Phase 1 trial of MOv18, a first-in-class IgE antibody therapy for cancer James Spicer 1,2 , Bristi Basu 3,4 , Ana Montes 2 , Udai Banerji 5,6 , Rebecca Kristeleit 7,8 , Gareth J Veal 9 , Christopher Corrigan 1,2 , Stephen Till 1,2 , George Nintos 2 , Tim Brier 1 , Ionut G Funingana 4 , Joo Ern Ang 5,6 , Kam Zaki 8 , Annie Griffin 10 , Claire Barton 11 , Paul Jones 12 , Sarah Mellor 12 , Susan Brook 12 , Katie Stoddart 12 , Christopher Selkirk 12 , Simon Carroll 12 , Heike Lentfer 12 , Natalie Woodman 1 , Amy Pope 1 , Giulia Pellizzari 1 , Mano Nakamura 1 , Kristina M Ilieva 1 , Atousa Khiabany 1 , Chara Stavraka 1 , Hannah Gould 1 , Jitesh Chauhan 1 , Heather J Bax 1 , Sarah Pinder 1,2 , Debra H Josephs 1,2 & Sophia N Karagiannis 1 1. King’s College London, London, UK 7. University College London, London, UK 8. University College London Hospitals NHS Foundation Trust, 2. Guy’s and St Thomas’ NHS Foundation Trust, London, UK London, UK 3. University of Cambridge, Cambridge, UK 4. Cambridge University Hospitals NHS Foundation Trust, 9. Newcastle University, Newcastle upon Tyne, UK 10. University of Southampton, Southampton, UK Cambridge, UK 5. Institute of Cancer Research, Sutton, UK 11. Barton Oncology Ltd, London, UK 12. Cancer Research UK, London, UK 6. Royal Marsden Hospital, Sutton, UK
PBS IgG IgE Background • all antibodies approved for the treatment of cancer are monoclonal IgGs • IgE biology, compared with IgG, offers potential for enhanced immune surveillance and superior effector cell potency against tumors: - very high affinity for Fc e Rs - receptors expressed on tissue-resident effector cell types - no inhibitory Fc receptor for IgE IgG IgE Josephs D et al. Cancer Res (2017) • immunocompetent rat model • no IgE therapy previously tested in humans • syngeneic tumor expressing FR a • first GMP manufacture of IgE • efficacy assessed from number and density of pulmonary metastases • total starting dose = 70µg • no allergic tox
i) skin prick testing pre-IV dosing Study design and safety mitigation Eligible patients: • advanced FR a + solid tumours • adequate organ function 24 patients treated to date • no history of severe allergy Cohort Dose level • absence of conmeds or comorbidities 1 70 µg increasing risk in event of anaphylaxis ii) basophil activation test (BAT) pre-IV dosing 2 250 µg 100 Trial schema: Fold change in CD63 6x weekly 80 3 500 µg infusions 60 4 700 µg Bax et al. Allergy 2020 40 5 1.5 mg CT response 20 assessment 6 3 mg 4 2 3x 2-weekly 0 maintenance 1 2 3 E E E g g g l l l o o o I I I r r r infusion 8 8 l t t t o 1 1 n n n r o o o v v t O O n C C C o M M e e e C v v v b P i i i t t a M t i i i s s s L Off study I o o o P P P & follow-up
Anaphylaxis in single patient at 500µg Safety • clinical features; serum tryptase elevation 30 Treatment-related AEs: Serum tryptase (ng/mL) 20 100 urticaria day 1 Grade 3 Grade 2 10 Grade 1 80 % of patients 0 e t r r s h h r P o 2 6 P 60 • interpretation of positive BAT at baseline - prevalence in population 40 100 Fold change in CD63 80 20 60 40 0 20 a s a e e 0 i u m u h r 1 2 3 E E E g c a t g g g i e l l l o o o c a I I I r i h r r r 8 8 l t u t t t o i d n n n 1 1 a r v t t o o o v t r r y F a O O n C C C P o M M U e r e e e C E v v v b P H i i i t t t a M i i i s s s L I o o o P P P • subsequently, BAT+ = exclusion criterion
Anti-tumor activity Pharamcokinetics; ADA Patient 10/019: 700µg. Measurable response not RECIST PR Pharmacokinetics: 6 weeks 100 baseline Cohort 5 Cohort 4 Cohort 3 Cohort 2 MOv18 (ng/mL) Cohort 1 50 mean t 1/2 = 9.2 hours 300 CA125 (U/ml) 200 0 0 10 20 Hours 100 Anti-drug antibody : ADA detected in 3*/22 evaluable 6x weekly IMP 3x 2-weekly 0 patients at 6 weeks and/or at off study follow up (>8 weeks) -20 0 20 40 60 80 100 * 1 ADA is suspected: data under review Days
Conclusions • IgE biology is well suited for anti-cancer therapy • administration is tolerable in most patients; single episode of anaphylaxis: - resolved quickly with standard management - successful mitigation using baseline BAT for all subsequent patients • evidence of transient anti-tumor activity at 700 µg • dose escalation continues • these results support for the first time the safety and potential efficacy of IgE as a treatment for cancer • clinical testing of class-switched IgE versions of Josephs D et al. Cancer Res (2017) approved IgG drugs seems warranted Pellizzari G et al. EBioMedicine (2019)
Acknowledgements and disclosure The authors thank the patients and their families for participating in this study This trial was funded and sponsored by Cancer Research UK. Additional financial support was provided from the UK Department of Health and Cancer Research UK via Experimental Cancer Medicine Centre grants to King’s Health Partners, the University of Cambridge/Addenbrooke’s Hospital, University College London/UCL Hospital NHS Trust, and Institute of Cancer Research/Royal Marsden Hospital JS and SK are co-founders of IGEM Therapeutics Ltd. HB is employed through a fund from IGEM Therapeutics Ltd. SK holds a patent on anti-tumour IgE antibodies Contact: james.spicer@kcl.ac.uk
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