Patients ◽  
Grade 3

e15516 Background: The standard of care for patients with recurrent platinum resistant ovarian cancer is treatment with non cross-resistant drugs. Carboplatin retreatment is usually not an option in the platinum resistant population. Weekly paclitaxel has been tried in recurrent patients. But paclitaxel can cause hypersensitivity reactions due to its Cremophor based solvent. nab-paclitaxel being a nano-particle albumin bound paclitaxel is devoid of this toxictity. Also, it is thought that nab-paclitaxel may have a higher intratumoral uptake leading to enhanced anti-tumor action. We looked at a regimen using weekly carboplatin with weekly nab-paclitaxel in platinum resistantrelapsed carcinoma ovary who had failed multiple lines of treatment. Methods: We treated 10 patients with recurrent platinum resistant ovarian cancer with measurable disease with nab-paclitaxel 100mg/m2 on days 1,8,15 with carboplatin at AUC 1.5 on days 1,8,15 intravenously, repeated every 28 days for 4 cycles. All patients had received 3 or more lines of chemotherapy for recurrent disease. We looked for response rate, progression free survival and toxicities. Results: Three patients had complete response, 5 patients had partial response and 2 patients had disease progression. Median PFS was 6 months. There were no instances of paclitaxel induced hypersensitivity reactions. Two patients developed grade 3 neutropenia. One patient developed grade 3 thrombocytopenia. Three patients required blood transfusions. One patient developed grade 3 neuropathy. Conclusions: Weekly combination of nab-paclitaxel with weekly carboplatin is a safe and potentially active treatment in recurrent platinum resistant ovarian cancers who had failed multiple lines of treatment. Considering the efficacy and favorable toxicity profile, this weekly combination needs to be tested in a larger number of patients.

Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients (pts) with platinum-agnostic ovarian cancer: Final analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5504-5504
Author(s):  
David M. O'Malley ◽  
Ana Oaknin ◽  
Ursula A. Matulonis ◽  
Gina Mantia-Smaldone ◽  
Peter C Lim ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Folate Receptor ◽  
Ideal Body Weight ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Recurrent Ovarian Cancer ◽  
Staining Intensity ◽  
Antibody Drug Conjugate ◽  
Blurred Vision ◽  
Grade 3

5504 Background: Mirvetuximab soravtansine (MIRV) is an ADC comprising a FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. As part of the Phase 1b FORWARD II trial (NCT02606305), the combination of MIRV with bevacizumab (BEV) was evaluated in pts with FRα-positive (medium/high expression; ≥50%/ ≥75% of cells with PS2+ staining intensity), platinum agnostic ovarian cancer, defined as pts with either platinum resistant (PROC) (recurrence within 6 months after last platinum dose) or platinum sensitive (PSOC)responded to the last platinum therapy and did not progress within 6 months) for whom a non-platinum based doublet would be appropriate. Methods: Pts received MIRV (6 mg/kg; adjusted ideal body weight) and BEV (15 mg/kg) on Day 1 of a 21-day cycle. Responses were assessed by investigator according to RECIST 1.1 and adverse events (AEs) evaluated by CTCAE v4.03. Results: In total, 60 pts received the combination, with a median age of 60 years, a median of 2 prior lines of systemic therapy (range 1-4) and a median follow-up of 17.5 months. The cohort included 32 pts (53%) with PROC disease and 28 (47%) with PSOC disease. Objective responses were seen in 28 of 60 pts for a confirmed overall response rate (ORR) of 47% (95% CI, 34, 60), median duration of response (mDOR) of 9.7 months (95% CI 6.7, 12.9), and median progression free survival (mPFS) of 8.3 months (95% CI 5.6, 10.6). In pts with high FRα expression (n=33), the confirmed ORR was 64% (95% CI 45, 80), mDOR of 11.8 months (95% CI 6.7, 13.7), and mPFS of 10.6 months (95% CI 8.3, 13.3); efficacy results in PROC and PSOC subsets of pts with high FRα expression are shown in the table below. The most common treatment related AEs (all grade, grade 3+) were diarrhea (68%, 2%), blurred vision (63%, 2%), fatigue (58%, 7%), and nausea (57%, 0%). The most common treatment related grade 3 and 4 AEs were neutropenia and hypertension, (12%, 3% and 13%, 0%, respectively); all other grade 3+ events occurred in ≤ 10% of pts. Conclusions: The combination of MIRV with BEV demonstrates impressive anti-tumor activity with durable responses and favorable tolerability in high FRα recurrent ovarian cancer. These results build on data previously reported for MIRV/BEV in PROC patients ( Gyn Oncology O’Malley, et al 2020), suggesting that MIRV has the potential to be a preferred partner for BEV in patients with high FRα recurrent ovarian cancer regardless of platinum sensitivity. Clinical trial information: NCT02606305. [Table: see text]

Role of convalescent plasma therapy in new Coronavirus disease (nCOVID-19): A review

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 546-549
Author(s):  
Shweta Dadarao Parwe ◽  
Milind Abhimanyu Nisargandha ◽  
Rishikesh Thakre
Keyword(s):  
Clinical Trial ◽  
Immune Responses ◽  
Indian Population ◽  
Preventive Treatment ◽  
The Body ◽  
Therapeutic Antibodies ◽  
Plasma Therapy ◽  
Host Immune Responses ◽  
Transparent Liquid

Hitherto, there is no proper line of treatment for the new (nCOVID19). The development of unique antiviral drugs has taken precedence. Therapeutic antibodies () will be a significantly beneficial agent against nCOVID-19. Here the host immune responses to new discussed in this review provide strategy and further treatment and understanding of clinical interventions against nCOVID-19. Plasma therapy uses the antibodies found in the blood of people recovering (or convalesced) from an infection to treat infected patients. When an infection occurs, the body begins producing proteins specially made to kill the germ, called antibodies. Those antibodies coat specifically plasma in the blood of survivors, the yellow transparent liquid blood portion for months or even years. research assesses plasma use from Convalescent patients of infected with nCOVID-19 as a possible preventive treatment. But it is not yet recommended as a line of treatment, and it is used as a clinical trial in the new in Indian population.

scholarly journals Current FDA-Approved Therapies for High-Grade Malignant Gliomas

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 324
Author(s):  
Jacob P. Fisher ◽  
David C. Adamson
Keyword(s):  
Controlled Trial ◽  
Malignant Gliomas ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
High Grade ◽  
Tumor Treatment ◽  
Free Survival ◽  
Randomized Controlled ◽  
Significant Survival ◽  
One Year

The standard of care (SOC) for high-grade gliomas (HGG) is maximally safe surgical resection, followed by concurrent radiation therapy (RT) and temozolomide (TMZ) for 6 weeks, then adjuvant TMZ for 6 months. Before this SOC was established, glioblastoma (GBM) patients typically lived for less than one year after diagnosis, and no adjuvant chemotherapy had demonstrated significant survival benefits compared with radiation alone. In 2005, the Stupp et al. randomized controlled trial (RCT) on newly diagnosed GBM patients concluded that RT plus TMZ compared to RT alone significantly improved overall survival (OS) (14.6 vs. 12.1 months) and progression-free survival (PFS) at 6 months (PFS6) (53.9% vs. 36.4%). Outside of TMZ, there are four drugs and one device FDA-approved for the treatment of HGGs: lomustine, intravenous carmustine, carmustine wafer implants, bevacizumab (BVZ), and tumor treatment fields (TTFields). These treatments are now mainly used to treat recurrent HGGs and symptoms. TTFields is the only treatment that has been shown to improve OS (20.5 vs. 15.6 months) and PFS6 (56% vs. 37%) in comparison to the current SOC. TTFields is the newest addition to this list of FDA-approved treatments, but has not been universally accepted yet as part of SOC.

scholarly journals Evaluation of dsRNA delivery methods for targeting macrophage migration inhibitory factor MIF in RNAi-based aphid control

2021 ◽  
Author(s):  
Shaoshuai Liu ◽  
Maria Jose Ladera-Carmona ◽  
Minna M. Poranen ◽  
Aart J. E. van Bel ◽  
Karl-Heinz Kogel ◽  
...  
Keyword(s):  
Immune Responses ◽  
Artificial Diet ◽  
Sieve Tube ◽  
Feeding Strategies ◽  
Macrophage Migration ◽  
Delivery Methods ◽  
Host Immune Responses ◽  
Aphid Control ◽  
Barley Leaves ◽  
Sieve Tubes

AbstractMacrophage migration inhibitory factors (MIFs) are multifunctional proteins regulating major processes in mammals, including activation of innate immune responses. In invertebrates, MIF proteins participate in the modulation of host immune responses when secreted by parasitic organisms, such as aphids. In this study, we assessed the possibility to use MIF genes as targets for RNA interference (RNAi)-based control of the grain aphid Sitobion avenae (Sa) on barley (Hordeum vulgare). When nymphs were fed on artificial diet containing double-stranded (ds)RNAs (SaMIF-dsRNAs) that target sequences of the three MIF genes SaMIF1, SaMIF2 and SaMIF3, they showed higher mortality rates and these rates correlated with reduced MIF transcript levels as compared to the aphids feeding on artificial diet containing a control dsRNA (GFP-dsRNA). Comparison of different feeding strategies showed that nymphs’ survival was not altered when they fed from barley seedlings sprayed with naked SaMIF-dsRNAs, suggesting they did not effectively take up dsRNA from the sieve tubes of these plants. Furthermore, aphids’ survival was also not affected when the nymphs fed on leaves supplied with dsRNA via basal cut ends of barley leaves. Consistent with this finding, the use of sieve tube-specific YFP-labeled Arabidopsis reporter lines confirmed that fluorescent 21 nt dsRNACy3, when supplied via petioles or spraying, co-localized with xylem structures, but not with phloem tissue. Our results suggest that MIF genes are a potential target for insect control and also imply that application of naked dsRNA to plants for aphid control is inefficient. More efforts should be put into the development of effective dsRNA formulations.

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