The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: a phase 1 trial.

Tebotelimab, a bispecific PD-1×LAG-3 DART molecule that blocks both PD-1 and LAG-3, was investigated for clinical safety and activity in a phase 1 dose-escalation and cohort-expansion clinical trial in patients with solid tumors or hematologic malignancies and disease progression on previous treatment. Primary endpoints were safety and maximum tolerated dose of tebotelimab when administered as a single agent (n = 269) or in combination with the anti-HER2 antibody margetuximab (n = 84). Secondary endpoints included anti-tumor activity. In patients with advanced cancer treated with tebotelimab monotherapy, 68% (184/269) experienced treatment-related adverse events (TRAEs; 22% were grade ≥3). No maximum tolerated dose was defined; the recommended phase 2 dose (RP2D) was 600 mg once every 2 weeks. There were tumor decreases in 34% (59/172) of response-evaluable patients in the dose-escalation cohorts, with objective responses in multiple solid tumor types, including PD-1-refractory disease, and in LAG-3+ non-Hodgkin lymphomas, including CAR-T refractory disease. To enhance potential anti-tumor responses, we tested margetuximab plus tebotelimab. In patients with HER2+ tumors treated with tebotelimab plus margetuximab, 74% (62/84) had TRAEs (17% were grade ≥3). The RP2D was 600 mg once every 3 weeks. The confirmed objective response rate in these patients was 19% (14/72), including responses in patients typically not responsive to anti-HER2/anti-PD-1 combination therapy. ClinicalTrials.gov identifier: NCT03219268 .

Development and Preliminary Clinical Activity of PD-1-Guided CTLA-4 Blocking Bispecific DART Molecule.

Combination immunotherapy with antibodies directed against PD-1 and CTLA-4 shows improved clinical benefit across cancer indications compared to single agents, albeit with increased toxicity. Leveraging the observation that PD-1 and CTLA-4 are co-expressed by tumor-infiltrating lymphocytes, an investigational PD-1 x CTLA-4 bispecific DART molecule, MGD019, is engineered to maximize checkpoint blockade in the tumor microenvironment via enhanced CTLA-4 blockade in a PD-1-binding-dependent manner. In vitro, MGD019 mediates the combinatorial blockade of PD-1 and CTLA-4, confirming dual inhibition via a single molecule. MGD019 is well tolerated in non-human primates, with evidence of both PD-1 and CTLA-4 blockade, including increases in Ki67+CD8 and ICOS+CD4 T cells, respectively. In the ongoing MGD019 first-in-human study enrolling patients with advanced solid tumors (NCT03761017), an analysis undertaken following the dose escalation phase revealed acceptable safety, pharmacodynamic evidence of combinatorial blockade, and objective responses in multiple tumor types typically unresponsive to checkpoint inhibitor therapy.

Multispecific, Multivalent Antibody-Based Molecules Engineered on the DART® and TRIDENTTM Platforms.

Multispecific antibodies bind two or more different antigens and enable new therapeutic applications that cannot be replicated with conventional monoclonal antibodies, such as bridging different cells or bringing soluble proteins in close proximity. The DART and TRIDENT platforms enable the engineering of such antibodies. A DART molecule combines two independent antigen-binding sites in a stabilized, diabody-like structure. A DART molecule can be expressed with or without an Fc domain and thus can be tailored to have a long or short half-life in vivo and to induce or ablate effector function. Linking two DART units or a DART unit and a Fab domain (the latter structure is called TRIDENT format) via an Fc domain creates a monospecific, bispecific, trispecific, or tetraspecific molecule with up to tetravalent targeting of antigens. This article focuses on the design of DART and TRIDENT molecules that target two or three different antigens. © 2020 by John Wiley & Sons, Inc. Basic Protocol 1: Design and generation of expression plasmids encoding DART and TRIDENT molecules Basic Protocol 2: Expression of DART and TRIDENT molecules by transient transfection of CHO cells Basic Protocol 3: Purification of DART and TRIDENT molecules from CHO cell supernatants.

Development of MGD007, a gpA33 x CD3-Bispecific DART Protein for T-Cell Immunotherapy of Metastatic Colorectal Cancer.

We have developed MGD007 (anti-glycoprotein A33 x anti-CD3), a DART protein designed to redirect T cells to target gpA33 expressing colon cancer. The gpA33 target was selected on the basis of an antibody-based screen to identify cancer antigens universally expressed in both primary and metastatic colorectal cancer specimens, including putative cancer stem cell populations. MGD007 displays the anticipated-bispecific binding properties and mediates potent lysis of gpA33-positive cancer cell lines, including models of colorectal cancer stem cells, through recruitment of T cells. Xenograft studies showed tumor growth inhibition at doses as low as 4 µg/kg. Both CD8 and CD4 T cells mediated lysis of gpA33-expressing tumor cells, with activity accompanied by increases in granzyme and perforin. Notably, suppressive T-cell populations could also be leveraged to mediate lysis of gpA33-expressing tumor cells. Concomitant with CTL activity, both T-cell activation and expansion are observed in a gpA33-dependent manner. No cytokine activation was observed with human PBMC alone, consistent with the absence of gpA33 expression on peripheral blood cell populations. Following prolonged exposure to MGD007 and gpA33 positive tumor cells, T cells express PD-1 and LAG-3 and acquire a memory phenotype but retain ability to support potent cell killing. In cynomolgus monkeys, 4 weekly doses of 100 µg/kg were well tolerated, with prolonged PK consistent with that of an Fc-containing molecule. Taken together, MGD007 displays potent activity against colorectal cancer cells consistent with a mechanism of action endowed in its design and support further investigation of MGD007 as a potential novel therapeutic treatment for colorectal cancer. Mol Cancer Ther; 17(8); 1761-72. ©2018 AACR.

Efficacy and Safety of Wheat Grass in Thalassemic Children on Regular Blood Transfusion.

BACKGROUND: In thalassemia, mutations either in alpha or beta chain synthesis results in low hemoglobin (Hb). Wheatgrass has been used for many years for health purposes. Some reports suggest the beneficial effect of wheatgrass on transfusion requirements. Folic acid is also known to play an important role in several biochemical reactions. In some patients with thalassemia, the supplementation of folic acid is useful. OBJECTIVE: To evaluate the efficacy and safety of wheatgrass in children with thalassemia receiving chronic blood transfusions. MATERIAL AND METHODS: In this randomized prospective study, 69 children with thalassemia were divided into the wheatgrass group and the control group (no wheatgrass). Both groups received a regular blood transfusion and folic acid. The treatment duration was 18 months. Anthropometric parameters, number of transfusions, and amount of blood transfused were compared within and between the groups at the end of the therapy. Clinical examinations, laboratory investigations, and ultrasounds for liver and spleen span were performed at the baseline and then every six months till 18 months. Adverse effects (if any) were noted on every visit. Quality of life (QOL) was evaluated before and at the end of the study using a questionnaire. RESULTS: Sixty-nine (study group (n=45; mean age 6.35 ± 2.65 yrs); control group (n=24; 4.86 ± 2.77 yrs)) patients were enrolled, of which 12 from the study group and three from the control group did not complete the study. The difference in liver size within the wheatgrass group was significant (P <0.021) only at 18 months but not in the control group at any time point. The difference in spleen size was significant within the wheatgrass group (P<0.005) as well as the control group (P<0.001) at 18 months only. The difference in serum ferritin levels was not significant between the two groups. The increase in serum ferritin levels at the end of the study was significant in the control group when compared to the baseline (P<0.01). There was no difference in the average number of transfusions or in the blood transfusion requirement between the two groups. The difference in the QOL at the start and end was significant in the wheatgrass group (P<0.05). CONCLUSION: Wheatgrass appears to play a promising role in children with thalassemia receiving chronic blood transfusions.

Rates, indications, and outcomes of caesarean section deliveries: A comparison of tribal and non-tribal women in Gujarat, India.

BACKGROUND: Even though the caesarean section is an essential component of comprehensive obstetric and newborn care for reducing maternal and neonatal mortality, there is a lack of data regarding caesarean section rates, its determinants and health outcomes among tribal communities in India. OBJECTIVE: The aim of this study is to estimate and compare rates, determinants, indications and outcomes of caesarean section. The article provides an assessment on how the inequitable utilization can be addressed in a community-based hospital in tribal areas of Gujarat, India. METHOD: Prospectively collected data of deliveries (N = 19923) from April 2010 to March 2016 in Kasturba Maternity Hospital was used. The odds ratio of caesarean section was estimated for tribal and non-tribal women. Decomposition analysis was done to decompose the differences in the caesarean section rates between tribal and non-tribal women. RESULTS: The caesarean section rate was significantly lower among tribal compared to the non-tribal women (9.4% vs 15.6%, p-value < 0.01) respectively. The 60% of the differences in the rates of caesarean section between tribal and non-tribal women were unexplained. Within the explained variation, the previous caesarean accounted for 96% (p-value < 0.01) of the variation. Age of the mother, parity, previous caesarean and distance from the hospital were some of the important determinants of caesarean section rates. The most common indications of caesarean section were foetal distress (31.2%), previous caesarean section (23.9%), breech (16%) and prolonged labour (11.2%). There was no difference in case fatality rate (1.3% vs 1.4%, p-value = 0.90) and incidence of birth asphyxia (0.3% vs 0.6%, p-value = 0.26) comparing the tribal and non-tribal women. CONCLUSION: Similar to the prior evidences, we found higher caesarean rates among non-tribal compare to tribal women. However, the adverse outcomes were similar between tribal and non-tribal women for caesarean section deliveries.

ProSeal laryngeal mask airway as an alternative to standard endotracheal tube in securing upper airway in the patients undergoing beating-heart coronary artery bypass grafting.

BACKGROUND: ProSeal laryngeal mask airways (PLMAs) are routinely used after failed tracheal intubation as airway rescue, facilitating tracheal intubation by acting as a conduit and to secure airway during emergencies. In long duration surgeries, use of endotracheal tube (ETT) is associated with various hemodynamic complications, which are minimally affected during PLMA use. However, except for few studies, there are no significant data available that promote the use of laryngeal mask during cardiac surgery. This prospective study was conducted with the objective of demonstrating the advantages of PLMA over ETT in the patients undergoing beating-heart coronary artery bypass graft (CABG). METHODOLOGY: This prospective, interventional study was carried out in 200 patients who underwent beating-heart CABG. Patients were randomized in equal numbers to either ETT group or PLMA group, and various hemodynamic and respiratory parameters were observed at different time points. RESULTS: Patients in PLMA group had mean systolic blood pressure 126.10 ± 5.31 mmHg compared to the patients of ETT group 143.75 ± 6.02 mmHg. Pulse rate in the PLMA group was less (74.52 ± 10.79 per min) (P < 0.05) compared to ETT group (81.72 ± 9.8). Thus, hemodynamic changes were significantly lower (P < 0.05) in PLMA than in ETT group. Respiratory parameters such as oxygen saturation, pressure CO 2 (pCO 2 ), peak airway pressure, and lung compliance were similar to ETT group at all evaluation times. The incidence of adverse events was also lower in PLMA group. CONCLUSION: In experience hand, PLMA offers advantages over the ETT in airway management in the patients undergoing beating-heart CABG.

RS3PE revisited: a systematic review and meta-analysis of 331 cases.

OBJECTIVES: Remitting seronegative symmetrical synovitis with pitting oedema (RS(3)PE) syndrome is a rare inflammatory arthritis, characterised by symmetrical distal synovitis, pitting oedema of the hands and feet, absence of rheumatoid factor, and favourable response to glucocorticoids. The aim of our study is to further delineate the clinical and laboratory features, and response to treatment. METHODS: We performed a systematic electronic search of Medline, PubMed, EMBASE, ACR and EULAR databases for case reports, case series, and related articles of RS(3)PE. Statistical analysis was done comparing categorical variables with Chi-square tests and frequencies of means via t-tests. Binary logistic regression analysis was performed to identify predictors of erosions, recurrence, malignancy and rheumatologic disorders. RESULTS: 331 cases of RS(3)PE were identified from 121 articles. RS(3)PE was found in older patients (71±10.42 years) predominantly in males (n= 211, 63.36%), was symmetrical (n=297/311, 95.50%) involved the hands (n=294/311, 94.53%) A concurrent rheumatologic condition was reported in 22 cases (6.65%), and malignancy in 54 cases (16.31%). Radiographic joint erosions were found in 5.5%. Most patients responded to medium-dose glucocorticoids (16.12±9.5 mg/day). Patients with concurrent malignancy requiring non-significantly higher doses of prednisone (18.12 vs. 15.76 mg, p 0.304) and higher likelihood of recurrence of disease (OR 4.04, 95% CI 1.10-14.88, p=0.03). CONCLUSIONS: The symptoms and unique findings that make up RS(3)PE appear to represent a steroid-responsive disease that may be a harbinger of an underlying malignancy. More study is needed to understand the molecular origins of RS(3)PE in order to determine whether it is a separate disease process. Patients with concurrent cancer tend to have more severe presentations and higher rates of recurrence.

Touch me not.

Central Poststroke Pain syndrome (CPSP) can occur due to disruption of the somatosensory pathways of the brain at any level such as the thalamus, medulla, or cerebral cortex. It is characterized by sensory abnormalities and hyperesthesia in the part of the body correlating to the central lesion. The treatment of this pain syndrome is often difficult, and it does not usually respond to traditional analgesics. The first line of treatment is drugs aimed at lowering neuronal hyperexcitability, for example, amitriptyline or lamotrigine, with gabapentin considered a second line.

Application of dual affinity retargeting molecules to achieve optimal redirected T-cell killing of B-cell lymphoma.

We describe the application of a novel, bispecific antibody platform termed dual affinity retargeting (DART) to eradicate B-cell lymphoma through coengagement of the B cell-specific antigen CD19 and the TCR/CD3 complex on effector T cells. Comparison with a single-chain, bispecific antibody bearing identical CD19 and CD3 antibody Fv sequences revealed DART molecules to be more potent in directing B-cell lysis. The enhanced activity with the CD19xCD3 DART molecules was observed on all CD19-expressing target B cells evaluated using resting and prestimulated human PBMCs or purified effector T-cell populations. Characterization of a CD19xTCR bispecific DART molecule revealed equivalent potency with the CD19xCD3 DART molecule, demonstrating flexibility of the DART structure to support T-cell/B-cell associations for redirected T cell-killing applications. The enhanced level of killing mediated by DART molecules was not accompanied by any increase in nonspecific T-cell activation or lysis of CD19(-) cells. Cell-association studies indicated that the DART architecture is well suited for maintaining cell-to-cell contact, apparently contributing to the high level of target cell killing. Finally, the ability of the CD19xTCR DART to inhibit B-cell lymphoma in NOD/SCID mice when coadministered with human PBMCs supports further evaluation of DART molecules for the treatment of B-cell malignancies.