Infectious Disease Programs:

Transcription

1 Infectious Disease Programs: Valortim (MDX-133) Fully Human Anti-Anthrax Toxin MAb Candidate for Project BioShield Procurement Israel Lowy, M.D., Ph.D. Senior Director, Clinical Science and Infectious Diseases Medarex, Inc. R&D Day December 9, 25 Anthrax: Bacillus Anthracis B. Anthracis is a gram-positive, spore-forming bacillus that can cause acute infection in animals and humans Infection can occur through a break in the skin, ingestion, or by inhalation Mortality in GI and inhalational forms, if left untreated, approaches 1% Agent of Bioterrrorism 5 of 11 inhalational cases led to death despite antibiotics and ICU care 1

2 Antibodies to PA As Antitoxins: Multiple Potential Targets Potential MAb Activity: 1. Attachment 2. Processing 3. Multimerization 4. Binding of EF/LF 5. Internalization 6. Pore formation How to Identify Most Potent Anti-PA MAb? Affinity of Binding to PA-83/ PA-63 - Highest affinity screening by Biacore, ELISA, etc Blockade of Binding of PA to: toxin receptor or to EF/LF - Anthrax Toxin Receptor: eg murine MAb 14B7 - LF or EF component: eg murine MAb 1G3 Potency in Toxin Neutralization Assay (TNA) - High titer immune sera correlate with TNA activity - Standard for vaccine response in clinical trials We chose HuMAbs with best TNA potency, and let the biology identify the optimal target in the toxin pathway 2

3 Toxin Neutralization Assay PA 83 + LF or EF macrophage cell line J774 3 hours 37 o C % Viabilty Valortim (MDX-133): Toxin Neutralization Activity Viability, % ED5=.8µg/mL 14B7 ED5=1.1µg/mL 1G3 ED5=.3µg/mL Control IgG 1G3- Most potent murine mab Characterized by S. Little (USAMRIID) 14B7- Receptor blocking murine mab Characterized by S. Little (USAMRIID) 1 Antibody Concentration, µg/ml 3

4 TNA Activity of Valortim (MDX-133) vs. CDC Human Reference Plasma % Viability AVR81 = 19 µg/ml anti-pa IgG CDC ref. plasma Valortim.8 µg/ml.68 µg/ml Valortim: ~ 85x > specific activity relative to AVR81 AVR81 Reference Standard: pooled polyclonal antisera from individuals vaccinated with approved AVA vaccine Anti-PA antibody concentration, µg/ml Results confirmed by CDC Receptor Binding Studies with Human Monocytes Control PA-FITC MDX-133 and AVR81 DO NOT block receptor binding by Anthrax PA +mmab 14B7 % blocking 78% +MDX-133 % PA-FITC + AVR81 4

5 Valortim (MDX-133) in Rabbit Inhalation Model: Post-Exposure Prophylactic and Therapeutic Activity Saline Saline 1 mg/kg (day 1) + 1 mg/kg (day 5) 1 mg/kg (day 2) + 1 mg/kg (day 6) 1 1 % Survival hours post % Survival hours post Days post exposure Days post exposure Exposure ~ 3 LD 5 Valortim (MDX-133) in Cynomolgus Monkey Model: Potent Activity with Intramuscular (IM) Dosing 6 Number surviving saline 1. mg/kg 1. mg/kg Days after challenge 5

6 Antigen Binding How Does Valortim Work? Fc domain Valortim DOES NOT prevent binding of PA to cells Are other regions of the MAb required for activity? Fc domain interacts with FcR on macrophages/dc Fc-FcR mediates common effector functions of antibodies Does Valortim require the Fc region? Interact with FcR? In Vitro Toxin Neutralization: Valortim (MDX-133) Activity is Markedly Enhanced by FcR Interaction Lethal Toxin Neutralization mab 133 F'2 133mAb + FcR block EC-5s: 6.5 ng/ml 5 ng/ml 22 ng/ml % Viability Antibody Concentration, µg/ml 6

7 FcR Augmentation of Toxin Neutralization: Found in Some, But Not All MAbs 1 without 2.4G2 with 2.4G2 Blocking of Toxin Neutralization 8 % Viability MDX133 ms1g3 5D5 14B7 Human Toxin Neutralizing Antisera Elicited by Anthrax Vaccine Also Augmented by FcR Interaction 1 Lethal Toxin Neutralization with Human Reference Standard Serum 8 without FcR block with FcR block % Viability µg/mL.5µg/mL.25µg/mL AVR-81 Human Reference Standard Serum anti-pa IgG Concentration 7

8 Anthrax Toxin and Proposed Mechanism of Neutralization by Valortim (MDX-133) PA 2 PA 63 LF or EF PA 83 Anthrax toxin receptor Fc receptor Valortim (MDX-133): Summary Attractive candidate for BioShield Biodefense procurement - Post-Exposure Prophylaxis (PEP): non-human primates at 1 mg/kg IM lowest dose tested to date - Durable pharmacokinetic level of protection at 1 mg/kg IM - Therapeutic activity in symptomatic animals High TNA potency in vitro is FcR dependent - Demonstrated by independent experimental approaches - Property shared with other MAbs and polyclonal sera including the human protective immune response to anthrax vaccination - Not seen with MAbs that simply block PA binding to cell - May contribute to high potency seen in vivo 8

9 How Did We Get Here? Valortim development initiates as collaborative effort with Dartmouth Medical and USAMRIID (October 21) - First Valortim Rabbit Data in June 23 NIH/NIAID awards two grants (>$7 M) for research and development of Valortim (September 24) PharmAthene and Medarex enter into a collaborative agreement for advanced development and commercialization of Valortim (November 24) Where Are We Going? Manufacturing Progress - High-yield production process developed - High concentration IM formulation developed Phase I initiated September 25 - Completion expected by 1Q6 Additional animal efficacy studies supported by NIH - Post-exposure prophylaxis, therapeutic Second round of HHS procurement RFP for anthrax - Expect to be issued in 1Q6 - Will be led by PharmAthene 9

10 Acknowledgements Valortim (MDX-133) Product Development NIAID Valortim R&D Program Medarex, Inc. Laura Vitale Tom O Neill Diann Blanset Joel Goldstein Haile Ghebremariam Xi-Tao Wang Tibor Keler Geoff Nichol Dartmouth Medical School Ron Taylor Michael Fanger 1