Ulocuplumab (BMS-936564 / MDX1338): a fully human anti-CXCR4 antibody induces cell death in chronic lymphocytic leukemia mediated through a reactive oxygen species-dependent pathway.

The CXCR4 receptor (Chemokine C-X-C motif receptor 4) is highly expressed in different hematological malignancies including chronic lymphocytic leukemia (CLL). The CXCR4 ligand (CXCL12) stimulates CXCR4 promoting cell survival and proliferation, and may contribute to the tropism of leukemia cells towards lymphoid tissues. Therefore, strategies targeting CXCR4 may constitute an effective therapeutic approach for CLL. To address that question, we studied the effect of Ulocuplumab (BMS-936564), a fully human IgG4 anti-CXCR4 antibody, using a stroma--CLL cells co-culture model. We found that Ulocuplumab (BMS-936564) inhibited CXCL12 mediated CXCR4 activation-migration of CLL cells at nanomolar concentrations. This effect was comparable to AMD3100 (Plerixafor--Mozobil), a small molecule CXCR4 inhibitor. However, Ulocuplumab (BMS-936564) but not AMD3100 induced apoptosis in CLL at nanomolar concentrations in the presence or absence of stromal cell support. This pro-apoptotic effect was independent of CLL high-risk prognostic markers, was associated with production of reactive oxygen species and did not require caspase activation. Overall, these findings are evidence that Ulocuplumab (BMS-936564) has biological activity in CLL, highlight the relevance of the CXCR4-CXCL12 pathway as a therapeutic target in CLL, and provide biological rationale for ongoing clinical trials in CLL and other hematological malignancies

Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia.

BackgroundThe CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL)-microenvironment interaction. Overexpression of CXCR4 has been reported in different hematological malignancies including CLL. Binding of the pro-survival chemokine CXCL12 with its cognate receptor CXCR4 induces cell migration. CXCL12/CXCR4 signaling axis promotes cell survival and proliferation and may contribute to the tropism of leukemia cells towards lymphoid tissues and bone marrow. Therefore, we hypothesized that targeting CXCR4 with an IgG1 antibody, PF-06747143, may constitute an effective therapeutic approach for CLL.MethodsPatient-derived primary CLL-B cells were assessed for cytotoxicity in an in vitro model of CLL microenvironment. PF-06747143 was analyzed for cell death induction and for its potential to interfere with the chemokine CXCL12-induced mechanisms, including migration and F-actin polymerization. PF-06747143 in vivo efficacy was determined in a CLL murine xenograft tumor model.ResultsPF-06747143, a novel-humanized IgG1 CXCR4 antagonist antibody, induced cell death of patient-derived primary CLL-B cells, in presence or absence of stromal cells. Moreover, cell death induction by the antibody was independent of CLL high-risk prognostic markers. The cell death mechanism was dependent on CXCR4 expression, required antibody bivalency, involved reactive oxygen species production, and did not require caspase activation, all characteristics reminiscent of programmed cell death (PCD). PF-06747143 also induced potent B-CLL cytotoxicity via Fc-driven antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity activity (CDC). PF-06747143 had significant combinatorial effect with standard of care (SOC) agents in B-CLL treatment, including rituximab, fludarabine (F-ara-A), ibrutinib, and bendamustine. In a CLL xenograft model, PF-06747143 decreased tumor burden and improved survival as a monotherapy, and in combination with bendamustine.ConclusionsWe show evidence that PF-06747143 has biological activity in CLL primary cells, supporting a rationale for evaluation of PF-06747143 for the treatment of CLL patients

Determinación de la prevalencia de Dirofilaria immitis, mediante la Prueba Rápida de Inmunocromatografía en perros del municipio de puerto barrios, Izabal, en el año 2016

La Dirofilariasis, es una infección causada por Dirofilaria immitis que afecta el corazón del perro, y menos frecuente en el gato. Es una enfermedad que utiliza a los mosquitos de los géneros Aedes, Anopheles y Culex , y es así como se disemina la enfermedad. Además, puede llegar a infectar al humano de una forma accidental. Se realizó un estudio en el municipio de Puerto Barrios, Izabal, con el objetivo de establecer la prevalencia de perros seropositivos y contribuir con el estudio epidemiológico de D. immitis¸ en Guatemala. Para este estudio transversal descriptivo, se muestrearon 80 caninos completamente al azar. En el estudio se incluyeron caninos machos y hembras, mayores de un año de edad, sin previo tratamiento a ivermectina. Se tomó una muestra de sangre periférica de la vena cefálica o safena, de cada uno. Cada una de las muestras fue sometida a la de prueba inmunocromatografía rápida (Uranotest Dirofilaria®,) para determinar la presencia de antígenos de D. immitis. En el estudio, no se encontró la presencia de antígenos circulantes en los perros muestreados, por lo tanto la prevalencia fue de cero. Sin embargo, este hallazgo no descarta la presencia del parásito en el municipio de Puerto Barrios, Izabal. Debido al resultado obtenido fue establecer alguna relación entre sexo, edad, raza y procedencia con la seropositividad

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Integrated budget impact model to estimate the impact of introducing selpercatinib as a tumor-agnostic treatment option for patients with <i>RET</i>-altered solid tumors in the US

Objective: To estimate the potential budget impact on US third party payers (commercial or Medicare) associated with addition of selpercatinib as a tumor-agnostic treatment for patients with Rearranged during Transfection (RET)-altered solid tumors. Methods: An integrated budget impact model (iBIM) with three-year (Y) time horizon was developed for 19 RET-altered tumors. It is referred to as an integrated model because it is a single model that integrated results across multiple tumor types (as opposed to tumor-specific models developed traditionally). The model estimated eligible patient populations and included tumor-specific comparator treatments for each tumor type. Estimated annual total costs (2022USD, $) included costs of drug, administration, supportive care, and toxicity. For a one-million-member plan, the number of patients with RET-altered tumors eligible for treatment, incremental total costs, and incremental per-member per-month (PMPM) costs associated with introduction of selpercatinib treatment were estimated. Uncertainty associated with model parameters was assessed using various sensitivity analyses. Results: Commercial perspective estimated 11.68 patients/million with RET-altered tumors as treatment-eligible annually, of which 7.59 (Y1), 8.17 (Y2), and 8.76 (Y3) patients would be selpercatinib-treated (based on forecasted market share). The associated incremental total and PMPM costs (commercial) were estimated to be:$873,099 and $0.073 (Y1),$2,160,525 and $0.180 (Y2), and$2,561,281 and $0.213 (Y3), respectively. The Medicare perspective estimated 55.82 patients/million with RET-altered tumors as treatment-eligible annually, of which 36.29 (Y1), 39.08 (Y2), and 41.87 (Y3) patients would be selpercatinib-treated. The associated incremental total and PMPM costs (Medicare) were estimated to be:$4,447,832 and $0.371 (Y1),$11,076,422 and $0.923 (Y2), and$12,637,458 and $1.053 (Y3), respectively. One-way sensitivity analyses across both perspectives identified drug costs, selpercatinib market share, incidence of RET, and treatment duration as significant drivers of incremental costs. Conclusions: Three-year incremental PMPM cost estimates suggest modest impact on payer-budgets associated with introduction of tumor-agnostic selpercatinib treatment.</p

Ulocuplumab (BMS-936564 / MDX1338): a fully human anti-CXCR4 antibody induces cell death in chronic lymphocytic leukemia mediated through a reactive oxygen species-dependent pathway.

The CXCR4 receptor (Chemokine C-X-C motif receptor 4) is highly expressed in different hematological malignancies including chronic lymphocytic leukemia (CLL). The CXCR4 ligand (CXCL12) stimulates CXCR4 promoting cell survival and proliferation, and may contribute to the tropism of leukemia cells towards lymphoid tissues. Therefore, strategies targeting CXCR4 may constitute an effective therapeutic approach for CLL. To address that question, we studied the effect of Ulocuplumab (BMS-936564), a fully human IgG4 anti-CXCR4 antibody, using a stroma--CLL cells co-culture model. We found that Ulocuplumab (BMS-936564) inhibited CXCL12 mediated CXCR4 activation-migration of CLL cells at nanomolar concentrations. This effect was comparable to AMD3100 (Plerixafor--Mozobil), a small molecule CXCR4 inhibitor. However, Ulocuplumab (BMS-936564) but not AMD3100 induced apoptosis in CLL at nanomolar concentrations in the presence or absence of stromal cell support. This pro-apoptotic effect was independent of CLL high-risk prognostic markers, was associated with production of reactive oxygen species and did not require caspase activation. Overall, these findings are evidence that Ulocuplumab (BMS-936564) has biological activity in CLL, highlight the relevance of the CXCR4-CXCL12 pathway as a therapeutic target in CLL, and provide biological rationale for ongoing clinical trials in CLL and other hematological malignancies

Additional file 3: Figure S3. of Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia

The PF-06747143 parent IgG1 antibody (m15 IgG1) induces cell death and this activity is similar in HR and LR CLL patients. Primary CLL-B cells derived from CLL patients were incubated either alone (n = 10) or co-cultured with stroma-NK-tert cells (n = 10) and treated with vehicle, IgG1 control Ab, or m15-IgG1 antibody for 48 h. Cell death was measured using CD19/CD5/Annexin V staining followed by flow cytometry analysis. The data is derived from five high-risk (HR) and five low-risk (LR) CLL patients. The HR patients are presented with solid symbols (•) and LR patients denoted with hollow symbols (○). The individual data points for each group are shown. The horizontal lines represent the mean for each group Statistical comparisons were performed using Bonferroni’s correction test. (PDF 744 kb

Additional file 4: Figure S4. of Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia

m15-IgG1 and m15-IgG4 have similar cell death activity in HR and LR CLL patients, in presence or absence of stromal cells. The primary CLL-B cells derived from CLL patients were incubated either alone (n = 4) or co-cultured with stroma-NK-tert cells (n = 4) and treated with vehicle, m15-IgG1, m15-IgG4, IgG1 control antibody, or IgG4 control antibody for 48 h. Cell death was measured using CD19/CD5/Annexin V staining followed by flow cytometry analysis. The data is presented as % specific induced cell death (% SICD). The data shown is derived from two high-risk (HR) and two low-risk (LR) CLL patients. The HR patients are presented with solid symbols (•) and LR patients denoted with hollow symbols (○). The individual data points for each group are shown. The horizontal lines represent the mean for each group. Statistical comparisons were performed using Bonferroni’s correction test. (PDF 1032 kb

Additional file 6: Figure S6. of Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia

m15-IgG1-induced LR or HR CLL-B cell death is independent of caspase activation. CLL-B cells were treated for 6 h with m15-IgG1 (1, 10, or 100 nM) or IgG1 control antibody. Caspases 3, 8, and 9 were measured using a colometric detection method. The data shown is derived from four high-risk (HR) and four low-risk (LR) CLL patients. The HR patients are denoted by triangles and LR patients denoted by circles. The individual data points for each group are shown. The horizontal lines represent the mean for each group. Statistical comparisons were performed using Bonferroni’s correction test. (PDF 915 kb