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1. CC-96673 (BMS-986358), an affinity-tuned anti-CD47 and CD20 bispecific antibody with fully functional fc, selectively targets and depletes non-Hodgkin’s lymphoma

Author

Dan Zhu, Haralambos Hadjivassiliou, Catherine Jennings, David Mikolon, Massimo Ammirante, Sharmistha Acharya, Jon Lloyd, Mahan Abbasian, Rama Krishna Narla, Joseph R. Piccotti, Katie Stamp, Ho Cho, and Kandasamy Hariharan

Subjects
CD20, CD47, detune, non-Hodgkin’s lymphoma, phagocytosis, Therapeutics. Pharmacology, RM1-950, Immunologic diseases. Allergy, RC581-607
Abstract

Cluster of differentiation 47 (CD47) is a transmembrane protein highly expressed in tumor cells that interacts with signal regulatory protein alpha (SIRPα) and triggers a “don’t eat me” signal to the macrophage, inhibiting phagocytosis and enabling tumor escape from immunosurveillance. The CD47-SIRPα axis has become an important target for cancer immunotherapy. To date, the advancement of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hematologic toxicity including anemia. To overcome those challenges a bispecific approach was taken. CC-96673, a humanized IgG1 bispecific antibody co-targeting CD47 and CD20, is designed to bind CD20 with high affinity and CD47 with optimally lowered affinity. As a result of the detuned CD47 affinity, CC-96673 selectively binds to CD20-expressing cells, blocking the interaction of CD47 with SIRPα. This increased selectivity of CC-96673 over monospecific anti-CD47 approaches allows for the use of wild-type IgG1 Fc, which engages activating crystallizable fragment gamma receptors (FcγRs) to fully potentiate macrophages to engulf and destroy CD20+ cells, while sparing CD47+CD20− normal cells. The combined targeting of anti-CD20 and anti-CD47 results in enhanced anti- tumor activity compared to anti-CD20 targeting antibodies alone. Furthermore, preclinical studies have demonstrated that CC-96673 exhibits acceptable pharmacokinetic properties with a favorable toxicity profile in non-human primates. Collectively, these findings define CC-96673 as a promising CD47 × CD20 bispecific antibody that selectively destroys CD20+ cancer cells via enhanced phagocytosis and other effector functions.

Published
2024
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2. Neutralising antibody potency against SARS-CoV-2 wild-type and omicron BA.1 and BA.4/5 variants in patients with inflammatory bowel disease treated with infliximab and vedolizumab after three doses of COVID-19 vaccine (CLARITY IBD): an analysis of a prospective multicentre cohort study

Author

Zhigang Liu, Kaixing Le, Xin Zhou, James L Alexander, Simeng Lin, Claire Bewshea, Neil Chanchlani, Rachel Nice, Timothy J McDonald, Christopher A Lamb, Shaji Sebastian, Klaartje Kok, Charlie W Lees, Ailsa L Hart, Richard C Pollok, Rosemary J Boyton, Daniel M Altmann, Katrina M Pollock, James R Goodhand, Nicholas A Kennedy, Tariq Ahmad, Nick Powell, Madiha Islam, Nick Croft, Bessie Cipriano, Caroline Francia, Nosheen Khalid, Ashley Kingston, Irish Lee, Anouk Lehmann, Kinnari Naik, Kevin Samuels, Nicolene Plaatjies, Hafiza Khatun, Farjana Bokth, Elise Pabriaga, Rebecca Saich, Hayley Cousins, Wendy Fraser, Rachel Thomas, Matthew Brown, Benjamin White, Nikolaos Kirkineziadis, Bernadette Tilley, Pennie Porter, Rachel Bryant, Natalia Robaczewska, Rafeeq Muhammed, Rehana Bi, Catherine Cotter, Jayne Grove, Kate Hong, Ruth Howman, Monica Mitchell, Sophie Clayton, Louise Rogers, Sugrah Sultan, Melanie Rooney, Charlotte Cottrill, Salil Singh, Chris Dawe, Robert Hull, Natalie Silva, Julie Chadwick, Laura Robertson, Jonathan Manning, Lauren Finlayson, Allison Roebuck, Joy Dawson, Sunil Sonwalkar, Naomi Chambers, Matthew Robinson, Andrew Haigh, Lear Matapure, Tim Raine, Varun George, Christina Kapizioni, Konstantina Strongili, Tina Thompson, Mohamed Ahmed, Christos Kontos, Claire Dawson, Christophe Bourges, Isabella Barbutti, Megan E Gozzard, Philip Hendy, Rhian Bull, Patricia Costa, Lisa Davey, Hayley Hannington, Kribashnie Nundlall, Catarina Martins, Laura Avanzi, Jaime Carungcong, Sabrina Barr, Richard Appleby, Emma Johnson, Eathar Shakweh, Kath Phillis, Rachel Gascoyne, Amanda Crowder, Amanda Whileman, Ian London, Jenny Grounds, Emmeline Martin, Susie Pajak, Jude Price, Kathryn Cawley, Sandra Powell, Nichola Kearsley, Anjan Dhar, Ellen Brown, Amanda Cowton, Kimberley Stamp, Ben Warner, Carmel Stuart, Louise Lacey, Shanika de Silva, Clare Allcock, Philip Harvey, Lesley Jones, Elise Cooke, Jayne Slater, Dominic King, Johanne Brooks, Pearl Baker, Hannah Beadle, Carina Cruz, Debbie Potter, Joe Collum, Farzana Masters, Aashish Kumar, Samantha Coetzee, Mihaela Peiu, Becky Icke, Jill Williams, Meena Raj, Edward Gaynor, Sibongile Chadokufa, Bonita Huggett, Hamza Meghari, Sara El-Khouly, Fevronia Kiparissi, Waffa Girshab, Lynda Russell-Walker, Christopher Jackson, Sara Sidler, Andrew Claridge, Emily Fowler, Laura McCafferty, Lesley Haxton, Peter Irving, Karolina Christodoulides, Angela Clifford, Patrick Dawson, Sailish Honap, Samuel Lim, Raphael Luber, Karina Mahiouz, Susanna Meade, Parizade Raymode, Rebecca Reynolds, Anna Stanton, Sherill Tripoli, Naomi Hare, Sopuluchukwu Odukwe, Senthuran Balachandran, Emma North, Jessica North, Bria Browne, Jessica Cordle, Ella Jameson, Yih Harn Siaw, Lane Manzano, Jonathan Segal, Ibrahim Al-Bakir, Imran Khakoo, Sofiya Portukhay, Nora Thoua, Katherine Davidson, Jagrul Miah, Lisa Canclini, Alex Hall, Hassina Furreed, Christine Mitchell-Inwang, Melony Hayes, Sally Myers, Alison Talbot, Jack Turnbull, Emma Whitehead, Katie Stamp, Alison Pattinson, Verghese Mathew, Leanne Sherris, Julie Wilcox, Sankaranarayanan Ramachandran, Hayley Robertson, Angela Harvey, Lucy Hicks, Tara-Marie Byrne, Leilani Cabreros, Hannah Downing-Wood, Sophie Hunter, Mohammad Aamir Saifuddin, Hemanth Prabhudev, Sharmili Balarajah, Jan Krucznski, Kalliopi Driva, Andrea D'Mello, Parith Shah, Rocio Castro-Seoane, Hajir Ibraheim, Laura E Constable, Jonathan W Lo, Melissa Torkizadeh, Sherine K Hermangild, Helen Sutherland, Elva Wilhelmsen, Katherine Mackintosh, Ajay M Verma, Juliemol Sebastian, Mohammad Farhad Peerally, Anne-marie Guerdette, Susan Coburn, Ching Yee Novem lam, Donna Durrant, Belinda Schaefer, Solange Serna, Muhammad Shahzad, Alexandra Kent, Lee Meng Choong, Benedetta Pantaloni, Pantelis Ravdas, Babu Vadamalayan, Stephen Foley, Becky Arnold, Cheryl Heeley, Wayne Lovegrove, Donna Sowton, Lynne Allsop, Heidi Gregory, Mandy Gill, Megan Holmes, Valeria Balan, Susan Smith, Sarah Turner, Philip J Smith, Alan Steel, Giovanna Bretland, Sarah King, Martina Lofthouse, Lindsey Rigby, Sreedhar Subramanian, David Tyrer, Kate Martin, Christopher Probert, Nikolaos Kamperidis, Temi Adedoyin, Manisha Baden, Jeannette Brown, Feba Chacko, Lisa Young, Michela Cicchetti, Mohammad Saifuddin, Priya Yesupatham, Rohit Gowda, Maureen Williams, Karen Kemp, Rima Akhand, Glaxy Gray, Anu John, Maya John, Tasnim Mohammed, Diamond Sathe, Natasha Jones, Jennifer Soren, Michael Sprakes, Julie Burton, Patricia Kane, Stephanie Lupton, Jacqueline Bartholomew, Elizabeth Denis, Alison Daniels, George MacFaul, Diane Scaletta, Loria Siamia, Felicity Williams, Chloe Green, Zeljka Ver, Chris Lamb, Mary Doona, Ashleigh Hogg, Lesley Jeffrey, Andrew King, R Alexander Speight, Jennifer Doyle, Ruth Owen, Jenny Haworth, Linda Patterson, Vithusa Varnaulasingam, Craig Mowat, Debbie Rice, Susan MacFarlane, Anne MacLeod, Samera Mohammed, Shona Murray, Anne Elliott, Mary Anne Morris, Louise Coke, Grace Hindle, Eirini Kolokouri, Catherine Wright, Claire Lee, Nicola Ward, Adele Dann, Melanie Lockett, Charlotte Cranfield, Louise Jennings, Ankur Srivastava, Lana Ward, Nouf Jeynes, Poonam Ranga, Praveen Rajasekhar, Lisa Gallagher, Jill Ward, Rae Basnett, Judy Murphy, Lauren Parking, Emma Lawson, Stacey Short, David Devadason, Gordon Moran, Neelam Khan, Lauren Tarr, Charmaine Olivia, Samantha Warbarton, Sian Kelly, Jimmy Limdi, Kay Goulden, Asad Javed, Lauren McKenzie, Julie Melville, Eleanor Liu, Joseph Sabine, Patricia Jacob, Denise McSorland, Nick Schofield, Lisa Cornwall, James Quirke, Emma Crook, Anne Turner, Pradeep Bhandari, Michelle Baker-Moffatt, Joanne Dash, Alison Le Poidevin, Hayley Downe, Lucille Bombeo, Helen Blackman, Rebecca Smith, Alan Wiles, Hannah Bloxham, Jose Dias, Evelyn Nadar, Hollie Curgenven, Ellie Gilham, Jonathan Macdonald, Shona Finan, Faye McMeeken, Misbah Mahmood, Stephanie Shields, John Paul Seenan, Des DeSilva, Susanna Malkakorpi, Rachel Carson, Holly Lawrence, Ofori Boateng, Felix Kpodo, Simon Whiteoak, Kelli Edger-Earley, Luke Vamplew, Joanna Samways, Sue Roffe, Sarah Ingram, Joel James, Sharon Botfield, Fiona Hammonds, Clare James, Zoe Berry, Gemma Aspinall, Sarah Hawkins, Marian Parkinson, Helen Gardner-Thorpe, Suzie Marriott, Clare Redstone, Halina Windak, Ana-Marie Adam, Hannah Mabb, Emma Stevenson, Jessica Record, Charles Murray, Cynthia Diaba, Fexy Joseph, Glykeria Pakou, Yvonne Gleeson, Annalyn Nunag, James Berrill, Natalie Stroud, Carla Pothecary, Lisa Roche, Keri Turner, Lisa Deering, Lynda Israel, Evelyn Baker, Maxine Nash, Andrew Fagbemi, Felicia Jennings, Imelda Mayor, Jill Wilson, Alice Wheeler, Nicola Phillips, John Gordon, Emma Levell, Silvia Zagalo, Ina Hoad, Bindu Anil, Richard Russell, Paul Henderson, Margaret Millar, Christopher Alexakis, Natalia Michalak, Cheryl Marriott, Sarah Stone, Veronika Pristopan, John Saunders, Helen Burton, Vanessa Cambridge, Tonia Clark, Charlotte Ekblad, Sarah Hierons, Joyce Katebe, Emma Saunsbury, Rachel Perry, Matthew Brookes, Kathryn Davies, Marie Green, Ann Plumbe, Clare Ormerod, Helen Christensen, Hannah Howlett, Anne Keen, Jonathan Ogor, Marie Greenhaigh, Karen Knowles, Shanzi Yin, Maria Poulaka, Alpha Anthony, Emily Newitt, Fiona Trim, Ruth Casey, Katherine Seymour, Catherine Reed, Lijo Joy, Edward Fogden, Kalisha Russell, Samia Hussain, Anne Phillips, Muaad Abdulla, Jeff Butterworth, Colene Adams, Mandy Carnahan, Elizabeth Buckingham, Danielle Childs, Alison Magness, Jo Stickley, Nichola Motherwell, Louise Tonks, Hannah Gibson, Kate Wistance, Caradog Thomas, Elaine Brinkworth, Lynda Connor, Amanda Cook, Tabitha Rees, Rachel Harford, Sean Farley, Marie Jones, Emma Wesley, Alison Moss, Jacob Lucas, Claire Lorimer, Maria Oleary, Maxine Dixon, Fiona Goodchild, Rebecca Twenlow, Corinne Pawley, Arvind Ramadas, Julie Tregonning, Olaku Okeke, Wendy Jackson, Ioannis Koumoutsos, Viji George, Swapna Kunhunny, Sophie Laverick, Isla Anderson, Sophie Smith, Joan Joyce, Sarala Janarthan, Kamal Patel, Mariam Ali, Hilda Mhandu, Aleem Rana, Katherine Spears, Joana Teixeira, Mark Mencias, Abigail Seaward, Jessica Sousa, Nooria Said, Mark Soomaroo, Valentina Raspa, Asha Tacouri, Nicholas Reps, Rebecca Martin, Tinashe Samakomva, Christian Selinger, Jenelyn Carbonell, Felicia Onovira, Doris Quartey, Alice L'Anson, Andrew Ashworth, Jessica Bailey, Angie Dunn, Gjuzel Bespaloi, Harold Rasalan, Zahid Mahmood, Racheal Campbell, Liane Marsh, Tricia Coughlan, Wisam Jafar, Janet Marrs, Christopher McPheat, Monira Rahman, Sarah Davies, Ruth Habibi, Ellen Jessup-Dunton, Teishel Joefield, Reina Layug, Vinod Patel, Joanne Vere, Victoria Turner, Susan Kilroy, Martina Coulding, Martyn Clark, Jacqueline McCormick, Attiya Nisar, Gareth Walker, Stacey Atkins, Jasmine Growdon, Becky George, Charlotte McNeill, Bryony Reed, Angela Foulds, Catherine Marshall, Michele Allison, Briony Dillon, Rachel Cooney, Lillie Bennett, Louise Bowlas, Sharafaath Shariff, Aileen Fraser, Dwayne Punnette, Rebecca Lambert, Charlotte Bishop-Hurman, Elizabeth Undrell, Katherine Belfield, Said Din, Catherine Addleton, Marie Appleby, Johanna Brown, Kathleen Holding, Catherine Fraser, Janice Birkenshaw, Jodie Williams, Kamille Maulion, Meg Lane, Arita Kravale, Claud Smith, Patricia Hooper, John deCaestecker, Olivia Watchorn, Ellie Clarke, Chris Hayward, Susan Inniss, Lucy Pritchard, Karen Rudge, Amanda Carney, Sarah Griffee, Jervoise Andreyev, Sathish Babu, Caroline Hayhurst, Carol Lockwood, Lynn Osborne, Amanda Roper, Karen Warner, Julia Hindle, Tara Lawrence, Kimberley Netherton, Caroline Watt, Kinga Szymiczek, Shameer Mehta, James Bell, William Blad, Lisa Whitley, Roman Jastrub, Dhamaraj Durai, Mark Baker, Elizabeth John Sivamurugan, Mim Evans, Fraser Cummings, Clare Harris, Amy Jones, Liga Krauze, Sohail Rahmany, Michelle Earl, Jenny Vowles, Audrey Torokwa, Mirela Petrova, Andrew Procter, Jo Stanley, Claudia Silvamoniz, Marion Bettey, Amar Wahid, Zoe Morrison, Rhian Thomas-Turner, Louise Yendle, Jennifer Muller, Marcus Mitchell, John Kirkwood, Anna Barnes, Rakesh Chaudhary, Melanie Claridge, Chiara Ellis, Cheryl Kemp, Ogwa Tobi, Jentus Milton, Emma Johnston, Metod Oblak, Carmen Winpenny, Marie-Louise Svensson, Jo Godden, Marium Ashhar, Debbie Alexander, Kate Covil, Lauranne Derikx, Sryros Siakavellas, Helen Baxter, Scott Robertson, Linda Smith, Beena Poulose, Anne Colemam, Margareta Balint, Gareth Rhys-Jones, Helen Watters, Susan Begg, Beatriz Grosalcalde, Judy Coyle, Kerrie Johns, Rachel Hughes, Janet Phipps, Abigail Taylor, Catherine MacPhee, Suzanne Brooks, Jolene John, Michelle Edwards, Katie Smith, Linda Howard, Dianne Wood, Ajay Muddu, Laura Barman, Janine Mallinson, Tania Neale, Diana Ionita, Kerry Elliot, Alison Turnball, Iola Thomas, Alice Thomas, Kelly Andrews, Jonathon Sutton, Caroline Mulvaney Jones, Julia Roberts, and Jeannie Bishop

Subjects
Hepatology, Gastroenterology, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5]
Abstract

Contains fulltext : 291657.pdf (Publisher’s version ) (Open Access) BACKGROUND: Anti-TNF drugs, such as infliximab, are associated with attenuated antibody responses after SARS-CoV-2 vaccination. We aimed to determine how the anti-TNF drug infliximab and the anti-integrin drug vedolizumab affect vaccine-induced neutralising antibodies against highly transmissible omicron (B.1.1.529) BA.1, and BA.4 and BA.5 (hereafter BA.4/5) SARS-CoV-2 variants, which possess the ability to evade host immunity and, together with emerging sublineages, are now the dominating variants causing current waves of infection. METHODS: CLARITY IBD is a prospective, multicentre, observational cohort study investigating the effect of infliximab and vedolizumab on SARS-CoV-2 infection and vaccination in patients with inflammatory bowel disease (IBD). Patients aged 5 years and older with a diagnosis of IBD and being treated with infliximab or vedolizumab for 6 weeks or longer were recruited from infusion units at 92 hospitals in the UK. In this analysis, we included participants who had received uninterrupted biological therapy since recruitment and without a previous SARS-CoV-2 infection. The primary outcome was neutralising antibody responses against SARS-CoV-2 wild-type and omicron subvariants BA.1 and BA.4/5 after three doses of SARS-CoV-2 vaccine. We constructed Cox proportional hazards models to investigate the risk of breakthrough infection in relation to neutralising antibody titres. The study is registered with the ISRCTN registry, ISRCTN45176516, and is closed to accrual. FINDINGS: Between Sept 22 and Dec 23, 2020, 7224 patients with IBD were recruited to the CLARITY IBD study, of whom 1288 had no previous SARS-CoV-2 infection after three doses of SARS-CoV-2 vaccine and were established on either infliximab (n=871) or vedolizumab (n=417) and included in this study (median age was 46·1 years [IQR 33·6-58·2], 610 [47·4%] were female, 671 [52·1%] were male, 1209 [93·9%] were White, and 46 [3·6%] were Asian). After three doses of SARS-CoV-2 vaccine, 50% neutralising titres (NT50s) were significantly lower in patients treated with infliximab than in those treated with vedolizumab, against wild-type (geometric mean 2062 [95% CI 1720-2473] vs 3440 [2939-4026]; p

Published
2023

4. React, reset and restore: Adaptation of a large inflammatory bowel disease service during COVID-19 pandemic

Author

Emma Whitehead, Amy Wilkinson, Shaji Sebastia, Greg Haire, Bethia Featherstone, Jessica Lisle, Haidee A. Gonzalez, Jack Turnbull, Rebecca Fory, Eileen Henderson, Alisson Pattinson, Katie Stamp, and Sally Myers

Subjects
Male, Referral, Pneumonia, Viral, 030204 cardiovascular system & hematology, Inflammatory bowel disease, Patient Care Planning, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Ambulatory care, Pandemic, Health care, Ambulatory Care, Humans, Medicine, 030212 general & internal medicine, Pandemics, Retrospective Studies, Service (business), Cross Infection, business.industry, Patient Selection, COVID-19 rapid report, COVID-19, Retrospective cohort study, General Medicine, Inflammatory Bowel Diseases, medicine.disease, Organizational Innovation, Telemedicine, United Kingdom, digestive system diseases, Female, Medical emergency, Coronavirus Infections, business, Delivery of Health Care, Cohort study
Abstract

Introduction Healthcare organisations have had to make adaptations to reduce the impact of the Coronavirus 2019 (COVID-19) pandemic. This has necessitated urgent reconfiguration within inflammatory bowel disease (IBD) services to ensure safety of patients and staff and seamless continuity of care provision. Aim To describe the adaptations made by a large inflammatory bowel disease service, caring for over 3,500 IBD patients, in response to the COVID-19 pandemic. Methods A diary record of responses to the pandemic were logged, and meeting minutes were reviewed. Data were recorded from IBD advice lines, multidisciplinary team (MDT) meeting minutes, infusion unit attendances, and electronic referral systems for the 8-week period from 9 March 2020 until 2 May 2020. Descriptive analysis was performed. Results The IBD service at Hull University Teaching Hospitals NHS Trust (IBD Hull) instituted rapid structural and functional changes to the service. Outpatient services were suspended and substituted by virtual consultations, and inpatient services were reduced and moved to ambulatory care where possible. The delivery of biologic and immunomodulatory therapies was significantly modified to ensure patient and staff safety. There was a substantial increase in IBD advice line calls. Conclusion The rapidly evolving COVID-19 pandemic required a prompt response, regular reassessment and planning, and continues to do so. We share our experience in of the successful adaptations made to our IBD service.

Published
2020
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5. HMO-5 Association of anti-infliximab antibodies and HLA-DQA1*05 variant in ulcerative colitis: A retrospective single centre study

Author

Alison Pattinson, Sally Myers, Alison Talbot, Haidee A. Gonzalez, Emma Whitehead, Sankaranarayanan Ramachandran, Jack Turnbull, Katie Stamp, and Shaji Sebastian

Subjects
Single centre, business.industry, Anti infliximab antibodies, Immunology, Medicine, Human leukocyte antigen, business, medicine.disease, Ulcerative colitis
Published
2021
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6. PMO-42 Accelerated dosing schedule with Ustekinumab in anti-TNF refractory Crohn's disease

Author

Emma Whitehead, Sally Myers, Alison Pattinson, Jack Turnbull, Haidee A. Gonzalez, Shaji Sebastian, Katie Stamp, and Alison Talbot

Subjects
Oncology, Schedule, medicine.medical_specialty, Crohn's disease, business.industry, medicine.disease, Refractory, Internal medicine, Ustekinumab, medicine, Tumor necrosis factor alpha, Dosing, business, medicine.drug
Published
2021
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10. SALL4 mediates teratogenicity as a thalidomide-dependent cereblon substrate

Author

Mariko Riley, Katie Stamp, Xinde Zheng, Yan Ren, Kate Blease, Chin-Chun Lu, Julia Hui, Lawrence G Hamann, Philip P Chamberlain, Gang Lu, Polat Abdubek, Mary E Matyskiela, Gondi Kumar, Maria Wang, Wei Fang, Aaron Carpenter, Thomas Clayton, Clifton Drew, Suzana Couto, Chung-Wein Lee, Mark Rolfe, Rupert Vessey, and James Hartke

Subjects
Male, 0301 basic medicine, Ubiquitin-Protein Ligases, Transgene, Induced Pluripotent Stem Cells, Mice, Transgenic, Nerve Tissue Proteins, Phocomelia, Protein degradation, Ligands, medicine.disease_cause, 01 natural sciences, Mice, 03 medical and health sciences, SALL4, Testis, Animals, Humans, Medicine, Molecular Biology, Adaptor Proteins, Signal Transducing, Zinc finger, Mutation, 010405 organic chemistry, business.industry, Cereblon, Homozygote, Zinc Fingers, Cell Biology, medicine.disease, Immunohistochemistry, eye diseases, Thalidomide, 0104 chemical sciences, DNA-Binding Proteins, Teratogens, 030104 developmental biology, Gene Expression Regulation, Proteolysis, Cancer research, Rabbits, business, Peptide Hydrolases, Transcription Factors, medicine.drug
Abstract

Targeted protein degradation via small-molecule modulation of cereblon offers vast potential for the development of new therapeutics. Cereblon-binding therapeutics carry the safety risks of thalidomide, which caused an epidemic of severe birth defects characterized by forelimb shortening or phocomelia. Here we show that thalidomide is not teratogenic in transgenic mice expressing human cereblon, indicating that binding to cereblon is not sufficient to cause birth defects. Instead, we identify SALL4 as a thalidomide-dependent cereblon neosubstrate. Human mutations in SALL4 cause Duane-radial ray, IVIC, and acro-renal-ocular syndromes with overlapping clinical presentations to thalidomide embryopathy, including phocomelia. SALL4 is degraded in rabbits but not in resistant organisms such as mice because of SALL4 sequence variations. This work expands the scope of cereblon neosubstrate activity within the formerly 'undruggable' C2H2 zinc finger family and offers a path toward safer therapeutics through an improved understanding of the molecular basis of thalidomide-induced teratogenicity.

Published
2018
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11. Target organ toxicities in studies conducted to support first time in man dosing: An analysis across species and therapy areas

Author

Katie Stamp, Steve Horner, R.D. Callander, Ruth Roberts, David Ryan, and Sally Robinson

Subjects
Central Nervous System, Male, Pathology, medicine.medical_specialty, Rodent, Drug Evaluation, Preclinical, Physiology, Spleen, Inflammation, Genitalia, Male, Toxicology, Risk Assessment, Species Specificity, Animals, Laboratory, biology.animal, Toxicity Tests, medicine, Animals, Humans, Dosing, Respiratory system, Kidney, biology, Drugs, Investigational, General Medicine, medicine.anatomical_structure, Liver, Toxicity, Female, Bone marrow, Chemical and Drug Induced Liver Injury, medicine.symptom
Abstract

An analysis of target organ toxicities in first time in man (FTiM) toxicity studies for 77 AstraZeneca candidate drugs (CDs) was conducted across a range of therapy areas. In the rodent, the most frequently affected organ was the liver followed by adrenal glands, kidney, spleen, bone marrow and thymus. In non-rodent, liver and thymus were the most frequently affected organs, followed closely by the testis and GI tract. The profile of affected organs was largely similar across the therapy areas of respiratory and inflammation, cardiovascular/gastrointestinal and CNS/pain. The oncology/infection therapy area differed with a larger range of organs affected. For the 75 CDs for which both rodent and non-rodent studies were conducted, new target organs were identified in non-rodents for 43 of the CDs. Notably, the changes seen only in non-rodents included organ systems of high relevance for human risk assessment such as the liver, male reproductive tissues and CNS. Additionally, profiles were similar for those CDs that progressed into human trials and those that did not. Overall, our data provide new insights into drug toxicity profiles in pre-clinical species and additionally confirm the value of using non-rodents as a second species in toxicity testing to support human safety.

Published
2013
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12. Comparison of computerized image analysis with traditional semiquantitative scoring of Perls' Prussian Blue stained hepatic iron deposition

Author

A. Peter Hall, Katie Stamp, Alison L. Bigley, Isabel Clamp, and Wendy Davies

Subjects
Male, Pathology, medicine.medical_specialty, Computer science, Iron, Toxicology, Histochemical staining, Statistics, Nonparametric, Pathology and Forensic Medicine, Image (mathematics), medicine, Image Processing, Computer-Assisted, Animals, Hepatic iron, Rats, Wistar, Molecular Biology, Protocol (science), business.industry, Histocytochemistry, Pattern recognition, Cell Biology, Organ Size, Rats, Liver, Data analysis, Female, Artificial intelligence, Sources of error, business, Perls' Prussian blue, Ferrocyanides
Abstract

Image analysis is now routinely employed as a tool in toxicologic pathology to help quantitate end points of efficacy and safety. It is regarded as a proficient and a sensitive technique to generate numerical data that can be easily interrogated for statistical evaluation. Traditional semiquantitative pathology scoring on the other hand is sometimes regarded as less accurate due to the limitations of the scoring systems employed and the day-to-day variations often noted between pathologists. We therefore decided to generate an optimized histochemical staining and image analysis protocol to compare the accuracy of semiquantitative scoring with computerized image analysis. In order to achieve this, we describe a standardized protocol for staining and image analysis that eliminates or minimizes as many sources of error as possible. The results of this experiment demonstrate that despite consistent variations in scoring between two independent pathologists, correlation with image analysis data of 0.91 to 0.95 (Spearman’s Rho test) was achieved. These data indicate that either image analysis or traditional semiquantitative scoring can generate accurate data. As a result of this, it appears that it is equally safe to employ either method dependent upon the complexity and the practicality of the task at hand provided that the experimental conditions are rigorously optimized and rigidly adhered to.

Published
2013

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