Publications by authors named "Jacqueline McBride"

35 Publications

Intratumoral CD103+ CD8+ T cells predict response to PD-L1 blockade.

J Immunother Cancer 2021 Apr;9(4)

Department of OMNI Biomarker Development, Genentech Inc, South San Francisco, California, USA

Background: CD8+ tissue-resident memory T (T) cells, marked by CD103 () expression, are thought to actively suppress cancer progression, leading to the hypothesis that their presence in tumors may predict response to immunotherapy.

Methods: Here, we test this by combining high-dimensional single-cell modalities with bulk tumor transcriptomics from 1868 patients enrolled in lung and bladder cancer clinical trials of atezolizumab (anti-programmed cell death ligand 1 (PD-L1)).

Results: was identified as the most significantly upregulated gene in inflamed tumors. Tumor CD103+ CD8+ T cells exhibited a complex phenotype defined by the expression of checkpoint regulators, cytotoxic proteins, and increased clonal expansion.

Conclusions: Our analyses indeed demonstrate that the presence of CD103+ CD8+ T cells, quantified by tracking intratumoral CD103 expression, can predict treatment outcome, suggesting that patients who respond to PD-1/PD-L1 blockade are those who exhibit an ongoing antitumor T-cell response.
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http://dx.doi.org/10.1136/jitc-2020-002231DOI Listing
April 2021

Pharmacokinetics of the Monoclonal Antibody MHAA4549A Administered in Combination With Oseltamivir in Patients Hospitalized With Severe Influenza A Infection.

J Clin Pharmacol 2020 11 4;60(11):1509-1518. Epub 2020 Jul 4.

Genentech, Inc, South San Francisco, California, USA.

MHAA4549A is a human anti-influenza A monoclonal antibody developed to treat influenza A. We report MHAA4549A serum, nasopharyngeal, and tracheal aspirate pharmacokinetics from a phase 2b study in hospitalized patients with severe influenza A. Patients were randomized 1:1:1 into 3 groups receiving single intravenous doses of 3600 mg (n = 55) or 8400 mg (n = 47) MHAA4549A or placebo (n = 56). Patients also received oral oseltamivir twice daily for ≥5 days. Serum, nasopharyngeal, and tracheal aspirate pharmacokinetic samples were collected on days 1-60 from MHAA4549A-treated groups. Day 5 plasma samples from all groups were collected for assessing the pharmacokinetics of oseltamivir and its active metabolite, oseltamivir carboxylate. Noncompartmental pharmacokinetic analysis was performed using Phoenix WinNonlin. Data were collected during a preplanned interim analysis that became final when the trial terminated because of a lack of efficacy. Serum MHAA4549A concentrations were dose-proportional and biphasic. Mean MHAA4549A clearance was 288-350 mL/day, and mean half-life was 17.8-19.0 days. Nasopharyngeal MHAA4549A concentrations were non-dose-proportional. We detected MHAA4549A in tracheal aspirate samples, but intersubject variability was high. MHAA4549A serum and nasopharyngeal exposures were confirmed in all MHAA4549A-treated patients. Serum MHAA4549A had faster clearance and a shorter half-life in influenza A-infected patients compared with healthy subjects. MHAA4549A detection in tracheal aspirate samples indicated exposure in the lower respiratory tract. Oseltamivir and oseltamivir carboxylate exposures were similar between MHAA4549A-treated and placebo groups, suggesting a lack of MHAA4549A interference with oseltamivir pharmacokinetics.
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http://dx.doi.org/10.1002/jcph.1652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586956PMC
November 2020

Perinatal psychosocial assessment of women of refugee background.

Women Birth 2020 Jun 19. Epub 2020 Jun 19.

Centre for Educational Development Appraisal and Research, University of Warwick, Coventry, United Kingdom; Centre for Developmental Psychiatry & Psychology, Department of Psychiatry, School of Clinical Sciences at Monash Health, Monash University, Victoria, Australia.

Background: Women of refugee background may be particularly vulnerable to perinatal mental illness, possibly due to increased exposure to psychosocial stressors associated with their forced migration and post-resettlement adjustment.

Aim: This study aimed to compare psychosocial risk factors reported by women of refugee background receiving maternity services at a public hospital, to those reported by Australian-born women in the same hospital. It further aimed to examine the referrals offered, and accepted, by the women of refugee background reporting psychosocial risk factors for perinatal mental illness.

Methods: A retrospective hospital record review was conducted to compare the antenatal and postnatal psychosocial risk factors of 100 women of refugee background and 100 Australian-born women who gave birth at a public hospital in Victoria between 1 July 2015 and 30 April 2016, and who had completed the Maternity Psychosocial Needs Assessment.

Findings: Women of refugee background were more likely than Australian-born women to report financial concerns and low social support at antenatal assessment, but were less likely to report prior mental health problems than Australian-born women at either assessment point. Both groups reported low rates of family violence compared to published prevalence rates. Of the women of refugee background assessed antenatally, 23% were offered referrals, with 52% take-up. Postnatally, 11.2% were offered referrals, with 93% take-up.

Discussion/conclusion: This study showed elevated rates of psychosocial risk factors among women of refugee background, however, possible under-reporting of mental health problems and family violence raises questions regarding how to assess psychosocial risk factors with different cultural groups. Lower antenatal referral take-up suggests barriers to acceptance of referrals may exist during pregnancy.
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http://dx.doi.org/10.1016/j.wombi.2020.05.009DOI Listing
June 2020

Early Amplified Respiratory Bioactive Lipid Response Is Associated With Worse Outcomes in Pediatric Influenza-Related Respiratory Failure.

Open Forum Infect Dis 2020 May 9;7(5):ofaa122. Epub 2020 Apr 9.

Department of Biomarker Development, Genentech, Inc., South San Francisco, California, USA.

Background: Biomarkers are needed for early identification of patients at risk of severe complications from influenza infection, including prolonged respiratory failure and death. Eicosanoids are bioactive lipid mediators with pro- and anti-inflammatory properties produced in response to infection. This study assessed the relationships between the host bioactive lipid response, influenza viral load, and clinical outcomes.

Methods: Influenza-positive, intubated children ≤18 years old were enrolled across 26 US pediatric intensive care units (PICUs). Mass spectrometry was used to measure >100 lipid metabolites in endotracheal and nasopharyngeal samples. Influenza viral load was measured by quantitative polymerase chain reaction.

Results: Age and bacterial co-infection were associated with multiple bioactive lipids ( < .05). Influenza viral load was lower in patients with bacterial co-infection compared with those without, and pro-inflammatory bioactive lipids positively correlated with viral load in bacterially co-infected children ( < .05). Lipids associated with disease resolution correlated with viral load in patients without bacterial co-infection ( < .01). After adjusting for age and bacterial co-infection status, elevated pro- and anti-inflammatory lipids measured early in the intensive care unit course were associated with higher mortality, whereas influenza viral load and endotracheal cytokine levels were not associated with clinical outcomes. Prostaglandin E, arachidonic acid, docosahexaenoic acid, and 12-hydroxyeicosatetraenoic acid measured within 72 hours of PICU admission predicted death or prolonged (≥28 days) mechanical ventilator support (area under the curve, 0.72-0.79;  < .02) not explained by admission illness severity.

Conclusions: Children with influenza-related complications have early bioactive lipid responses that may reflect lung disease severity. Respiratory bioactive lipids are candidate prognostic biomarkers to identify children with the most severe clinical outcomes.
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http://dx.doi.org/10.1093/ofid/ofaa122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216777PMC
May 2020

A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial of MHAA4549A, a Monoclonal Antibody, plus Oseltamivir in Patients Hospitalized with Severe Influenza A Virus Infection.

Antimicrob Agents Chemother 2020 06 23;64(7). Epub 2020 Jun 23.

Genentech, Inc., South San Francisco, California, USA.

For patients hospitalized with severe influenza A virus infection, morbidity and mortality remain high. MHAA4549A, a human monoclonal antibody targeting the influenza A virus hemagglutinin stalk, has demonstrated pharmacological activity in animal studies and in a human influenza A challenge study. We evaluated the safety and efficacy of MHAA4549A plus oseltamivir against influenza A virus infection in hospitalized patients. The CRANE trial was a phase 2b randomized, double-blind, placebo-controlled study of single intravenous (i.v.) doses of placebo, 3,600 mg MHAA4549A, or 8,400 mg MHAA4549A each combined with oral oseltamivir (+OTV) in patients hospitalized with severe influenza A virus infection. Patients, enrolled across 68 clinical sites in 18 countries, were randomized 1:1:1. The primary outcome was the median time to normalization of respiratory function, defined as the time to removal of supplemental oxygen support to maintain a stable oxygen saturation (SpO) of ≥95%. Safety, pharmacokinetics, and effects on influenza viral load were also assessed. One hundred sixty-six patients were randomized and analyzed during a preplanned interim analysis. Compared to placebo+OTV, MHAA4549A+OTV did not significantly reduce the time to normalization of respiratory function (placebo+OTV, 4.28 days; 3,600 mg MHAA4549A+OTV, 2.78 days; 8,400 mg MHAA4549A+OTV, 2.65 days), nor did it improve other secondary clinical outcomes. Adverse event frequency was balanced across cohorts. MHAA4549A+OTV did not further reduce viral load versus placebo+OTV. In hospitalized patients with influenza A virus infection, MHAA4549A did not improve clinical outcomes over OTV alone. Variability in patient removal from oxygen supplementation limited the utility of the primary endpoint. Validated endpoints are needed to assess novel treatments for severe influenza A virus infection. (This study has been registered at ClinicalTrials.gov under registration no. NCT02293863.).
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http://dx.doi.org/10.1128/AAC.00352-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318030PMC
June 2020

"If you don't ask … you don't tell": Refugee women's perspectives on perinatal mental health screening.

Women Birth 2020 Sep 20;33(5):e429-e437. Epub 2019 Nov 20.

Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Level 1, 43-51 Kanooka Grove, Clayton, Victoria 3168, Australia; Department of Obstetrics & Gynaecology, Monash Health, 246 Clayton Road, Clayton, Victoria 3168, Australia. Electronic address:

Problem: National guidelines recommending mental health screening in pregnancy have not been implemented well in routine maternity care. Women of refugee background are likely to have experienced traumatic events and resettlement stressors, yet are not often identified with mental health issues in the perinatal period.

Background: Globally, perinatal mental health conditions affect up to 20% of women. Many difficulties in accessing mental health care in pregnancy exist for women of refugee background including stigma, and cultural and language barriers. Technology can provide an efficient and effective method to overcome some of these barriers.

Aim: To determine if a digital perinatal mental health screening program is feasible and acceptable for women of refugee background.

Methods: This qualitative evaluation study used focus group and semi-structured telephone interviews with refugee and migrant women from four communities. Interpreters were used with women who spoke little or no English. Data were analysed using both an inductive and deductive approach to thematic analysis.

Findings: Under the three key themes: 'Women's experiences of perinatal mental health screening in pregnancy'; 'Barriers and enablers to accessing ongoing mental health care' and 'Improvements to the program: the development of audio versions', women found the program feasible and acceptable.

Discussion: Screening using a mobile device offered women more privacy and opened up discussions with midwives on emotional health. Improvements in service coordination and access to further mental health management for women is required.

Conclusion: Perinatal mental health screening is an acceptable and feasible option for women of refugee background. Integrated models of care, case management, and patient navigators are options for improvements in uptake of referral and treatment services.
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http://dx.doi.org/10.1016/j.wombi.2019.10.003DOI Listing
September 2020

"If you don't ask … you don't tell": Refugee women's perspectives on perinatal mental health screening.

Women Birth 2020 Sep 20;33(5):e429-e437. Epub 2019 Nov 20.

Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Level 1, 43-51 Kanooka Grove, Clayton, Victoria 3168, Australia; Department of Obstetrics & Gynaecology, Monash Health, 246 Clayton Road, Clayton, Victoria 3168, Australia. Electronic address:

Problem: National guidelines recommending mental health screening in pregnancy have not been implemented well in routine maternity care. Women of refugee background are likely to have experienced traumatic events and resettlement stressors, yet are not often identified with mental health issues in the perinatal period.

Background: Globally, perinatal mental health conditions affect up to 20% of women. Many difficulties in accessing mental health care in pregnancy exist for women of refugee background including stigma, and cultural and language barriers. Technology can provide an efficient and effective method to overcome some of these barriers.

Aim: To determine if a digital perinatal mental health screening program is feasible and acceptable for women of refugee background.

Methods: This qualitative evaluation study used focus group and semi-structured telephone interviews with refugee and migrant women from four communities. Interpreters were used with women who spoke little or no English. Data were analysed using both an inductive and deductive approach to thematic analysis.

Findings: Under the three key themes: 'Women's experiences of perinatal mental health screening in pregnancy'; 'Barriers and enablers to accessing ongoing mental health care' and 'Improvements to the program: the development of audio versions', women found the program feasible and acceptable.

Discussion: Screening using a mobile device offered women more privacy and opened up discussions with midwives on emotional health. Improvements in service coordination and access to further mental health management for women is required.

Conclusion: Perinatal mental health screening is an acceptable and feasible option for women of refugee background. Integrated models of care, case management, and patient navigators are options for improvements in uptake of referral and treatment services.
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http://dx.doi.org/10.1016/j.wombi.2019.10.003DOI Listing
September 2020

The role of integrins in the pathogenesis of inflammatory bowel disease: Approved and investigational anti-integrin therapies.

Med Res Rev 2020 01 19;40(1):245-262. Epub 2019 Jun 19.

Department of Research and Early Development, Genentech, South San Francisco, California.

Inflammatory bowel disease (IBD) is characterized by uncontrolled inflammation in the gastrointestinal tract. The underlying pathobiology of IBD includes an increase in infiltrating gut-homing lymphocytes. Although lymphocyte homing is typically a tightly regulated and stepwise process involving multiple integrins and adhesion molecules expressed on endothelial cells, the distinct roles of integrin-expressing immune cells is not fully understood in the pathology of IBD. In this review, we detail the involvement of integrins expressed on specific lymphocyte subsets in the pathogenesis of IBD and discuss the current status of approved and investigational integrin-targeted therapies.
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http://dx.doi.org/10.1002/med.21601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973243PMC
January 2020

In Vivo Assessment of Antibody-Dependent Enhancement of Influenza B Infection.

Toxicol Sci 2019 06;169(2):409-421

Department of Safety Assessment, Genentech, Inc., South San Francisco, California 94080.

A theoretical safety concern proposed in the influenza literature is that therapeutic antiviral antibodies could have the potential for antibody-dependent enhancement (ADE) of infection and disease. ADE may occur when virus-specific antibodies at subtherapeutic, nonneutralizing concentrations facilitate virus uptake and, in some cases, enhance replication, which can lead to an exacerbation of virus-mediated disease. Alternatively, ADE may occur due to antibody-dependent complement activation exacerbating virus-mediated disease in the absence of increased replication. As a result of this theoretical safety concern, safety assessment of anti-influenza antibodies may include an in vivo evaluation of ADE of infection and/or disease. These studies were conducted to investigate the potential of MHAB5553A, a broadly specific, neutralizing therapeutic anti-influenza B antibody, to elicit ADE of infection and disease in mouse models of influenza B infection. In parallel studies, female DBA/2J mice were infected with either influenza B/Victoria/504/2000 or influenza B/Brisbane/60/2008 representing distinct lineages. Assessment of ADE was based on an integration of results from multiple endpoints, including infectious lung viral titers and genomes, body weight, mortality, lung weight, and histopathology. In these studies, the high dose of 15 mg/kg MHAB5553A resulted in substantial attenuation of influenza pneumonia, with more modest effects at 1.5 mg/kg; whereas MHAB5553A treatment at 0.15 or 0.015 mg/kg was generally comparable to vehicle-treated controls. Our results demonstrate that MHAB5553A across a broad range of doses did not enhance primary influenza B infection or disease in this model, and represent a nonclinical de-risking of the ADE potential with this antibody.
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http://dx.doi.org/10.1093/toxsci/kfz053DOI Listing
June 2019

Correlation of Cytomegalovirus (CMV) Disease Severity and Mortality With CMV Viral Burden in CMV-Seropositive Donor and CMV-Seronegative Solid Organ Transplant Recipients.

Open Forum Infect Dis 2019 Feb 14;6(2):ofz003. Epub 2019 Jan 14.

Department of Medicine and the Division of Geographic Medicine and Infectious Disease, Tufts Medical Center, and Tufts University School of Medicine, Boston, Masschusetts.

Background: The rate of cytomegalovirus (CMV) viral load increase and peak viral loads are associated with CMV disease in kidney and liver transplant recipients, but relationships to disease severity or mortality have not been shown.

Methods: Using stored serial serum specimens from renal (n = 59) and liver (n = 35) transplant recipients (D+R-; CMV-seropositive donors, CMV-seronegative recipients) from 2 prospective, randomized, controlled, interventional prophylaxis trials of CMV immune globulin (CMVIG), CMV viral load was measured using the COBAS quantitative polymerase chain reaction assay and the World Health Organization CMV standard. Patients with severe CMV-associated disease were classified according to trial definitions. Pairwise comparisons of mean viral load among deceased, surviving diseased, and nondiseased patients were analyzed by 2-way analysis of variance. To determine if viral load could predict mortality, receiver operating characteristic (ROC) curves were constructed using area under the curve (AUC) of the viral load and peak viral concentration (V).

Results: Viral load (mean log [AUC], peak viral load [V]) for patients with severe CMV disease was significantly higher compared with nondiseased patients ( < .001). Similarly, higher viral burden was significantly associated with mortality ( < .001). Viral load AUC and V AUROCs for predicting mortality were 0.796 and 0.824, respectively, for renal patients, and 0.769 and 0.807, respectively, for liver patients.

Conclusions: Using specimens from studies preceding the antiviral prophylaxis era, CMV viral load was associated with severe CMV disease and death, supporting CMV viral load quantification as a proxy for CMV disease severity and disease-associated mortality end points in solid organ transplantation.
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http://dx.doi.org/10.1093/ofid/ofz003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366655PMC
February 2019

Cellular Mechanisms of Etrolizumab Treatment in Inflammatory Bowel Disease.

Front Pharmacol 2019 1;10:39. Epub 2019 Feb 1.

Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Kussmaul Campus for Medical Research and Translational Research Center, Erlangen, Germany.

Anti-integrin therapy is a new frontline strategy in the treatment of inflammatory bowel diseases (IBD). The anti-β7 integrin antibody etrolizumab is currently being investigated for safety and efficacy in Crohn's disease (CD) and ulcerative colitis (UC) in several phase III trials. Mechanistically, etrolizumab is known to block β7 integrin ligand binding and reduces intestinal trafficking of β7-expressing cells. Etrolizumab blocks β7 integrin ligand binding and reduces β7-positive lymphocyte migration and retention in the inflamed gut mucosa, but the exact mechanisms by which this inhibition occurs are not fully understood. Cellular effects of etrolizumab or etrolizumab surrogate antibody (etrolizumab-s) were investigated in cell culture models and analyzed by flow cytometry, fluorescence microscopy, ImageStream, stimulated emission depletion (STED) microscopy and functional dynamic adhesion assays. Moreover, effects on α4β7 integrin were compared with the pharmacodynamically similar antibody vedolizumab. As demonstrated by several different approaches, etrolizumab and etrolizumab-s treatment led to internalization of β7 integrin. This resulted in impaired dynamic adhesion to MAdCAM-1. Internalized β7 integrin localized in endosomes and re-expression of β7 was dependent on protein synthesis. etrolizumab treatment did not lead to cellular activation or cytokine secretion and did not induce cytotoxicity. Internalization of α4β7 integrin was increased with etrolizumab compared with vedolizumab. Our data suggest that etrolizumab does not elicit secondary effector functions on the single cell level. Integrin internalization may be an important mechanism of action of etrolizumab, which might explain some but not all immunological effects observed with etrolizumab.
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http://dx.doi.org/10.3389/fphar.2019.00039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367223PMC
February 2019

Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma.

Blood Cancer J 2019 02 4;9(2):17. Epub 2019 Feb 4.

Sarah Cannon Research Institute, Nashville, TN, USA.

FcRH5 is a cell surface marker enriched on malignant plasma cells when compared to other hematologic malignancies and normal tissues. DFRF4539A is an anti-FcRH5 antibody-drug conjugated to monomethyl auristatin E (MMAE), a potent anti-mitotic agent. This phase I study assessed safety, tolerability, maximum tolerated dose (MTD), anti-tumor activity, and pharmacokinetics of DFRF4539A in patients with relapsed/refractory multiple myeloma. DFRF4539A was administered at 0.3-2.4 mg/kg every 3 weeks or 0.8-1.1 mg/kg weekly as a single-agent by intravenous infusion to 39 patients. Exposure of total antibody and antibody-conjugate-MMAE analytes was linear across the doses tested. There were 37 (95%) adverse events (AEs), 8 (21%) serious AEs, and 15 (39%) AEs ≥ grade 3. Anemia (n = 10, 26%) was the most common AE considered related to DFRF4539A. Two cases of grade 3 acute renal failure were attributed to DFRF4539A. There were no deaths; the MTD was not reached. DFRF4539A demonstrated limited activity in patients at the doses tested with 2 (5%) partial response, 1 (3%) minimal response, 18 (46%) stable disease, and 16 (41%) progressive disease. FcRH5 was confirmed to be expressed and occupied by antibody post-treatment and thus remains a valid myeloma target. Nevertheless, this MMAE-based antibody-drug-conjugate targeting FcRH5 was unsuccessful for myeloma.
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http://dx.doi.org/10.1038/s41408-019-0178-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362066PMC
February 2019

Pharmacokinetics and Exposure-Response Analysis of RG7667, a Combination of Two Anticytomegalovirus Monoclonal Antibodies, in a Phase 2a Randomized Trial To Prevent Cytomegalovirus Infection in High-Risk Kidney Transplant Recipients.

Antimicrob Agents Chemother 2018 02 25;62(2). Epub 2018 Jan 25.

Genentech, Inc., South San Francisco, California, USA.

RG7667, a novel combination of two anticytomegalovirus (anti-CMV) monoclonal IgG1 antibodies (MCMV5322A and MCMV3068A), was designed to block CMV entry into host cells. It was developed as a potential therapy for preventing CMV infection and disease in transplant recipients. RG7667 was assessed for preventing CMV infection in a phase 2a trial with CMV-seronegative recipients of kidney transplants from CMV-seropositive donors. The patients received 4 intravenous doses of RG7667 (10 mg/kg of body weight of each antibody, = 60) or placebo ( = 60) at the time of the transplant and at 1, 4, and 8 weeks after the transplant. Serum samples were collected for pharmacokinetic (PK) analysis and antidrug antibody (ADA) evaluation. To guide future dose selection, the relationships between RG7667 exposure and pharmacological activity were evaluated. MCMV5322A and MCMV3068A exposures were confirmed in all RG7667-treated patients. Mean clearances for MCMV5322A and MCMV3068A were 2.97 and 2.65 ml/day/kg, respectively, and the terminal half-lives of MCMV5322A and MCMV3068A were 26.9 and 27.4 days, respectively. The ADA incidence was low and was not associated with lower drug exposure. Patients with RG7667 or component antibody exposures greater than the respective median values had a lower incidence of viremia at 12 weeks and 24 weeks after transplantation and a longer delayed time to detectable CMV viremia than patients with exposures less than the median values. MCMV5322A and MCMV3068A exhibited expected IgG1 PK profiles in high-risk kidney transplant recipients, consistent with the earlier PK behavior of RG7667 in healthy subjects. Higher drug exposure was associated with better anti-CMV pharmacological activity. (This study has been registered at ClinicalTrials.gov under identifier NCT01753167.).
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http://dx.doi.org/10.1128/AAC.01108-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786805PMC
February 2018

Phase 2 Randomized Trial of the Safety and Efficacy of MHAA4549A, a Broadly Neutralizing Monoclonal Antibody, in a Human Influenza A Virus Challenge Model.

Antimicrob Agents Chemother 2017 11 24;61(11). Epub 2017 Oct 24.

Genentech, Inc., South San Francisco, California, USA.

MHAA4549A, a human monoclonal antibody targeting the hemagglutinin stalk region of influenza A virus (IAV), is being developed as a therapeutic for patients hospitalized with severe IAV infection. The safety and efficacy of MHAA4549A were assessed in a randomized, double-blind, placebo-controlled, dose-ranging study in a human IAV challenge model. One hundred healthy volunteers were inoculated with A/Wisconsin/67/2005 (H3N2) IAV and, 24 to 36 h later, administered a single intravenous dose of either placebo, MHAA4549A (400, 1,200, or 3,600 mg), or a standard oral dose of oseltamivir. Subjects were assessed for safety, pharmacokinetics (PK), and immunogenicity. The intent-to-treat-infected (ITTI) population was assessed for changes in viral load, influenza symptoms, and inflammatory biomarkers. MHAA4549A was well tolerated in all IAV challenge subjects. The 3,600-mg dose of MHAA4549A significantly reduced the viral burden relative to that of the placebo as determined by the area under the curve (AUC) of nasopharyngeal virus infection, quantified using quantitative PCR (98%) and 50% tissue culture infective dose (TCID) (100%) assays. Peak viral load, duration of viral shedding, influenza symptom scores, mucus weight, and inflammatory biomarkers were also reduced. Serum PK was linear with a half-life of ∼23 days. No MHAA4549A-treated subjects developed anti-drug antibodies. In conclusion, MHAA4549A was well tolerated and demonstrated statistically significant and substantial antiviral activity in an IAV challenge model. (This study has been registered at ClinicalTrials.gov under identifier NCT01980966.).
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http://dx.doi.org/10.1128/AAC.01154-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655070PMC
November 2017

Tumour and host cell PD-L1 is required to mediate suppression of anti-tumour immunity in mice.

Nat Commun 2017 02 21;8:14572. Epub 2017 Feb 21.

Department of Cancer Immunology, Genentech, Inc., South San Francisco, California 94080, USA.

Expression of PD-L1, the ligand for T-cell inhibitory receptor PD-1, is one key immunosuppressive mechanism by which cancer avoids eradication by the immune system. Therapeutic use of blocking antibodies to PD-L1 or its receptor PD-1 has produced unparalleled, durable clinical responses, with highest likelihood of response seen in patients whose tumour or immune cells express PD-L1 before therapy. The significance of PD-L1 expression in each cell type has emerged as a central and controversial unknown in the clinical development of immunotherapeutics. Using genetic deletion in preclinical mouse models, here we show that PD-L1 from disparate cellular sources, including tumour cells, myeloid or other immune cells can similarly modulate the degree of cytotoxic T-cell function and activity in the tumour microenvironment. PD-L1 expression in both the host and tumour compartment contribute to immune suppression in a non-redundant fashion, suggesting that both sources could be predictive of sensitivity to therapeutic agents targeting the PD-L1/PD-1 axis.
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http://dx.doi.org/10.1038/ncomms14572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321797PMC
February 2017

Anti-CD22 and anti-CD79b antibody-drug conjugates preferentially target proliferating B cells.

Br J Pharmacol 2017 04 6;174(8):628-640. Epub 2017 Mar 6.

Department of Pharmacodynamic Biomarkers, Genentech, Inc., South San Francisco, CA, USA.

Background And Purpose: CD22 and CD79b are cell-surface receptors expressed on B-cell-derived malignancies such as non-Hodgkin's lymphoma (NHL). An anti-mitotic agent, monomethyl auristatin E, was conjugated to anti-CD22 and anti-CD79b antibodies to develop target-specific therapies for NHL. The mechanism of action (MOA) and pharmacological and pharmacokinetic (PK) profiles of these antibody-drug conjugates (ADCs) were investigated in cynomolgus monkeys.

Experimental Approach: Animals were administered anti-CD22 or anti-CD79b ADCs, respective unconjugated antibodies or vehicle. Pharmacodynamic effects on total and proliferating B cells and serum PK were then assessed. Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) of the ADCs were evaluated in vitro.

Key Results: Depletion of B cells was observed after administration of either ADC or the respective unconjugated antibodies. An extended duration of depletion was observed in animals administered ADCs. Similarly, preferential depletion of proliferating B cells in blood and germinal centre B cells in spleen were only observed in animals administered ADCs. Serum PK profiles of ADCs and respective unconjugated antibodies were comparable. In vitro, anti-human CD22 and anti-human CD79b antibodies showed no or only moderate ADCC activity, respectively; neither antibody had CDC activity.

Conclusions And Implications: The findings support the proposed MOA: initial depletion of total B cells by antibody-mediated opsonization, followed by preferential, sustained depletion of proliferating B cells by the auristatin conjugate due to its anti-mitotic action. Delivering potent anti-mitotic agents to B cells via the specificity of monoclonal antibodies provides a means to eliminate pathogenic B cells in NHL with improved risk-benefit profiles over traditional chemotherapeutics.
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http://dx.doi.org/10.1111/bph.13697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5368047PMC
April 2017

Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial of RG7667, a Combination Monoclonal Antibody, for Prevention of Cytomegalovirus Infection in High-Risk Kidney Transplant Recipients.

Antimicrob Agents Chemother 2017 02 24;61(2). Epub 2017 Jan 24.

Genentech, Inc., South San Francisco, California, USA

Cytomegalovirus (CMV) infection is a significant complication after kidney transplantation. We examined the ability of RG7667, a combination of two monoclonal antibodies, to prevent CMV infection in high-risk kidney transplant recipients in a randomized, double-blind, placebo-controlled trial. CMV-seronegative recipients of a kidney transplant from a CMV-seropositive donor (D+R-) were randomized to receive RG7667 (n = 60) or placebo (n = 60) at the time of transplant and 1, 4, and 8 weeks posttransplant. Patients were monitored for CMV viremia every 1 to 2 weeks posttransplant for 24 weeks. Patients who had seroconverted (D+R+) or withdrawn before dosing were excluded from the analysis (n = 4). CMV viremia occurred in 27 of 59 (45.8%) patients receiving RG7667 and 35 of 57 (61.4%) patients receiving placebo (stratum-adjusted difference, 15.3%; P = 0.100) within 12 weeks posttransplant and in 30 of 59 (50.8%) patients receiving RG7667 and 40 of 57 (70.2%) patients receiving placebo (stratum-adjusted difference, 19.3%; P = 0.040) within 24 weeks posttransplant. Median time to CMV viremia was 139 days in patients receiving RG7667 compared to 46 days in patients receiving placebo (hazard ratio, 0.53; P = 0.009). CMV disease was less common in the RG7667 than placebo group (3.4% versus 15.8%; P = 0.030). Adverse events were generally balanced between treatment groups. In high-risk kidney transplant recipients, RG7667 was well tolerated, numerically reduced the incidence of CMV infection within 12 and 24 weeks posttransplant, delayed time to CMV viremia, and was associated with less CMV disease than the placebo. (This study has been registered at ClinicalTrials.gov under registration no. NCT01753167.).
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http://dx.doi.org/10.1128/AAC.01794-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278717PMC
February 2017

Generation and Protective Ability of Influenza Virus-Specific Antibody-Dependent Cellular Cytotoxicity in Humans Elicited by Vaccination, Natural Infection, and Experimental Challenge.

J Infect Dis 2016 09 28;214(6):945-52. Epub 2016 Jun 28.

Laboratory of Infectious Diseases.

Background: Nonneutralizing antibodies (Abs) involved in antibody-dependent cellular cytotoxicity (ADCC) may provide some protection from influenza virus infection. The ability of influenza vaccines to induce ADCC-mediating Abs (ADCC-Abs) in adults and children is unclear.

Methods: We quantified ADCC-Abs in serum samples from adults who received a dose of inactivated subunit vaccine (ISV) targeting monovalent 2009 pandemic influenza A(H1N1) virus or live-attenuated influenza vaccine (LAIV) or who had laboratory-confirmed influenza A(H1N1) virus infection. We also measured ADCC-Abs in children who either received a dose of trivalent seasonal ISV followed by trivalent seasonal LAIV or 2 doses of LAIV. Finally, we assessed the ability of low and high ADCC-Ab titers to protect adults from experimental challenge with influenza A/Wisconsin/67/131/2005(H3N2) virus.

Results: Adults and children who received a dose of ISV had a robust increase in ADCC-Ab titers to both recombinant hemagglutinin (rHA) protein and homologous virus-infected cells. There was no detectable increase in titers of ADCC-Abs to rHA or virus-infected cells in adults and children who received LAIV. Higher titers (≥320) of preexisting ADCC-Abs were associated with lower virus replication and a significant reduction in total symptom scores in experimentally infected adults.

Conclusions: ADCC-Ab titers increased following experimental influenza virus infection in adults and after ISV administration in both children and adults.
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http://dx.doi.org/10.1093/infdis/jiw262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996149PMC
September 2016

Two Escape Mechanisms of Influenza A Virus to a Broadly Neutralizing Stalk-Binding Antibody.

PLoS Pathog 2016 06 28;12(6):e1005702. Epub 2016 Jun 28.

Infectious Diseases Department, Genentech, South San Francisco, California, United States of America.

Broadly neutralizing antibodies targeting the stalk region of influenza A virus (IAV) hemagglutinin (HA) are effective in blocking virus infection both in vitro and in vivo. The highly conserved epitopes recognized by these antibodies are critical for the membrane fusion function of HA and therefore less likely to be permissive for virus mutational escape. Here we report three resistant viruses of the A/Perth/16/2009 strain that were selected in the presence of a broadly neutralizing stalk-binding antibody. The three resistant viruses harbor three different mutations in the HA stalk: (1) Gln387Lys; (2) Asp391Tyr; (3) Asp391Gly. The Gln387Lys mutation completely abolishes binding of the antibody to the HA stalk epitope. The other two mutations, Asp391Tyr and Asp391Gly, do not affect antibody binding at neutral pH and only slightly reduce binding at low pH. Interestingly, they enhance the fusion ability of the HA, representing a novel mechanism that allows productive membrane fusion even in the presence of antibody and hence virus escape from antibody neutralization. Therefore, these mutations illustrate two different resistance mechanisms used by IAV to escape broadly neutralizing stalk-binding antibodies. Compared to the wild type virus, the resistant viruses release fewer progeny viral particles during replication and are more sensitive to Tamiflu, suggesting reduced viral fitness.
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http://dx.doi.org/10.1371/journal.ppat.1005702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924800PMC
June 2016

Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor.

MAbs 2016 26;8(3):593-603. Epub 2016 Feb 26.

a Genentech Research and Early Development, Genentech, Inc. , South San Francisco , CA , USA.

MPDL3280A is a human monoclonal antibody that targets programmed cell death-1 ligand 1 (PD-L1), and exerts anti-tumor activity mainly by blocking PD-L1 interaction with programmed cell death-1 (PD-1) and B7.1. It is being investigated as a potential therapy for locally advanced or metastatic malignancies. The purpose of the study reported here was to characterize the pharmacokinetics, pharmacodynamics, tissue distribution and tumor penetration of MPDL3280A and/or a chimeric anti-PD-L1 antibody PRO304397 to help further clinical development. The pharmacokinetics of MPDL3280A in monkeys at 0.5, 5 and 20 mg · kg(-1) and the pharmacokinetics / pharmacodynamics of PRO304397 in mice at 1, 3 10 mg · kg(-1) were determined after a single intravenous dose. Tissue distribution and tumor penetration for radiolabeled PRO304397 in tumor-bearing mouse models were determined. The pharmacokinetics of MPDL3280A and PRO304397 were nonlinear in monkeys and mice, respectively. Complete saturation of PD-L1 in blood in mice was achieved at serum concentrations of PRO304397 above ∼ 0.5 µg · mL(-1). Tissue distribution and tumor penetration studies of PRO304397 in tumor-bearing mice indicated that the minimum tumor interstitial to plasma radioactivity ratio was ∼ 0.3; saturation of target-mediated uptake in non-tumor tissues and desirable exposure in tumors were achieved at higher serum concentrations, and the distribution into tumors was dose-and time-dependent. The biodistribution data indicated that the efficacious dose is mostly likely higher than that estimated based on simple pharmacokinetics/pharmacodynamics in blood. These data also allowed for estimation of the target clinical dose for further development of MPDL3280A.
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http://dx.doi.org/10.1080/19420862.2015.1136043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966836PMC
December 2016

A Phase II study of the efficacy and safety of rontalizumab (rhuMAb interferon-α) in patients with systemic lupus erythematosus (ROSE).

Ann Rheum Dis 2016 Jan 2;75(1):196-202. Epub 2015 Jun 2.

Genentech, South San Francisco, California, USA.

Objectives: To examine the safety and efficacy of rontalizumab, a humanised IgG1 anti-interferon α (anti-IFN-α) monoclonal antibody, in patients with moderate-to-severe systemic lupus erythematosus (SLE).

Methods: Patients with active SLE were randomised (2:1) to 750 mg intravenous rontalizumab every 4 weeks or placebo (Part 1), and 300 mg subcutaneous rontalizumab every 2 weeks or placebo (Part 2).

Background: Hydroxychloroquine and corticosteroids were allowed. Patients taking immunosuppressants at baseline were required per protocol to discontinue. Efficacy end points included reduction in disease activity by British Isles Lupus Disease Activity Group (BILAG)-2004 (primary), and SLE response index (SRI, secondary) at Week 24. Efficacy was also examined by an exploratory measure of IFN-regulated gene expression (interferon signature metric, ISM).

Results: Patients (n=238) received rontalizumab (n=159) or placebo (n=79). At baseline, the mean Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI) score in all cohorts was ~10, and 75.6% of patients had a high ISM (ISM-High). Efficacy response rates by BILAG and SRI were similar between rontalizumab and placebo groups. However, in the exploratory subgroup of ISM-Low patients, SRI response was higher and steroid use was lower in the rontalizumab-treated patients. There was also a reduction in SELENA-SLEDAI flare index rates (HR 0.61, 0.46 to 0.81, p=0.004) in this subgroup. Adverse events were similar between placebo and rontalizumab groups.

Conclusions: The primary and secondary end points of this trial were not met in all patients or in patients with high ISM scores. In an exploratory analysis, rontalizumab treatment was associated with improvements in disease activity, reduced flares and decreased steroid use in patients with SLE with low ISM scores.

Trial Registration Number: NCT00962832.
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http://dx.doi.org/10.1136/annrheumdis-2014-206090DOI Listing
January 2016

Association of the interferon signature metric with serological disease manifestations but not global activity scores in multiple cohorts of patients with SLE.

Lupus Sci Med 2015 28;2(1):e000080. Epub 2015 Mar 28.

Department of ITGR Diagnostics Discovery , Genentech , South San Francisco, California , USA.

Objectives: The interferon (IFN) signature (IS) in patients with systemic lupus erythematosus (SLE) includes over 100 genes induced by type I IFN pathway activation. We developed a method to quantify the IS using three genes-the IS metric (ISM)-and characterised the clinical characteristics of patients with SLE with different ISM status from multiple clinical trials.

Methods: Blood microarray expression data from a training cohort of patients with SLE confirmed the presence of the IS and identified surrogate genes. We assayed these genes in a quantitative PCR (qPCR) assay, yielding an ISM from the IS. The association of ISM status with clinical disease characteristics was assessed in patients with extrarenal lupus and lupus nephritis from four clinical trials.

Results: Three genes, HERC5, EPSTI and CMPK2, correlated well with the IS (p>0.96), and composed the ISM qPCR assay. Using the 95th centile for healthy control data, patients with SLE from different studies were classified into two ISM subsets-ISM-Low and ISM-High-that are longitudinally stable over 36 weeks. Significant associations were identified between ISM-High status and higher titres of anti-dsDNA antibodies, presence of anti extractable nuclear antigen autoantibodies, elevated serum B cell activating factor of the tumour necrosis factor family (BAFF) levels, and hypocomplementaemia. However, measures of overall clinical disease activity were similar for ISM-High and ISM-Low groups.

Conclusions: The ISM is an IS biomarker that divides patients with SLE into two subpopulations-ISM-High and ISM-Low-with differing serological manifestations. The ISM does not distinguish between high and low disease activity, but may have utility in identifying patients more likely to respond to treatment(s) targeting IFN-α.

Clinicaltrialsgov Registration Number: NCT00962832.
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http://dx.doi.org/10.1136/lupus-2014-000080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4379884PMC
April 2015

DCDT2980S, an anti-CD22-monomethyl auristatin E antibody-drug conjugate, is a potential treatment for non-Hodgkin lymphoma.

Mol Cancer Ther 2013 Jul 18;12(7):1255-65. Epub 2013 Apr 18.

Genentech Research and Early Development, 1 DNA Way, South San Francisco, CA 94080, USA.

Antibody-drug conjugates (ADC), potent cytotoxic drugs linked to antibodies via chemical linkers, allow specific targeting of drugs to neoplastic cells. We have used this technology to develop the ADC DCDT2980S that targets CD22, an antigen with expression limited to B cells and the vast majority of non-Hodgkin lymphomas (NHL). DCDT2980S consists of a humanized anti-CD22 monoclonal IgG1 antibody with a potent microtubule-disrupting agent, monomethyl auristatin E (MMAE), linked to the reduced cysteines of the antibody via a protease cleavable linker, maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-vc-PAB). We describe the efficacy, safety, and pharmacokinetics of DCDT2980S in animal models to assess its potential as a therapeutic for the treatment of B-cell malignancies. We did not find a strong correlation between in vitro or in vivo efficacy and CD22 surface expression, nor a correlation of sensitivity to free drug and in vitro potency. We show that DCDT2980S was capable of inducing complete tumor regression in xenograft mouse models of NHL and can be more effective than rituximab plus combination chemotherapy at drug exposures that were well tolerated in cynomolgus monkeys. These results suggest that DCDT2980S has an efficacy, safety, and pharmacokinetics profile that support potential treatment of NHL.
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http://dx.doi.org/10.1158/1535-7163.MCT-12-1173DOI Listing
July 2013

Safety and pharmacodynamics of rontalizumab in patients with systemic lupus erythematosus: results of a phase I, placebo-controlled, double-blind, dose-escalation study.

Arthritis Rheum 2012 Nov;64(11):3666-76

Genentech, South San Francisco, California, USA.

Objective: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies and inflammation in multiple organ systems. Elevation of messenger RNA levels of interferon (IFN)-regulated genes (IRGs) has been described in the peripheral blood of SLE patients and has been associated with disease activity. The safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of rontalizumab, a humanized IgG1 monoclonal antibody that neutralizes IFNα, were assessed in a phase I dose-escalation study of single and repeat doses of rontalizumab in adults with mildly active SLE. The present report describes the safety results and the impact of rontalizumab on expression of IRGs, IFN-inducible proteins, and autoantibodies.

Methods: Patients were enrolled into dose groups ranging from 0.3 to 10 mg/kg, administered via intravenous (IV) or subcutaneous routes. Expression levels of 7 IRGs and IFN-inducible serum proteins were monitored as potential biomarkers for the PD activity of rontalizumab.

Results: An acceptable safety profile was demonstrated for rontalizumab in patients with SLE. Prespecified criteria for dose-limiting toxicity were not met. The incidence of serious adverse events was comparable across cohorts. The PK properties were as expected for an IgG1 monoclonal antibody and were proportional to dose. Following administration of rontalizumab, a rapid decline in the expression of IRGs was observed in the 3 mg/kg and 10 mg/kg IV cohorts, and this effect could be sustained with repeat dosing. There was no apparent decline in the levels of IFN-inducible proteins or levels of anti-double-stranded DNA and anti-extractable nuclear antigen autoantibodies following treatment with rontalizumab.

Conclusion: The preliminary safety, PK profile, and observed PD effects of rontalizumab support further evaluation of its safety and efficacy in SLE.
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http://dx.doi.org/10.1002/art.34632DOI Listing
November 2012

FcRL5 as a target of antibody-drug conjugates for the treatment of multiple myeloma.

Mol Cancer Ther 2012 Oct 17;11(10):2222-32. Epub 2012 Jul 17.

Genentech Research and Early Development. 1 DNA Way, South San Francisco, CA 94080, USA.

Fc receptor-like 5 (FcRL5/FcRH5/IRTA2/CD307) is a surface protein expressed selectively on B cells and plasma cells. We found that FcRL5 was expressed at elevated levels on the surface of plasma cells from the bone marrow of patients diagnosed with multiple myeloma. This prevalence in multiple myeloma and narrow pattern of normal expression indicate that FcRL5 could be a target for antibody-based therapies for multiple myeloma, particularly antibody-drug conjugates (ADC), potent cytotoxic drugs linked to antibodies via specialized chemical linkers, where limited expression on normal tissues is a key component to their safety. We found that FcRL5 is internalized upon antibody binding, indicating that ADCs to FcRL5 could be effective. Indeed, we found that FcRL5 ADCs were efficacious in vitro and in vivo but the unconjugated antibody was not. The two most effective consisted of our anti-FcRL5 antibody conjugated through cysteines to monomethylauristatin E (MMAE) by a maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (MC-vcPAB) linker (anti-FcRL5-MC-vcPAB-MMAE) or conjugated via lysines to the maytansinoid DM4 through a disulfide linker (anti-FcRL5-SPDB-DM4). These two ADCs were highly effective in vivo in combination with bortezomib or lenalidomide, drugs in use for the treatment of multiple myeloma. These data show that the FcRL5 ADCs described herein show promise as an effective treatment for multiple myeloma.
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http://dx.doi.org/10.1158/1535-7163.MCT-12-0087DOI Listing
October 2012

Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma.

Blood 2009 Sep 24;114(13):2721-9. Epub 2009 Jul 24.

Genentech Inc, South San Francisco, CA 94080, USA.

Here we describe the generation of an antibody-drug conjugate (ADC) consisting of a humanized anti-CD79b antibody that is conjugated to monomethylauristatin E (MMAE) through engineered cysteines (THIOMABs) by a protease cleavable linker. By using flow cytometry, we detected the surface expression of CD79b in almost all non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia patients, suggesting that anti-CD79b-vcMMAE could be widely used in these malignancies. By using NHL cell lines to simulate a patient population we discovered that a minimal cell-surface expression level of CD79b was required for in vitro activity. Within the subpopulation of cell lines above this minimal threshold, we found that sensitivity to free MMAE, mutation of cancer genes, and cell doubling time were poorly correlated with in vitro activity; however, the expression level of BCL-XL was correlated with reduced sensitivity to anti-CD79b-vcMMAE. This observation was supported by in vivo data showing that a Bcl-2 family inhibitor, ABT-263, strikingly enhanced the activity of anti-CD79b-vcMMAE. Furthermore, anti-CD79b-vcMMAE was significantly more effective than a standard-of-care regimen, R-CHOP (ie, rituximab with a single intravenous injection of 30 mg/kg cyclophosphamide, 2.475 mg/kg doxorubicin, 0.375 mg/kg vincristine, and oral dosing of 0.15 mg/kg prednisone once a day for 5 days), in 3 xenograft models of NHL. Together, these data suggest that anti-CD79b-vcMMAE could be broadly efficacious for the treatment of NHL.
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http://dx.doi.org/10.1182/blood-2009-02-205500DOI Listing
September 2009

Genetic deletion of JAM-C reveals a role in myeloid progenitor generation.

Blood 2009 Feb 24;113(9):1919-28. Epub 2008 Dec 24.

Department of Immunology, Genentech, South San Francisco, CA, USA.

Hematopoietic stem cells (HSCs) have the capacity to self-renew and continuously differentiate into all blood cell lineages throughout life. At each branching point during differentiation, interactions with the environment are key in the generation of daughter cells with distinct fates. Here, we examined the role of the cell adhesion molecule JAM-C, a protein known to mediate cellular polarity during spermatogenesis, in hematopoiesis. We show that murine JAM-C is highly expressed on HSCs in the bone marrow (BM). Expression correlates with self-renewal, the highest being on long-term repopulating HSCs, and decreases with differentiation, which is maintained longest among myeloid committed progenitors. Inclusion of JAM-C as a sole marker on lineage-negative BM cells yields HSC enrichments and long-term multilineage reconstitution when transferred to lethally irradiated mice. Analysis of Jam-C-deficient mice showed that two-thirds die within 48 hours after birth. In the surviving animals, loss of Jam-C leads to an increase in myeloid progenitors and granulocytes in the BM. Stem cells and myeloid cells from fetal liver are normal in number and homing to the BM. These results provide evidence that JAM-C defines HSCs in the BM and that JAM-C plays a role in controlling myeloid progenitor generation in the BM.
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http://dx.doi.org/10.1182/blood-2008-06-159574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651011PMC
February 2009

Cryopyrin activates the inflammasome in response to toxins and ATP.

Nature 2006 Mar 11;440(7081):228-32. Epub 2006 Jan 11.

Molecular Oncology Department, Genentech Inc, 1 DNA Way, South San Francisco, California 94080, USA.

A crucial part of the innate immune response is the assembly of the inflammasome, a cytosolic complex of proteins that activates caspase-1 to process the proinflammatory cytokines interleukin (IL)-1beta and IL-18. The adaptor protein ASC is essential for inflammasome function, binding directly to caspase-1 (refs 3, 4), but the triggers of this interaction are less clear. ASC also interacts with the adaptor cryopyrin (also known as NALP3 or CIAS1). Activating mutations in cryopyrin are associated with familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease, diseases that are characterized by excessive production of IL-1beta. Here we show that cryopyrin-deficient macrophages cannot activate caspase-1 in response to Toll-like receptor agonists plus ATP, the latter activating the P2X7 receptor to decrease intracellular K+ levels. The release of IL-1beta in response to nigericin, a potassium ionophore, and maitotoxin, a potent marine toxin, was also found to be dependent on cryopyrin. In contrast to Asc-/- macrophages, cells deficient in the gene encoding cryopyrin (Cias1-/-) activated caspase-1 and secreted normal levels of IL-1beta and IL-18 when infected with Gram-negative Salmonella typhimurium or Francisella tularensis. Macrophages exposed to Gram-positive Staphylococcus aureus or Listeria monocytogenes, however, required both ASC and cryopyrin to activate caspase-1 and secrete IL-1beta. Therefore, cryopyrin is essential for inflammasome activation in response to signalling pathways triggered specifically by ATP, nigericin, maitotoxin, S. aureus or L. monocytogenes.
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http://dx.doi.org/10.1038/nature04515DOI Listing
March 2006

Ex vivo expanded dendritic cells home to T-cell zones of lymphoid organs and survive in vivo after allogeneic bone marrow transplantation.

Am J Pathol 2005 Nov;167(5):1321-31

Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University, Center for Clinical Science Building, Room 2205, 269 West Campus Dr., Stanford, CA 94305, USA.

Little is known about adoptive transfer of allogeneic ex vivo expanded dendritic cells (eDCs). We investigated the trafficking pattern of eDCs in mice after allogeneic bone marrow transplantation by using bioluminescence imaging. eDCs were expanded from bone marrow precursors in the presence of GM-CSF, interleukin-4, and Flt3L and retrovirally transduced to express luciferase (luc) and green fluorescence protein (gfp). Flow cytometry showed polyclonal DC populations after expansion that consisted of CD11c+CD11b+ and CD11c-CD11b+ cells that co-expressed CD40, CD80, CD86, and MHCII. eDCs were functional in mixed lymphocyte reactions and produced tumor necrosis factor-alpha on phytohemagglutinin stimulation. The eDCs were then injected intravenously into BALB/c recipient mice that had received allogeneic bone marrow transplantation 6 weeks previously. On day 1 after transfer, eDCs were detected by bioluminescence imaging throughout the lungs and spleen. In the later course, signals were observed throughout thymus, lower abdomen, and spleen throughout a period of more than 42 days. Immunofluorescence microscopy confirmed CD11c positivity on the gfp+ donor cells, which localized in T-cell zones of mesenteric lymph nodes, Peyer's patches, spleen, and thymus. These findings are important for adoptive immunotherapies because they indicate that eDCs migrate efficiently in vivo and are capable of surviving long term.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1603780PMC
http://dx.doi.org/10.1016/S0002-9440(10)61219-9DOI Listing
November 2005