Publications by authors named "Gwendlyn Kollmorgen"

23 Publications

  • Page 1 of 1

Associations between air pollution and biomarkers of Alzheimer's disease in cognitively unimpaired individuals.

Environ Int 2021 Sep 16;157:106864. Epub 2021 Sep 16.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain. Electronic address:

Background: Air quality contributes to incidence of Alzheimer's disease (AD) although the underlying neurobiological mechanisms are unclear. This study was aimed to examine the association between air pollution and concentrations of cerebrospinal fluid (CSF) AD biomarkers and amyloid-β (Aβ) deposition. Participants and methods The sample included 156 cognitively unimpaired adults aged 57 years (61 at biomarkers assessment) with increased risk of AD from the ALFA + Study. We examined CSF levels of Aβ42, Aβ40, p-Tau, t-Tau, neurofilament light (NfL) and cerebral amyloid load (Centiloid). A Land Use Regression model from 2009 was used to estimate residential exposure to air pollutants including nitrogen dioxide (NO,) and particulate matter (PM, PM, PM). This model was considered a surrogate of long-term exposure until time of data collection in 2013-2014. Participants have resided in the same residence for at least the previous 3 years. Multiple linear regression models were used to estimate associations between air pollutants and biomarkers. The effect modification by CSF Aβ status and APOE-ε4 carriership was also assessed.

Results: A consistent pattern of results indicated that greater exposure to NO and PM absorbance was associated with higher levels of brain Aβ deposition, while greater exposure to PM and PMwas associated with higher levels of CSF NfL. Most associations were driven by individuals that were Aβ-positive. Although APOE-ε4 status did not significantly modify these associations, the effect of air pollutants exposure on CSF NfL levels was stronger in APOE-ε4 carriers.

Conclusion: In a population of cognitively unimpaired adults with increased risk of AD, long-term exposure to air pollution was associated with higher levels in biomarkers of AD pathology. While further research is granted to elucidate the mechanisms involved in such associations, our results reinforce the role of air pollution as an environmental risk factor for AD.
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http://dx.doi.org/10.1016/j.envint.2021.106864DOI Listing
September 2021

Perivascular spaces are associated with tau pathophysiology and synaptic dysfunction in early Alzheimer's continuum.

Alzheimers Res Ther 2021 08 5;13(1):135. Epub 2021 Aug 5.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Background: Perivascular spaces (PVS) have an important role in the elimination of metabolic waste from the brain. It has been hypothesized that the enlargement of PVS (ePVS) could be affected by pathophysiological mechanisms involved in Alzheimer's disease (AD), such as abnormal levels of CSF biomarkers. However, the relationship between ePVS and these pathophysiological mechanisms remains unknown.

Objective: We aimed to investigate the association between ePVS and CSF biomarkers of several pathophysiological mechanisms for AD. We hypothesized that ePVS will be associated to CSF biomarkers early in the AD continuum (i.e., amyloid positive cognitively unimpaired individuals). Besides, we explored associations between ePVS and demographic and cardiovascular risk factors.

Methods: The study included 322 middle-aged cognitively unimpaired participants from the ALFA + study, many within the Alzheimer's continuum. NeuroToolKit and Elecsys® immunoassays were used to measure CSF Aβ42, Aβ40, p-tau and t-tau, NfL, neurogranin, TREM2, YKL40, GFAP, IL6, S100, and α-synuclein. PVS in the basal ganglia (BG) and centrum semiovale (CS) were assessed based on a validated 4-point visual rating scale. Odds ratios were calculated for associations of cardiovascular and AD risk factors with ePVS using logistic and multinomial models adjusted for relevant confounders. Models were stratified by Aβ status (positivity defined as Aβ42/40 < 0.071).

Results: The degree of PVS significantly increased with age in both, BG and CS regions independently of cardiovascular risk factors. Higher levels of p-tau, t-tau, and neurogranin were significantly associated with ePVS in the CS of Aβ positive individuals, after accounting for relevant confounders. No associations were detected in the BG neither in Aβ negative participants.

Conclusions: Our results support that ePVS in the CS are specifically associated with tau pathophysiology, neurodegeneration, and synaptic dysfunction in asymptomatic stages of the Alzheimer's continuum.
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http://dx.doi.org/10.1186/s13195-021-00878-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340485PMC
August 2021

Insulin resistance is related to cognitive decline but not change in CSF biomarkers of Alzheimer's disease in non-demented adults.

Alzheimers Dement (Amst) 2021 28;13(1):e12220. Epub 2021 Jul 28.

Wisconsin Alzheimer's Disease Research Center University of Wisconsin School of Medicine and Public Health Madison Wisconsin USA.

Introduction: We investigated whether insulin resistance (IR) was associated with longitudinal age-related change in cognition and biomarkers of Alzheimer's disease (AD) pathology and neurodegeneration in middle-aged and older adults who were non-demented at baseline.

Methods: IR was measured with homeostatic model assessment of insulin resistance (HOMA2-IR). Core AD-related cerebrospinal fluid (CSF) biomarkers and cognition were assessed, respectively, on n = 212 (1 to 5 visits) and n = 1299 (1 to 6 visits). Linear mixed models tested whether HOMA2-IR moderated age-related change in CSF biomarkers and cognition. Linear regressions tested whether HOMA2-IR x apolipoprotein E ε4 allele ( ε4) carrier status predicted amyloid beta [Aβ] chronicity (estimated duration of amyloid positron emission tomography [PET] positivity) (n = 253).

Results: Higher HOMA2-IR was associated with greater cognitive decline but not with changes in CSF biomarkers. HOMA2-IR x was not related to Aβ chronicity but was significantly associated with CSF phosphorylated tau (P-tau)/Aβ level.

Discussion: In non-demented adults IR may not be directly associated with age-related change in AD biomarkers. Additional research is needed to determine mechanisms linking IR to cognitive decline.
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http://dx.doi.org/10.1002/dad2.12220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319658PMC
July 2021

Cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF biomarker profile.

Alzheimers Res Ther 2021 07 27;13(1):134. Epub 2021 Jul 27.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Wellington 30, 08005, Barcelona, Spain.

Background: Understanding the changes that occur in the transitional stage between absent and overt amyloid-β (Aβ) pathology within the Alzheimer's continuum is crucial to develop therapeutic and preventive strategies. The objective of this study is to test whether cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF, structural, and functional neuroimaging biomarker profile.

Methods: Cross-sectional study of 318 middle-aged, cognitively unimpaired individuals from the ALFA+ cohort. We measured CSF Aβ42/40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100B, and α-synuclein. Participants also underwent cognitive assessments, APOE genotyping, structural MRI, [F]-FDG, and [F]-flutemetamol PET. To ensure the robustness of our results, we used three definitions of low burden of Aβ pathology: (1) positive CSF Aβ42/40 and < 30 Centiloids in Aβ PET, (2) positive CSF Aβ42/40 and negative Aβ PET visual read, and (3) 20-40 Centiloid range in Aβ PET. We tested CSF and neuroimaging biomarker differences between the low burden group and the corresponding Aβ-negative group, adjusted by age and sex.

Results: The prevalence and demographic characteristics of the low burden group differed between the three definitions. CSF p-tau and t-tau were increased in the low burden group compared to the Aβ-negative in all definitions. CSF neurogranin was increased in the low burden group definitions 1 and 3, while CSF NfL was only increased in the low burden group definition 1. None of the defined low burden groups showed signs of atrophy or glucose hypometabolism. Instead, we found slight increases in cortical thickness and metabolism in definition 2.

Conclusions: There are biologically meaningful Aβ-downstream effects in individuals with a low burden of Aβ pathology, while structural and functional changes are still subtle or absent. These findings support considering individuals with a low burden of Aβ pathology for clinical trials.

Trial Registration: NCT02485730.
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http://dx.doi.org/10.1186/s13195-021-00863-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314554PMC
July 2021

Interaction of amyloid and tau on cortical microstructure in cognitively unimpaired adults.

Alzheimers Dement 2021 May 13. Epub 2021 May 13.

Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.

Introduction: Neurite orientation dispersion and density imaging (NODDI), a multi-compartment diffusion-weighted imaging (DWI) model, may be useful for detecting early cortical microstructural alterations in Alzheimer's disease prior to cognitive impairment.

Methods: Using neuroimaging (NODDI and T1-weighted magnetic resonance imaging [MRI]) and cerebrospinal fluid (CSF) biomarker data (measured using Elecsys® CSF immunoassays) from 219 cognitively unimpaired participants, we tested the main and interactive effects of CSF amyloid beta (Aβ) /Aβ and phosphorylated tau (p-tau) on cortical NODDI metrics and cortical thickness, controlling for age, sex, and apolipoprotein E ε4.

Results: We observed a significant CSF Aβ /Aβ × p-tau interaction on cortical neurite density index (NDI), but not orientation dispersion index or cortical thickness. The directionality of these interactive effects indicated: (1) among individuals with lower CSF p-tau, greater amyloid burden was associated with higher cortical NDI; and (2) individuals with greater amyloid and p-tau burden had lower cortical NDI, consistent with cortical neurodegenerative changes.

Discussion: NDI is a particularly sensitive marker for early cortical changes that occur prior to gross atrophy or development of cognitive impairment.
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http://dx.doi.org/10.1002/alz.12364DOI Listing
May 2021

Amyloid-β positive individuals with subjective cognitive decline present increased CSF neurofilament light levels that relate to lower hippocampal volume.

Neurobiol Aging 2021 08 6;104:24-31. Epub 2021 Mar 6.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain; Present address: H. Lundbeck A/S, Denmark. Electronic address:

Neurofilament light chain (NfL) is an axonal protein that when measured in cerebrospinal fluid (CSF) serves as a biomarker of neurodegeneration. We aimed at investigating the association among CSF NfL, presence of Subjective Cognitive Decline (SCD) and hippocampal volume, and how CSF amyloid-β (Aβ) modifies these associations. We included 278 cognitively unimpaired participants from the Alfa+ cohort (78 SCD and 200 Controls). Linear models accounting for covariates (age, gender, and mood) were used to test the association between CSF NfL and SCD status, and between CSF NfL and bilateral hippocampal volumes. Interactions with Aβ were also explored. Individuals with SCD had higher CSF NfL and lower CSF Aβ42/40 than Controls. There was a significant interaction between SCD and CSF-Aβ42/40 levels. Stratified analyses showed a significant association between SCD and NfL only in Aβ+ individuals. Higher CSF NfL was significantly associated with lower hippocampal volume specifically in Aβ+ individuals with SCD. The presence of SCD in Aβ+ individuals may represent an early symptom in the Alzheimer's continuum related to incipient neurodegeneration.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.02.026DOI Listing
August 2021

Cerebral amyloid-β load is associated with neurodegeneration and gliosis: Mediation by p-tau and interactions with risk factors early in the Alzheimer's continuum.

Alzheimers Dement 2021 05 4;17(5):788-800. Epub 2021 Mar 4.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Introduction: The association between cerebral amyloid-β accumulation and downstream CSF biomarkers is not fully understood, particularly in asymptomatic stages.

Methods: In 318 cognitively unimpaired participants, we assessed the association between amyloid-β PET (Centiloid), and cerebrospinal fluid (CSF) biomarkers of several pathophysiological pathways. Interactions by Alzheimer's disease risk factors (age, sex and APOE-ε4), and the mediation effect of tau and neurodegeneration were also investigated.

Results: Centiloids were positively associated with CSF biomarkers of tau pathology (p-tau), neurodegeneration (t-tau, NfL), synaptic dysfunction (neurogranin) and neuroinflammation (YKL-40, GFAP, sTREM2), presenting interactions with age (p-tau, t-tau, neurogranin) and sex (sTREM2, NfL). Most of these associations were mediated by p-tau, except for NfL. The interaction between sex and amyloid-β on sTREM2 and NfL was also tau-independent.

Discussion: Early amyloid-β accumulation has a tau-independent effect on neurodegeneration and a tau-dependent effect on neuroinflammation. Besides, sex has a modifier effect on these associations independent of tau.
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http://dx.doi.org/10.1002/alz.12245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252618PMC
May 2021

Association of weight change with cerebrospinal fluid biomarkers and amyloid positron emission tomography in preclinical Alzheimer's disease.

Alzheimers Res Ther 2021 02 17;13(1):46. Epub 2021 Feb 17.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Background: Recognizing clinical manifestations heralding the development of Alzheimer's disease (AD)-related cognitive impairment could improve the identification of individuals at higher risk of AD who may benefit from potential prevention strategies targeting preclinical population. We aim to characterize the association of body weight change with cognitive changes and AD biomarkers in cognitively unimpaired middle-aged adults.

Methods: This prospective cohort study included data from cognitively unimpaired adults from the ALFA study (n = 2743), a research platform focused on preclinical AD. Cognitive and anthropometric data were collected at baseline between April 2013 and November 2014. Between October 2016 and February 2020, 450 participants were visited in the context of the nested ALFA+ study and underwent cerebrospinal fluid (CSF) extraction and acquisition of positron emission tomography images with [F]flutemetamol (FTM-PET). From these, 408 (90.1%) were included in the present study. We used data from two visits (average interval 4.1 years) to compute rates of change in weight and cognitive performance. We tested associations between these variables and between weight change and categorical and continuous measures of CSF and neuroimaging AD biomarkers obtained at follow-up. We classified participants with CSF data according to the AT (amyloid, tau) system and assessed between-group differences in weight change.

Results: Weight loss predicted a higher likelihood of positive FTM-PET visual read (OR 1.27, 95% CI 1.00-1.61, p = 0.049), abnormal CSF p-tau levels (OR 1.50, 95% CI 1.19-1.89, p = 0.001), and an A+T+ profile (OR 1.64, 95% CI 1.25-2.20, p = 0.001) and was greater among participants with an A+T+ profile (p < 0.01) at follow-up. Weight change was positively associated with CSF Aβ42/40 ratio (β = 0.099, p = 0.032) and negatively associated with CSF p-tau (β = - 0.141, p = 0.005), t-tau (β = - 0.147 p = 0.004) and neurogranin levels (β = - 0.158, p = 0.002). In stratified analyses, weight loss was significantly associated with higher t-tau, p-tau, neurofilament light, and neurogranin, as well as faster cognitive decline in A+ participants only.

Conclusions: Weight loss predicts AD CSF and PET biomarker results and may occur downstream to amyloid-β accumulation in preclinical AD, paralleling cognitive decline. Accordingly, it should be considered as an indicator of increased risk of AD-related cognitive impairment.

Trial Registration: NCT01835717 , NCT02485730 , NCT02685969 .
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http://dx.doi.org/10.1186/s13195-021-00781-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890889PMC
February 2021

An examination of a novel multipanel of CSF biomarkers in the Alzheimer's disease clinical and pathological continuum.

Alzheimers Dement 2021 03 18;17(3):431-445. Epub 2020 Dec 18.

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

Introduction: This study examines the utility of a multipanel of cerebrospinal fluid (CSF) biomarkers complementing Alzheimer's disease (AD) biomarkers in a clinical research sample. We compared biomarkers across groups defined by clinical diagnosis and pTau /Aβ status (+/-) and explored their value in predicting cognition.

Methods: CSF biomarkers amyloid beta (Aβ) , pTau , tTau, Aβ , neurogranin, neurofilament light (NfL), α-synuclein, glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), S100 calcium binding protein B (S100B), and interleukin 6 (IL6), were measured with the NeuroToolKit (NTK) for 720 adults ages 40 to 93 years (mean age = 63.9 years, standard deviation [SD] = 9.0; 50 with dementia; 54 with mild cognitive impairment [MCI], 616 unimpaired).

Results: Neurodegeneration and glial activation biomarkers were elevated in pTau /Aβ + MCI/dementia participants relative to all pTau /Aβ - participants. Neurodegeneration biomarkers increased with clinical severity among pTau /Aβ + participants and predicted worse cognitive performance. Glial activation biomarkers were unrelated to cognitive performance.

Discussion: The NTK contains promising markers that improve the pathophysiological characterization of AD. Neurodegeneration biomarkers beyond tTau improved statistical prediction of cognition and disease stages.
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http://dx.doi.org/10.1002/alz.12204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016695PMC
March 2021

Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer's continuum when only subtle changes in Aβ pathology are detected.

EMBO Mol Med 2020 12 10;12(12):e12921. Epub 2020 Nov 10.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

In Alzheimer's disease (AD), tau phosphorylation in the brain and its subsequent release into cerebrospinal fluid (CSF) and blood is a dynamic process that changes during disease evolution. The main aim of our study was to characterize the pattern of changes in phosphorylated tau (p-tau) in the preclinical stage of the Alzheimer's continuum. We measured three novel CSF p-tau biomarkers, phosphorylated at threonine-181 and threonine-217 with an N-terminal partner antibody and at threonine-231 with a mid-region partner antibody. These were compared with an automated mid-region p-tau181 assay (Elecsys) as the gold standard p-tau measure. We demonstrate that these novel p-tau biomarkers increase more prominently in preclinical Alzheimer, when only subtle changes of amyloid-β (Aβ) pathology are detected, and can accurately differentiate Aβ-positive from Aβ-negative cognitively unimpaired individuals. Moreover, we show that the novel plasma N-terminal p-tau181 biomarker is mildly but significantly increased in the preclinical stage. Our results support the idea that early changes in neuronal tau metabolism in preclinical Alzheimer, likely in response to Aβ exposure, can be detected with these novel p-tau assays.
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http://dx.doi.org/10.15252/emmm.202012921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721364PMC
December 2020

Amyloid beta, tau, synaptic, neurodegeneration, and glial biomarkers in the preclinical stage of the Alzheimer's continuum.

Alzheimers Dement 2020 10 23;16(10):1358-1371. Epub 2020 Jun 23.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Introduction: The biological pathways involved in the preclinical stage of the Alzheimer's continuum are not well understood.

Methods: We used NeuroToolKit and Elecsys immunoassays to measure cerebrospinal fluid (CSF) amyloid-β (Aβ)42, Aβ40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100, and α-synuclein in cognitively unimpaired participants of the ALFA+ study, many within the Alzheimer's continuum.

Results: CSF t-tau, p-tau, and neurogranin increase throughout aging only in Aβ-positive individuals, whereas NfL and glial biomarkers increase with aging regardless of Aβ status. We modelled biomarker changes as a function of CSF Aβ42/40, p-tau and p-tau/Aβ42 as proxies of disease progression. The first change observed in the Alzheimer's continuum was a decrease in the CSF Aβ42/40 ratio. This is followed by a steep increase in CSF p-tau; t-tau; neurogranin; and, to a lesser extent, in NfL and glial biomarkers.

Discussion: Multiple biological pathways are altered and could be targeted very early in the Alzheimer's continuum.
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http://dx.doi.org/10.1002/alz.12131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586814PMC
October 2020

Elecsys Total-Tau and Phospho-Tau (181P) CSF assays: Analytical performance of the novel, fully automated immunoassays for quantification of tau proteins in human cerebrospinal fluid.

Clin Biochem 2019 Oct 23;72:30-38. Epub 2019 May 23.

Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Göteborgsvägen 31, 431 80 Mölndal, Sweden; Institute of Neuroscience and Physiology, Dept. of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Wallinsgatan 6, 431 41 Mölndal, Sweden. Electronic address:

Background: Total tau (tTau) and phosphorylated 181P tau (pTau) are supportive diagnostic cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease. Manual CSF tau assays are limited by lot-to-lot and between-laboratory variability and long incubation/turnaround times. Elecsys Total-Tau CSF and Phospho-Tau (181P) CSF immunoassays were developed for fully automated cobas e analyzers, allowing broader access in clinical practice and trials.

Methods: Analytical performance, reproducibility, method comparisons with commercially available assays, and lot-to-lot and platform comparability (cobas e 601/411) of the Elecsys CSF assays were assessed. Tau distributions and concentration ranges were evaluated in CSF samples from two clinical cohorts.

Results: Both assays showed high sensitivity (limit of quantitation [LoQ]: 63 pg/mL [tTau]; 4 pg/mL [pTau]) and linearity over the measuring range (80-1300 pg/mL; 8-120 pg/mL), which covered the entire concentration range measured in clinical samples. Lot-to-lot and platform comparability demonstrated good consistency (Pearson's r: 0.998; 1.000). Multicenter evaluation coefficients of variation (CVs): repeatability, < 1.8%; intermediate precision, < 2.8%; between-laboratory variability, < 2.7% (both assays); and total reproducibility, < 6.7% (tTau) and < 4.7% (pTau). Elecsys CSF assays demonstrated good correlation with commercially available tau assays.

Conclusions: Elecsys Total-Tau CSF and Phospho-Tau (181P) CSF assays demonstrate good analytical performance with clinically relevant measuring ranges; data support their use in clinical trials and practice.
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http://dx.doi.org/10.1016/j.clinbiochem.2019.05.005DOI Listing
October 2019

Acquired Resistance to Antibody-Drug Conjugates.

Cancers (Basel) 2019 Mar 20;11(3). Epub 2019 Mar 20.

Beoro Therapeutics GmbH, 82229 Seefeld, Germany.

Antibody-drug conjugates (ADCs) combine the tumor selectivity of antibodies with the potency of cytotoxic small molecules thereby constituting antibody-mediated chemotherapy. As this inherently limits the adverse effects of the chemotherapeutic, such approaches are heavily pursued by pharma and biotech companies and have resulted in four FDA (Food and Drug Administration)-approved ADCs. However, as with other cancer therapies, durable responses are limited by the fact that under cell stress exerted by these drugs, tumors can acquire mechanisms of escape. Resistance can develop against the antibody component of ADCs by down-regulation/mutation of the targeted cell surface antigen or against payload toxicity by up-regulation of drug efflux transporters. Unique resistance mechanisms specific for the mode of action of ADCs have also emerged, like altered internalization or cell surface recycling of the targeted tumor antigen, changes in the intracellular routing or processing of ADCs, and impaired release of the toxic payload into the cytosol. These evasive changes are tailored to the specific nature and interplay of the three ADC constituents: the antibody, the linker, and the payload. Hence, they do not necessarily endow broad resistance to ADC therapy. This review summarizes preclinical and clinical findings that shed light on the mechanisms of acquired resistance to ADC therapies.
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http://dx.doi.org/10.3390/cancers11030394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468698PMC
March 2019

The Role of micro RNAs in Breast Cancer Metastasis: Preclinical Validation and Potential Therapeutic Targets.

Cancer Genomics Proteomics 2018 Jan-Feb;15(1):17-39

Roche Pharma Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Penzberg, Germany

Despite the approval of several molecular therapies in the last years, breast cancer-associated death ranks as the second highest in women. This is due to metastatic disease, which represents a challenge for treatment. A better understanding of the molecular mechanisms of metastasis is, therefore, of paramount importance. In this review we summarize the role of micro RNAs (miRs) involved in metastasis of breast cancer. We present an overview on metastasis-promoting, -suppressing and context-dependent miRs with both activities. We have categorized the corresponding miRs according to their target classes, interaction with stromal cells or exosomes. The pathways affected by individual miRs are outlined in regard to in vitro properties, activity in metastasis-related in vivo models and clinical significance. Current approaches that may be suitable for therapeutic inhibition or restauration of miR activity are outlined. Finally, we discuss the delivery bottlenecks which present as a major challenge in nucleic acid (miR)-based therapies.
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http://dx.doi.org/10.21873/cgp.20062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822183PMC
July 2018

A re-engineered immunotoxin shows promising preclinical activity in ovarian cancer.

Sci Rep 2017 12 22;7(1):18086. Epub 2017 Dec 22.

Discovery Oncology, Pharmaceutical Research and Early Development (pRED), Roche Innovation Center, Munich, Germany.

RG7787 is a re-engineered mesothelin-targeted immunotoxin with reduced immunogenicity composed of a humanized anti-mesothelin Fab fragment and a B-cell epitope silenced 24 kD fragment of Pseudomonas exotoxin A. High prevalence of mesothelin-positive cases and a large unmet medical need make ovarian cancer a promising indication for the clinical development of RG7787. However, ovarian cancer patients also frequently have elevated serum levels of the cancer antigen 125 (CA-125). In principle this could pose a problem, since the binding sites for CA-125 and RG7787 on mesothelin were reported to overlap. However, we show here that RG7787 can readily displace even excess amounts of CA-125 in different cellular assays. Moreover when tested in-vitro on a panel of 12 ovarian cancer cell lines, RG7787 had high cytotoxic activity on COV644, Caov-4, and SNU-119 cells and fully inhibited growth of EFO-21, KURAMOCHI, OVSAHO, and Caov-3 cells with potency values ranging from 1 to 86 pM. Finally, we evaluated the in-vivo efficacy of RG7787 in OvCa6668, a patient-derived ovarian cancer model with high levels of CA-125 expression. RG7787 had moderate monotherapy efficacy but in combination with standard chemotherapies (cisplatin, paclitaxel) achieved pronounced tumor regressions. In summary our data support clinical testing of RG7787 in ovarian cancer.
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http://dx.doi.org/10.1038/s41598-017-17329-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741731PMC
December 2017

Mechanisms and Targets Involved in Dissemination of Ovarian Cancer.

Cancer Genomics Proteomics 2016 11-12;13(6):407-423

Roche Innovation Center Munich, Roche Diagnostics GmbH, Penzberg, Germany

Ovarian carcinoma is associated with the highest death rate of all gynecological tumors. On one hand, its aggressiveness is based on the rapid dissemination of ovarian cancer cells to the peritoneum, the omentum, and organs located in the peritoneal cavity, and on the other hand, on the rapid development of resistance to chemotherapeutic agents. In this review, we focus on the metastatic process of ovarian cancer, which involves dissemination of, homing to and growth of tumor cells in distant organs, and describe promising molecular targets for possible therapeutic intervention. We provide an outline of the interaction of ovarian cancer cells with the microenvironment such as mesothelial cells, adipocytes, fibroblasts, endothelial cells, and other stromal components in the context of approaches for therapeutic interference with dissemination. The targets described in this review are discussed with respect to their validity as drivers of metastasis and to the availability of suitable efficient agents for their blockage, such as small molecules, monoclonal antibodies or antibody conjugates as emerging tools to manage this disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5219915PMC
http://dx.doi.org/10.21873/cgp.20004DOI Listing
January 2017

Characterization of a re-engineered, mesothelin-targeted Pseudomonas exotoxin fusion protein for lung cancer therapy.

Mol Oncol 2016 10 14;10(8):1317-29. Epub 2016 Jul 14.

Roche Pharma Research & Early Development (pRED), Discovery Oncology, Innovation Center Munich, Roche Diagnostics GmbH Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany. Electronic address:

Mesothelin overexpression in lung adenocarcinomas correlates with the presence of activating KRAS mutations and poor prognosis. Hence SS1P, a mesothelin-targeted immunotoxin, could offer valuable treatment options for these patients, but its use in solid tumor therapy is hampered by high immunogenicity and non-specific toxicity. To overcome both obstacles we developed RG7787, a de-immunized cytotoxic fusion protein comprising a humanized SS1 Fab fragment and a truncated, B-cell epitope silenced, 24 kD fragment of Pseudomonas exotoxin A (PE24). Reactivity of RG7787 with sera from immunotoxin-treated patients was >1000 fold reduced. In vitro RG7787 inhibited cell viability of lung cancer cell lines with picomolar potency. The pharmacokinetic properties of RG7787 in rodents were comparable to SS1P, yet it was tolerated up to 10 fold better without causing severe vascular leak syndrome or hepatotoxicity. A pharmacokinetic/pharmacodynamic model developed based on NCI-H596 xenograft studies showed that for RG7787 and SS1P, their in vitro and in vivo potencies closely correlate. At optimal doses of 2-3 mg/kg RG7787 is more efficacious than SS1P. Even large, well established tumors (600 mm(3)) underwent remission during three treatment cycles with RG7787. Also in two patient-derived lung cancer xenograft models, Lu7336 and Lu7187, RG7787 showed anti-tumor efficacy. In monotherapy two treatment cycles were moderately efficacious in the Lu7336 model but showed good anti-tumor activity in the KRAS mutant Lu7187 model (26% and 80% tumor growth inhibition, respectively). Combination of RG7787 with standard chemotherapies further enhanced efficacy in both models achieving near complete eradication of Lu7187 tumors.
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http://dx.doi.org/10.1016/j.molonc.2016.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423209PMC
October 2016

Dissection of the Process of Brain Metastasis Reveals Targets and Mechanisms for Molecular-based Intervention.

Cancer Genomics Proteomics 2016 Jul-Aug;13(4):245-58

Roche Innovation Center Munich, Roche Diagnostics GmbH, Penzberg, Germany

Brain metastases outnumber the incidence of brain tumors by a factor of ten. Patients with brain metastases have a dismal prognosis and current treatment modalities achieve only a modest clinical benefit. We discuss the process of brain metastasis with respect to mechanisms and involved targets to outline options for therapeutic intervention and focus on breast and lung cancer, as well as melanoma. We describe the process of penetration of the blood-brain-barrier (BBB) by disseminated tumor cells, establishment of a metastatic niche, colonization and outgrowth in the brain parenchyma. Furthermore, the role of angiogenesis in colonization of the brain parenchyma, interactions of extravasated tumor cells with microglia and astrocytes, as well as their propensity for neuromimicry, is discussed. We outline targets suitable for prevention of metastasis and summarize targets suitable for treatment of established brain metastases. Finally, we highlight the implications of findings revealing druggable mutations in brain metastases that cannot be identified in matching primary tumors.
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January 2017

Molecular Basis of Lung Tropism of Metastasis.

Cancer Genomics Proteomics 2016 Mar-Apr;13(2):129-39

Roche Pharma Research and Early Development, Roche Innovation Center Penzberg, Roche Diagnostics GmbH, Penzberg, Germany

A predilection of metastasis to the lungs has been noted for several types of cancer. Herein, we summarize underlying mechanisms for lung tropism of metastasis. We discuss the identification of a gene signature in primary breast tumors predicting metastasis to the lungs, as well as functional validation of selected genes of the signature. We outline the contribution of pre- and metastatic niches, the role of exosomes, activation of disseminated, dormant tumor cells and selected tumor-stromal cell interactions to lung metastasis and colonization. We also refer to metastasis-mediating mechanisms based on alterations of the tumor cell cytoskeleton, as well as lung metastasis-suppressing mechanisms.
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November 2016

Molecular Mechanisms of Bone Metastasis.

Cancer Genomics Proteomics 2016 Jan-Feb;13(1):1-12

Roche Pharma Research and Early Development, Roche Innovation Center Penzberg, Roche Diagnostics GmbH, Penzberg, Germany

Metastasis of breast and prostate cancer as well as multiple myeloma to the bones represents a significant medical problem. We herein discuss the molecular basis of the creation of pre-metastatic niches, the process of bone metastasis and the phenomenon of tumor dormancy in the bone marrow as well as its regulation. We describe the identification and validation of genes mediating bone metastasis by use of pre-clinical models of bone metastasis. Additionally, we discuss the role of small integrin binding N-linked glycoproteins (SIBLINGS), the chemokine/chemokine receptor CXCL12/CXCR4 pathway and the role of micro RNAs (miRNAs) as mediators of bone metastasis. Finally, we summarize clinical achievements for the treatment of bone metastases.
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November 2016

Antibody mediated CDCP1 degradation as mode of action for cancer targeted therapy.

Mol Oncol 2013 Dec 3;7(6):1142-51. Epub 2013 Sep 3.

Discovery Oncology, Pharmaceutical Research and Early Development (pRED), Roche Diagnostics GmbH, Nonnenwald 2, 82377 Penzberg, Germany.

CUB-domain-containing-protein-1 (CDCP1) is an integral membrane protein whose expression is up-regulated in various cancer types. Although high CDCP1 expression has been correlated with poor prognosis in lung, breast, pancreas, and renal cancer, its functional role in tumor formation or progression is incompletely understood. So far it has remained unclear, whether CDCP1 is a useful target for antibody therapy of cancer and what could be a desired mode of action for a therapeutically useful antibody. To shed light on these questions, we have investigated the cellular effects of a therapeutic antibody candidate (RG7287). In focus formation assays, prolonged RG7287 treatment prevented the loss of contact inhibition caused by co-transformation of NIH3T3 cells with CDCP1 and Src. In a xenograft study, MCF7 cells stably overexpressing CDCP1 reached the predefined tumor volume faster than the parental MCF7 cells lacking endogenous CDCP1. This tumor growth advantage was abolished by RG7287 treatment. In vitro, RG7287 induced rapid tyrosine phosphorylation of CDCP1 by Src, which was accompanied by translocation of CDCP1 to a Triton X-100 insoluble fraction of the plasma membrane. Triggering these effects required bivalency of the antibody suggesting that it involves CDCP1 dimerization or clustering. However, this initial activation of CDCP1 was only transient and prolonged RG7287 treatment induced internalization and down-regulation of CDCP1 in different cancer cell lines. Antibody stimulated CDCP1 degradation required Src activity and was proteasome dependent. Also in three different xenograft models with endogenous CDCP1 expression RG7287 treatment resulted in significant tumor growth inhibition concomitant with substantially reduced CDCP1 levels as judged by immunohistochemistry and Western blotting. Thus, despite transiently activating CDCP1 signaling, the RG7287 antibody has a therapeutically useful mode of action.
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http://dx.doi.org/10.1016/j.molonc.2013.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528444PMC
December 2013

Structural requirements for cub domain containing protein 1 (CDCP1) and Src dependent cell transformation.

PLoS One 2012 31;7(12):e53050. Epub 2012 Dec 31.

Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany.

Cub domain containing protein 1 (CDCP1) is strongly expressed in tumors derived from lung, colon, ovary, or kidney. It is a membrane protein that is phosphorylated and then bound by Src family kinases. Although expression and phosphorylation of CDCP1 have been investigated in many tumor cell lines, the CDCP1 features responsible for transformation have not been fully evaluated. This is in part due to the lack of an experimental system in which cellular transformation depends on expression of exogenous CDCP1 and Src. Here we use retrovirus mediated co-overexpression of c-Src and CDCP1 to induce focus formation of NIH3T3 cells. Employing different mutants of CDCP1 we show that for a full transformation capacity, the intact amino- and carboxy-termini of CDCP1 are essential. Mutation of any of the core intracellular tyrosine residues (Y734, Y743, or Y762) abolished transformation, and mutation of a palmitoylation motif (C689,690G) strongly reduced it. Src kinase binding to CDCP1 was not required since Src with a defective SH2 domain generated even more CDCP1 dependent foci whereas Src myristoylation was necessary. Taken together, the focus formation assay allowed us to define structural requirements of CDCP1/Src dependent transformation and to characterize the interaction of CDCP1 and Src.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0053050PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534080PMC
June 2013

Sharpin contributes to TNFα dependent NFκB activation and anti-apoptotic signalling in hepatocytes.

PLoS One 2012 9;7(1):e29993. Epub 2012 Jan 9.

Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

TNFα stimulates both pro- and anti-apoptotic signalling in hepatocytes. Anti-apoptotic signalling depends on a cascade of ubiquitylation steps leading to NFκB activation. Using Sharpin-deficient mice, we show that the ubiquitin binding protein Sharpin interacts with Hoip, an E3 ligase which generates linear ubiquitin chains. Sharpin-deficiency sensitized hepatocytes to induction of apoptosis by TNFα even in the absence of transcriptional inhibition. TNFα induced activation of NFκB was strongly reduced in hepatocytes from Sharpin-deficient mice, due to reduced and delayed phosphorylation and degradation of IκBα. Injection of TNFα-inducing lipopolysaccharides led to strongly exacerbated liver damage and premature death in Sharpin-deficient mice. Our findings point to an essential role of Sharpin in linear ubiquitin chain formation, NFκB activation, and protection of the liver against inflammatory damaging signals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0029993PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253811PMC
May 2012
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