On April 20, 2016 MEI Pharma, Inc. (Nasdaq: MEIP), an oncology company focused on the clinical development of novel therapies for cancer, announced new clinical data from a first-in-human study of MEI Pharma’s investigational drug candidate, ME-401, a next generation oral PI3K delta inhibitor (Press release, MEI Pharma, APR 20, 2016, View Source [SID:1234511147]). The data, presented today at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, suggest that ME-401 has an excellent pharmacokinetic (PK) and pharmacodynamic (PD) profile and the potential for an improved therapeutic window compared to other PI3K delta inhibitors, including the approved drug idelalisib (marketed as Zydelig), with a half-life that supports once-daily dosing.

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A copy of the poster presentation, entitled, "Clinical Pharmacokinetics and Pharmacodynamics of ME-401, an Oral, Potent, and Selective Inhibitor of Phosphatidylinositol 3-Kinase P110δ, Following Single Ascending Administration to Healthy Volunteers," is now available at www.meipharma.com.

"PI3K delta is a class of drugs that has shown great promise in the treatment of B-cell malignancies, but with certain toxicities," said Daniel P. Gold, Ph.D., President and Chief Executive Officer of MEI Pharma. "We believe this provides an opportunity for a next-generation drug that can produce therapeutic responses at a safe, effective dose. Thus far, ME-401 has demonstrated all of the attributes we had hoped to see, including linear PK and on-target activity at very low concentrations. Now the goal of our upcoming Phase Ib study will be to show a large therapeutic window in cancer patients. We expect to dose the first patient in this study by the end of June and look forward to providing an update later this year."

The Phase I study was designed to assess the safety and tolerability of ME-401 after single ascending oral doses in healthy volunteers to select the most appropriate dose for further clinical evaluation. The open label study enrolled a total of 15 healthy volunteers in 10, 30, 60, 90 and 150 mg dose levels. ME-401 was well tolerated at all dose levels. One subject experienced two treatment-emergent adverse events that were considered drug-related: pain and headache, graded as mild, after a 60 mg dose.

The first-in-human study of ME-401 was conducted using Quotient Clinical’s Translational Pharmaceutics platform, which collected PK PD data immediately after each dose and allowed for real-time decision making and manufacturing between dose groups.

About ME-401

ME-401 (formerly PWT143) is an orally bioavailable, potent and selective inhibitor of phosphatidylinositol 3 kinase (PI3K) delta, a molecular target that has been shown to play a critical role in the proliferation and survival of certain hematologic cancer cells. ME-401 has a distinct chemical structure from other PI3K delta inhibitors, including idelalisib. Data presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2012 demonstrated that ME-401 has superior pre-clinical activity compared to idelalisib. In March 2015, the U.S. Food and Drug Administration approved an Investigational New Drug application for ME-401 in B-cell malignancies. MEI Pharma expects to initiate a Phase Ib dose-escalation study of ME-401 in patients with relapsed refractory chronic lymphocytic leukemia (CLL) or follicular non-Hodgkin’s lymphoma (fNHL) in June 2016. The study is expected to enroll 42-84 patients at approximately 10 sites, with a starting dose of 60 mg.

On April 20, 2016 Medivation, Inc. (NASDAQ: MDVN) reported that data from an investigator-sponsored Phase II study of enzalutamide, an androgen receptor inhibitor, was presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans (Press release, Medivation, APR 20, 2016, View Source [SID:1234511146]). Preliminary data from a 12-patient subset demonstrated that treatment with enzalutamide alone resulted in potential immune-activating properties in patients with non-metastatic castration sensitive prostate cancer. The primary objective of the study was to evaluate the effect of a short-course of enzalutamide (three months) alone or in combination with a therapeutic cancer vaccine (PROSTVAC) on prostate specific antigen kinetics four months after completing enzalutamide. Data from 12 patients treated with enzalutamide alone was presented by the study’s lead investigator Ravi Madan, M.D., Principal Investigator of the Study and Clinical Director, Genitourinary Malignancies Branch at the National Cancer Institute.

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"Existing literature already suggests that inhibition of androgen receptor signaling can potentiate the function of the thymus and improve the profile of the immune system. These new data suggest that in prostate cancer patients, enzalutamide may also enhance immune cell killing of prostate cancer cells throughout the body," said David Hung M.D., Founder, President and Chief Executive Officer of Medivation. "We are very encouraged by these new data and believe that the potential immune-activating properties of enzalutamide warrant further investigation, particularly in combination with other immunotherapy agents."

The effect of enzalutamide on peripheral immune cells was measured in 12 patients who were receiving enzalutamide alone (160 mg daily for 84 days, without androgen deprivation therapy). Measurements of CD4+ and CD8+ T cells, T-regulatory cells (Treg), B cells, conventional and plasmacytoid dendritic cells (cDC, pDC), natural killer cells (NK), natural killer T cells (NKT), and myeloid derived suppressor cells (MDSC), as well as 114 subsets related to immune cell maturation and function, were evaluated. Peripheral blood mononuclear cells were also assessed for T cell receptor excision circles (TREC) to identity recent thymic emigrants and to determine changes in global gene expression.

Results showed that treatment with enzalutamide induced several notable alterations in immune cells consistent with general immune activation. These changes occurred early following treatment, and included an increase in NK cells, decreased frequencies of MDSCs with a suppressive phenotype and decreased frequencies of both CD4+ and CD8+ T-lymphocytes expressing the immune inhibitory checkpoint molecule CTLA4. Additionally, treatment with enzalutamide increased TREC levels by more than 75% in 7 of 12 patients compared with pre-therapy levels (p=0.012). Gene expression analysis of PBMCs corroborated these findings, showing that enzalutamide increased activation of interferon-gamma signaling and related immune-activating pathways. These immune-activating activities for enzalutamide support evaluating the drug in combination with a number of immune-stimulating treatments including checkpoint inhibitors and vaccines.

Enzalutamide is being developed through a collaboration between Medivation and Astellas. Enzalutamide, which is known by the brand name XTANDI, is currently approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

About XTANDI
XTANDI (enzalutamide) capsules is an androgen receptor inhibitor that blocks multiple steps in the androgen receptor signaling pathway within the tumor cell. In preclinical studies, enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors, and inhibit androgen receptor nuclear translocation and interaction with DNA. The clinical significance of this MOA is unknown.

XTANDI is approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Important Safety Information
Contraindications XTANDI is not indicated for women and is contraindicated in women who are or may become pregnant. XTANDI can cause fetal harm when administered to a pregnant woman.

Warnings and Precautions
Seizure In Study 1, conducted in patients with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of XTANDI patients and 0% of placebo patients. In Study 2, conducted in patients with chemotherapy-naive metastatic CRPC, seizure occurred in 0.1% of XTANDI patients and 0.1% of placebo patients. There is no clinical trial experience re-administering XTANDI to patients who experienced a seizure, and limited safety data are available in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold; Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Adverse Reactions
The most common adverse reactions ( ≥ 10%) reported from two combined clinical studies that occurred more commonly ( ≥ 2% over placebo) in XTANDI patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.

In Study 1, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In Study 2, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups.

Lab Abnormalities: Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4).
Infections: In Study 1, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Falls (including fall-related injuries), occurred in 9% of XTANDI patients and 4% of placebo patients. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.

Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of all patients.
Drug Interactions

Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI.

Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

For Full Prescribing Information for XTANDI (enzalutamide) capsules, please visit View Source

You are encouraged to report negative side effects of prescription drugs to the FDA.
Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

On April 20, 2016 Geron Corporation (Nasdaq:GERN) reported two poster presentations of data from non-clinical studies of the telomerase inhibitor, imetelstat, at the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting held in New Orleans, Louisiana (Press release, Geron, APR 20, 2016, View Source;p=RssLanding&cat=news&id=2158608 [SID:1234511145]). The first poster presentation described results that treating acute myeloid leukemia (AML) cell lines with imetelstat enhanced the effects of agents currently used for the treatment of AML. These data extend the rationale from prior non-clinical studies for the potential use of imetelstat in hematologic myeloid malignancies, such as AML, including in combination with standard therapies. The second poster presentation described results from non-clinical studies that provide further evidence of potential on-target mechanisms of telomerase inhibition by imetelstat underlying the reduction in platelets observed in previously conducted imetelstat clinical trials.

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The non-clinical studies were conducted by scientists at Janssen Research & Development, LLC and academic collaborators under the terms of the exclusive worldwide imetelstat license and collaboration agreement between Geron and Janssen Biotech, Inc. The poster presentations are available on Geron’s website at www.geron.com/presentations.

Impact of hypomethylating agents on hTERT expression and synergistic effect in combination with imetelstat, a telomerase inhibitor, in AML cell lines

AML cells express high levels of the telomerase catalytic subunit (hTERT). The expression of hTERT may be regulated through chemical changes to DNA, known as epigenetic modifications, such as the addition of a methyl group (methylation). Non-clinical studies by various cancer biologists have suggested a correlation between hTERT overexpression and hypermethylation in some cancers. Two compounds that are currently used for the treatment of AML, decitabine and 5-azacitidine, act as hypomethylating agents by inhibiting DNA methylating enzymes. Furthermore, these compounds have been reported to also reduce hTERT expression in AML cells in addition to inhibiting cell growth.

The aim of the non-clinical study in the AACR (Free AACR Whitepaper) poster was to determine whether combining hypomethylating agents and imetelstat can further inhibit AML cell viability in vitro compared with either agent alone. Combination treatment of the AML cell lines with either decitabine or 5-azacitidine followed by imetelstat, resulted in a greater reduction in cell viability or slower recovery of growth, respectively, than when a hypomethylating agent was administered alone. Similarly, when AML cell lines were treated with decitabine or 5-azacitidine followed by imetelstat, apoptosis, or cell death, increased in a dose-dependent manner.

Rusbuldt J, et al. 2016 AACR (Free AACR Whitepaper)

Myelosuppression in patients treated with the telomerase inhibitor imetelstat is not mediated through activation of toll-like receptors

Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns to trigger innate immune responses. For example, synthetic, single-stranded oligonucleotides with certain properties characteristic of bacteria and virus genomes activate the innate immune response through TLR9 signaling. In addition, TLR activation has been associated with lipopolysaccharide-induced thrombocytopenia in animal models.

The aim of the non-clinical study in the AACR (Free AACR Whitepaper) poster was to test a recent hypothesis that the thrombocytopenia observed in patients with myeloproliferative neoplasms (MPN) treated with imetelstat might occur through off-target effects by binding to and activating TLRs, such as TLR9. Results from the study suggest that the thrombocytopenia associated with imetelstat is not likely to be driven via interactions with TLRs. First, the oligonucleotide imetelstat is shorter and lacks certain features in its sequence required to activate TLR9. Second, in an assay for TLR activity, treatment with imetelstat at clinically relevant concentrations had no stimulatory effect on the majority of TLRs tested, including TLR9. Although a small induction of TLR8 was observed in the assay, such activity was not believed to be relevant because the induction was substantially lower than the positive control used in the experiment, and TLR8 has not been reported to be associated with thrombocytopenia.

The poster also cites results from previous non-clinical studies which suggest potential on-target mechanisms of telomerase inhibition for the observed thrombocytopenia in patients treated with imetelstat. Since telomerase activity is required for the differentiation of megakaryocyte progenitors into mature platelet-producing cells, previous ex vivo studies used cells taken from MPN patients and healthy individuals to show that treatment with imetelstat decreases hTERT expression and inhibits telomerase activity, which is concurrent with blocking the terminal maturation of normal megakaryocyte precursors, reducing the number of mature megakaryocytes available to produce platelets. Other prior ex vivo studies also included in the poster showed that imetelstat selectively inhibits the proliferation of malignant megakaryocyte progenitors from patients with essential thrombocythemia compared to normal progenitors from healthy individuals, suggesting that imetelstat may regulate telomerase differently in malignant versus normal cells.

Baerlocher GM, et al. 2016 AACR (Free AACR Whitepaper)

About Imetelstat

Imetelstat (GRN163L; JNJ-63935937) is a potent and specific inhibitor of telomerase that is administered by intravenous infusion. This first-in-class compound, discovered by Geron, is a specially designed and modified short oligonucleotide, which targets and binds directly with high affinity to the active site of telomerase. Preliminary clinical data suggest imetelstat has disease-modifying activity by inhibiting the progenitor cells of the malignant clones associated with hematologic myeloid malignancies in a relatively select manner. Most commonly reported adverse events in imetelstat clinical studies conducted previously by Geron included fatigue, gastrointestinal symptoms and cytopenias. Patients in those studies also experienced elevated liver enzymes, which resolved to normal or baseline in the majority of patients after imetelstat treatment was withdrawn. Imetelstat has not been approved for marketing by any regulatory authority.

About the Collaboration with Janssen

On November 13, 2014, Geron entered into an exclusive worldwide license and collaboration agreement with Janssen to develop and commercialize imetelstat for oncology, including hematologic myeloid malignancies, and all other human therapeutics uses. Under the terms of the agreement, Geron received an upfront payment of $35 million and is eligible to receive additional payments up to a potential total of $900 million for the achievement of development, regulatory and commercial milestones, as well as royalties on worldwide net sales. Certain regulatory, development, manufacturing and promotional activities are being managed through a joint governance structure, with Janssen responsible for these activities.

Janssen is conducting two imetelstat clinical trials: a Phase 2 clinical trial in patients with intermediate-2 and high risk myelofibrosis (MF) and a Phase 2/3 clinical trial in patients with low and intermediate-1 risk myelodysplastic syndromes (MDS). For more information about these clinical trials, please visit www.clinicaltrials.gov.

On April 20, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported that two daratumumab abstracts have been accepted for presentation at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, June 3 — 7 (Press release, Genmab, APR 20, 2016, View Source [SID:1234511144]). The titles of the abstracts are available on the ASCO (Free ASCO Whitepaper) website at www.asco.org via ASCO (Free ASCO Whitepaper)’s iPlanner. With the exception of the daratumumab Phase III Castor study data, which has been designated as a late breaking abstract by ASCO (Free ASCO Whitepaper), the full abstracts are scheduled to be published on the ASCO (Free ASCO Whitepaper) website on May 18 at 5:00PM EDT.

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Daratumumab Phase III Castor Study Data
Safety and efficacy data from the Phase III study of daratumumab in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma will be presented in the Plenary Session at the ASCO (Free ASCO Whitepaper) meeting on June 5. A total of 498 patients with relapsed or refractory multiple myeloma were enrolled in the study. The study met the primary endpoint of improving progression free survival (PFS); Hazard Ratio (HR) = 0.39, p<0.0001. The median PFS for patients treated with daratumumab has not been reached, compared to median PFS of 7.2 months for patients who did not receive daratumumab.

Daratumumab showed a manageable safety profile in the study consistent with the reported safety profile of monotherapy and background bortezomib/dexamethasone therapy.

As announced on March 30, 2016 an Independent Data Monitoring Committee recommended stopping the study as the primary endpoint had been reached at the time of the pre-specified interim analysis. Patients originally assigned to the bortezomib plus dexamethasone treatment group will be offered the option of receiving daratumumab following confirmed disease progression. Patients continue to be monitored for safety and overall survival.

Abstract details: Phase 3 randomized controlled study of daratumumab, bortezomib and dexamethasone (DVd) vs bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR study— Abstract # LBA4, Oral presentation, Sunday, June 5 at 3:10PM-3:25PM CDT

This abstract has been designated a late breaking abstract and the embargo will be lifted on Sunday, June 5 at 6:30AM CDT.
"ASCO is one of the premier medical conferences of the year and we are very pleased that highly impressive data with one of our key programs, daratumumab, will be presented again this year," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

List of Further Abstracts to Be Presented

Daratumumab
An open-label, dose-escalation Phase 1b study of subcutaneous daratumumab with recombinant human hyaluronidase in patients with relapsed or refractory multiple myeloma (PAVO) — Abstract # 333b, Trials in progress poster presentation, Monday, June 6 at 8:00AM -11.30AM CDT
The study described in this abstract is ongoing.

About DARZALEX (daratumumab)
DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.1 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. For more information, visit www.DARZALEX.com.

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through programmed cell death, or apoptosis,1,2 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,1,2 antibody-dependent cellular phagocytosis3,4 and antibody-dependent cellular cytotoxicity.1,2 In addition, daratumumab therapy results in a reduction of immune-suppressive myeloid derived suppressor cells (MDSCs) and subsets of regulatory T cells (Tregs) and B cells (Bregs), all of which express CD38. These reductions in MDSCs, Tregs and Bregs were accompanied by increases in CD4+ and CD8+ T cell numbers in both the peripheral blood and bone marrow.1

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing, and additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma, non-Hodgkin’s lymphoma and a solid tumor indication.

On April 20, 2016 Emergent BioSolutions Inc. (NYSE:EBS) reported that it presented preclinical data on its bispecific ADAPTIRTM (modular protein technology) molecule, ES425, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, Louisiana. The ES425 molecule is being developed as a potential therapeutic for triple-negative breast cancer (TNBC) (Press release, Emergent BioSolutions, APR 20, 2016, View Source;p=RssLanding&cat=news&id=2158702 [SID:1234511142]). This product candidate was constructed using the ADAPTIR platform technology and will be further developed by Emergent’s planned spin-off company Aptevo Therapeutics.

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ES425 is a bispecific immunotherapeutic protein that redirects T-cell cytotoxicity to tumor cells expressing ROR1 (receptor tyrosine kinase-like orphan receptor 1), an oncofetal antigen expressed on TNBC and other solid tumor and hematologic malignancies.
The presentation, "Anti-ROR1 x Anti-CD3 ADAPTIRTM Molecule, ES425, Redirects T-Cell Cytotoxicity and Inhibits Tumor Growth in Preclinical Models of Triple-Negative Breast Cancer," shared results of preclinical studies examining in vitro and in vivo activity of ES425. Results showed that ES425 efficiently redirected T-cell cytotoxicity against ROR1(+) cell lines at low picomolar concentrations in vitro. T cells were activated and proliferated in response to ES425 in the presence of ROR1(+) target cells. In vivo, pharmacokinetic analysis showed inhibition of tumor growth and an improvement in overall survival in preclinical models of TNBC.

"The encouraging preclinical data demonstrate that ES425 effectively redirects T-cell cytotoxicity in preclinical TNBC models and merits investigation as a potential therapeutic in TNBC and other malignancies," said Scott C. Stromatt, M.D., chief medical officer of Emergent BioSolutions. "Effective treatment of metastatic, triple-negative breast cancer remains a highly unmet medical need and we look forward to continuing development of this molecule to enable filing an Investigational New Drug application in the next year."

About the ADAPTIR Platform

ADAPTIR bispecific proteins are modular, single chain polypeptides that are comprised of two separate binding domains, a hinge segment, and an effector domain. They have a differentiated structure from monoclonal antibodies and can generate a unique signaling response. Some ADAPTIR molecules may mediate T-cell cytotoxicity by redirecting T cells against tumor cells and some by targeted cytokine delivery. In addition, other ADAPTIR proteins may mediate complement dependent cytotoxicity and Fc dependent cytotoxicity, similar to monoclonal antibodies. ADAPTIR and any and all Emergent BioSolutions Inc. brand, product, service and feature names, logos, and slogans are trademarks or registered trademarks of Emergent BioSolutions Inc. or its subsidiaries in the United States or other countries. All rights reserved.