ACTOBIOTICS, MICROBE-BASED BIOPHARMACEUTICALS - ActoBio Therapeutics
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© 2019 ActoBio Therapeutics, Inc. All rights reserved. ACTOBIOTICS®, MICROBE-BASED BIOPHARMACEUTICALS for expression and local delivery of therapeutics at disease sites including the intestine, the mouth and the nasopharynx. 1 Corporate presentation - Pieter Rottiers, PhD, Chief Executive Officer, Director – JAN 2019
FORWARD-LOOKING STATEMENTS Some of the statements made in this presentation are forward-looking statements. These forward-looking statements are based upon our current expectations and projections about future events and generally relate to our plans, objectives and expectations for the development of our business. © 2019 ActoBio Therapeutics, Inc. All rights reserved. Although management believes that the plans and objectives reflected in or suggested by these forward-looking statements are reasonable, all forward-looking statements involve risks and uncertainties and actual future results may be materially different from the plans, objectives and expectations expressed in this presentation. All information in this presentation is as of the date marked on the cover page, and ActoBio Therapeutics™ undertakes no duty to update this information unless required by law. © 2018 ActoBio Therapeutics, Inc. All rights reserved. ActoBio Therapeutics is sharing the following materials for informational purposes only. Such materials do not constitute an offer to sell or the solicitation of an offer to buy any securities of ActoBio Therapeutics™. Any offer and sale of Intrexon’s securities will be made, if at all, only upon the registration and qualification of such securities under all applicable federal and state securities laws or pursuant to an exemption from such requirements. The attached information has been prepared in good faith by Intrexon. However, ActoBio Therapeutics makes no representations or warranties as to the completeness or accuracy of any such information. Any representations or warranties as to ActoBio Therapeutics shall be limited exclusively to any agreements that may be entered into by ActoBio Therapeutics and to such representations and warranties as may arise under law upon distribution of any prospectus or similar offering document by ActoBio Therapeutics . Trademarks Intrexon, ActoBio Therapeutics, ActoBiotics, Powering the Bioindustrial Revolution with Better DNA, and Better DNA are trademarks of Intrexon and/or its affiliates. Other names may 2 be trademarks of their respective owners.
ACTOBIO THERAPEUTICS™ - KEY INVESTMENT HIGHLIGHTS PRODUCT PLATFORM EXPERIENCE PORTFOLIO © 2019 ActoBio Therapeutics, Inc. All rights reserved. • ActoBiotics® is a fully integrated, cost- • Two Clinical stage programs in Phase • Straightforward and reliable effective & unique food microbe-based IIb and Phase Ib, with other programs cGMP manufacturing process delivery platform for therapeutics, with close to clinical stage • IP portfolio across the technology potential for superior efficacy and safety • Broad therapeutic application across a platform: through oral or local targeted delivery wide set of diseases with strong growth • >250 granted patents • Designed to perform specific biological dynamics. • >50 pending patent applications interventions • Target the (gut) mucosal immune system • Extensive regulatory acceptance of • Accelerates development and validated for: platform and applications regulatory path for new IND candidates: • Mucosal healing and decreasing • Experienced leadership team with
ACTOBIOTICS® - AN INTEGRATED MICROBIAL DRUG PLATFORM L. lactis Therapeutic gene inserted essential gene removed GENETIC SCALABLE SAFETY ENGINEERING MANUFACTURING © 2019 ActoBio Therapeutics, Inc. All rights reserved. • L. lactis has a long history of safe use in • Construction strategy allows for human nutrition minimum genetic modifications • Non-colonizing, non-human commensal • Engineered through chromosomal species allowing for control of dosage integration of single or multiple genetic and timing of exposure elements through precise, targeted • No known pathogenicity double homologous recombination • Oral delivery platform demonstrated • Host is engineered for environmental • Industrial microorganism used for safe for use in humans containment¹, preventing accumulation large scale food production of bacteria outside the body • cGMP manufacturing process • Engineering process established in- established house to allow for continual creation of • Following fermentation, the modified new drug candidates bacteria are freeze-dried and packaged 4 ¹ Steidler et al., 2003. Nature Biotechnology 21: 785-789.
DELIVERY OF ACTOBIOTICS® THERAPEUTICS © 2019 ActoBio Therapeutics, Inc. All rights reserved. 1. Genetically engineered 2. Capsule opens and 3. Bacterium releases the bacterium freeze dried and releases the bacterium directly therapeutic agent locally at inserted into enteric coated at the disease target target site (e.g. in GI tract) capsule 5
ACTOBIOTICS COMPARED TO EXISTING TREATMENTS ActoBiotics Classic Protein Biologics • Can be delivered in an oral capsule or in a topical solution • Intravenous administration • No known toxicity or immunogenicity observed • Systemic toxicity, immunogenicity observed • Targeted delivery to mucosa • Limited tissue penetration (notably in the gut) © 2019 ActoBio Therapeutics, Inc. All rights reserved. • Simultaneous delivery of multiple proteins • Single protein administration Treatment with ROA Purified 50,000 Indication Biologicals (Biological) ActoBiotics ROA ActoBiotics (topical) Oral Mucositis Palifermin (HSCT) Injected Buccal rinse IBD Anti-TNF Injected Oral capsule are as effective as ActoBiotics 32 Type 1 Diabetes Injected Oral capsule injected biologicals Insulin (Replacement) 1 1,000 (Immunotherapy) even at 1/1000th Chronic Injected Nasal spray TFF1 dose (ng) delivered Rhinosinusitis Anti-IL5 / anti-IL4R the dose for efficacy Celiac Disease - - Oral capsule 6
© 2019 ActoBio Therapeutics, Inc. All rights reserved. 7 PIPELINE ACTOBIOTICS CLINICAL AND DEVELOPMENT
ACTOBIO THERAPEUTICS KEY MILESTONES 1Q18 2Q18 3Q18 4Q18 1Q19 2Q19 3Q19 4Q19 1Q20 2Q20 3Q20 4Q20 Metabolic Target selection IBD Allergy Disease Skin Disease © 2019 ActoBio Therapeutics, Inc. All rights reserved. Clinical strain IBD selection & GMP AG017 AG018 PKU Celiac Disease CRSwNP Allergy production AG019 AG019 AG017 AG018 IBD IND/CTA T1D T1D Celiac CRSwNP PKU (IND) (CTA) Disease Allergy AG017 First patient in AG019 Celiac AG018 study T1D Disease CRSwNP AG013 AG019 AG013 AG019 AG017 DSMB review/data OM T1D OM# T1D* CeD primary endpoint (DSMB) (DSMB) Interim Interim Interim EOP2b EOP2a EOP1b Last patient out of AG019/ AG013 study T1D** OM## #1 month Follow-up; ## 1 year Follow-up * 6 months Follow-up, ** 1 year Follow-up 88
© 2019 ActoBio Therapeutics, ActoBio © 2019Inc. Therapeutics, All rights reserved. Inc. All rights reserved. ActoBio Therapeutics™ in Autoimmune & Allergic Diseases
STRATEGY BUILT ON RESEARCH FOUNDATION © 2019 ActoBio Therapeutics, Inc. All rights reserved. Huibregtse et al. J. of Immunol. 2009 Takiishi et al. JCI 2012 10
THE BURDEN OF AUTOIMMUNE DISEASES A QUICK AUTOIMMUNE DISEASE CHALLENGES & OPPORTUNITIES BREAKDOWN The National Institutes of Allergy and Infectious Diseases (NIAID) has estimated that: Top Challenges to Antigen-Specific Immune Tolerance Therapies • Identification, validation and targeting of key antigens © 2019 ActoBio Therapeutics, Inc. All rights reserved. • Complex clinical heterogeneity: < 100 autoimmune diseases $100BN • Achieving durable tolerance while ensuring safety and efficacy Estimated cost of treating autoimmune diseases in the US Top Opportunities in Antigen-Specific Immune Tolerance Therapies • Rapid identification and validation of key antigens 50M • Developing combined therapies to target multiple antigens in complex disease Estimated number of Americans with an autoimmune disease • Achieving specific tolerization of self-reactive immune cells without altering host immunity • Reducing development and production costs compared to traditional antibody or immune transplant approaches AND THAT'S WITHOUT TAKING INTO ACCOUNT TYPE 1 DIABETES! Source: Infographic THE BURDEN OF AUTOIMMUNE DISEASES created by 2nd Antigen-Specific Immune Tolerance Drug Development – March 26-28, 2019 Boston, USA www.as-immunetolerance.com 11
OPPORTUNITIES IN AUTOIMMUNITY / ALLERGY WITH ORAL ACTOBIOTICS Mucosal immune system Pancreas – T1D AG019 GI-tract - CeD AG017 (Intestinal, Buccal, Gingival, Sublingual) • Targeted delivery at mucosal GI-tract Buccal immune system food © 2019 ActoBio Therapeutics, Inc. All rights reserved. (Sublingual/rinse) allergy • Efficacy at lower amounts vs. oral purified protein • Co-delivery of multiple antigens/allergens ANTIGEN-SPECIFIC Oral • Co-delivery of antigen/allergen TREGS MIGRATE TO Joints - RA ActoBiotics with cytokines INFLAMED TISSUE • Reduction of local & systemic response Intestinal • Proof of concept demonstrated in Respiratory (capsule) autoimmune and allergic models tract Asthma/Rhinitis CNS - MS Oral Immune Tolerance 12 Desensitization
ORAL TOLERANCE INDUCTION WITH ORAL ACTOBIOTICS Oral L. lactis Secreting Ovalbumin Induces Ovalbumin-Specific Immune Tolerance2 – Superior efficacy versus purified protein © 2019 ActoBio Therapeutics, Inc. All rights reserved. • Treatment is accompanied by a local and systemic OVA-specific increase in IL-10 production • Treatment suppresses OVA-specific CD4+ T cell • Oral Ovalbumin (OVA) secreting L. lactis proved to be proliferation mediated by T-reg cells very efficient in suppressing OVA-induced DTH • Induced Treg cells following LL-OVA Treatment • Indicate suppression of systemic T cell responses can transfer OVA tolerance in vivo 13 • Superior efficacy versus oral purified OVA 2 Huibregtse et al., Gastroenterology 2007.
© 2019 ActoBio Therapeutics, Inc. All rights reserved. 14 Case Study ActoBiotics® in Type 1 Diabetes
AG019 IN TYPE 1 DIABETES - OPPORTUNITY CURRENT TREATMENT ACTOBIOTICS OPPORTUNITY GLOBAL MARKET SIZE/EPIDEMIOLOGY • Exogenous insulin • Value Proposition • Diet and lifestyle modification • First disease-modifying treatment that can prevent, delay or reverse • Disadvantages T1D © 2019 ActoBio Therapeutics, Inc. All rights reserved. • Lifelong treatment with exogenous insulin required • Mode of Action for survival • Induction of antigen-specific Treg cells will re-establish long-lasting 2018 Addressable Population: • Impact on quality of life due to fear of hypoglycemia and immunological tolerance to > 70,000 newly diagnosed day-to-day management islet-antigens aiming to maintain children per year functional β-cell mass • Unmet Need United States: 36,133 • Enhance efficacy by combination European Union: 40,046 • No disease-modifying treatment with broad immunoregulatory available agents (e.g. anti-CD3) Target Patient Clinical recent-onset T1D Demographic patients 15
AG019 IN TYPE 1 DIABETES - OPPORTUNITY 89% of new-onset T1D in animals cured by AG019 plus low-dose anti-CD34 10-25% Enrollment criteria © 2019 ActoBio Therapeutics, Inc. All rights reserved. predict therapeutic success (89% of 60% mice cured) • AG019 (LL-[PINS] + IL-10) + anti-CD3 mAb most effective • 60% of diabetic mice • Reverted to normal blood sugar levels • Treatment effective in 89% of mice treated at the Takiishi et al. 2012 • Preserved residual β-cell function early stage of diabetes • Halted insulitis progression • Starting glycemia and insulin autoantibody (IAA+) • Treatment induced specific FoxP3+ Treg positivity at study entry predicted therapeutic success cells for long-term disease suppression • Normoglycemia remained stable for the least 16 15 weeks post-treatment that was followed 4 Takiishi et al., 2017. Diabetes.
AG019 IN TYPE 1 DIABETES - OPPORTUNITY PINS-specific FoxP3+ Treg cells accumulate and proliferate in the pancreatic & peripheral lymph nodes #; &: respectively © 2019 ActoBio Therapeutics, Inc. All rights reserved. vs. week 6 and 14 CT; 1 symbol: p
AG019 IN TYPE 1 DIABETES - EXECUTIVE SUMMARY • L. lactis delivering hPINS and hIL-10 – Capsule formulation • Intended for the treatment of clinical recent-onset T1D in patients with residual functional β-cell mass • High efficacy when combined with low dose systemic anti-CD3 © 2019 ActoBio Therapeutics, Inc. All rights reserved. • Treatment effective in 89% of mice treated at the early stage of diabetes • Superior efficacy compared to monotherapy (AG019 or anti-CD3 alone) • PK, safety pharmacology and Repeat Dose Toxicity (RDT) studies completed • cGMP production of AG019 DS/DP completed • IND open; CTA submitted (Belgium) • First Patient Dosed in October 2018 • Interim End Of Phase Ib/IIa data – Q1 2020 18
AG019 – PHASE IB/IIA – STUDY DESIGN • STUDY TITLE: A prospective, multi-center, Phase Ib/IIa study to assess the safety and tolerability of different doses of AG019 administered alone or in association with teplizumab [anti-CD3] in patients with clinical recent-onset Type 1 Diabetes Mellitus (T1D) • INDICATION: Clinical recent-onset T1D in patients with residual functional β-cell mass • STUDY OBJECTIVES: • The primary objective of this study is to assess the safety and tolerability of different doses of AG019 alone (monotherapy) as well as © 2019 ActoBio Therapeutics, Inc. All rights reserved. AG019 in association with teplizumab (co- administration therapy). • The secondary objectives of this study are to obtain pharmacodynamic data of AG019 alone as well as AG019 in association with teplizumab; and to determine the potential presence of AG019 in systemic circulation and the presence of L. lactis bacteria in fecal excretion (pharmacokinetic profile). • STUDY DESIGN: • The Phase Ib (AG019 monotherapy) part of the study will enroll 4 sequential AG019 cohorts of 4-6 patients, in ascending dose cohorts and descending age cohorts. All patients in these cohorts will be treated with AG019 in an open label fashion. • The Phase IIa (AG019 combination therapy) part of the study will evaluate 2 cohorts of patients administered AG019 and teplizumab. The first 2 patients will be treated with double active treatment in an open label fashion. Patients 3-12 will be randomized (4:1) to receive double active treatment or double placebo in a double-blind fashion. • STUDY POPULATION: 8 single dose patients (treatment for 1 day) and up to 48 repeat dose patients (treatment for 8 weeks) aged 12-40 years will be enrolled in up to 25 sites in USA and Belgium 19 ClinicalTrials.gov Identifier: NCT03751007
© 2019 ActoBio Therapeutics, Inc. All rights reserved. 20 ActoBiotics® in Gastrointestinal Diseases
STRATEGY BUILT ON RESEARCH FOUNDATION © 2019 ActoBio Therapeutics, Inc. All rights reserved. Vandenbroucke et al. Gastroenterology 2004 Steidler et al. Science 2000 Vandenbroucke et al. Mucosal Immunol. 2010 21
OPPORTUNITIES IN GASTROINTESTINAL DISEASES WITH ORAL ACTOBIOTICS Oro-Gastrointestinal mucosal Oral cavity - OM AG013 receptors • Oral capsules offer better patient compliance • Targeted delivery to mucosal © 2019 ActoBio Therapeutics, Inc. All rights reserved. tissues without systemic exposure GI-tract - IBD AG020 • Efficacy through localized release at the (inflamed) intestinal mucosa COMBINATION • No evidence of problems THERAPY TO TARGET demonstrated with systemic therapy MULTIPLE MUCOSAL • No known immunogenicity DISEASE PATHWAYS • POC demonstrated superior efficacy GI-tract – in experimental IBD models Mucositis • Can deliver combinations of GvHD bioactive proteins CRC Liver - Mucosal Immunotherapy Metabolic/inflammatory 22 diseases
ACTOBIOTICS ACTIVE DELIVERY OF THERAPEUTIC AGENTS AT SITE OF INFLAMMATION Outcome of PK studies with oral L. lactis in mice with chronic colitis3 - Targeted delivery to mucosa © 2019 ActoBio Therapeutics, Inc. All rights reserved. L. lactis locates to the inflamed gut tissue as seen in confocal and electron microscopic analysis Immunohistochemistry analysis demonstrated active delivery of anti- TNF antibodies at the intestinal mucosa 3 Waeytens et al., 2007. Infl Bowel Dis.; Vandebroucke et al., 2010. Mucosal Immunol. 23
EFFECT OF ACTOBIOTICS TREATMENT ON COLITIS IN MOUSE MODEL Oral L. lactis secreting IL-10 (LLmIL10) significantly reduces colitis4 - Targeted delivery to mucosa A B © 2019 ActoBio Therapeutics, Inc. All rights reserved. Treatment daily for 2 or 4 weeks efficiently: • (A) Cured colitis in chronic DSS model • (B) Prevented onset of colitis in IL-10-/- mice • With ActoBiotics LLmIL10, a 10,000-fold lower dose was as effective as injected mIL10 • Demonstrates local delivery of therapeutic agents at disease site LLmIL10 = L. lactis secreting mIL-10 Bars represent the mean ± SEM. *P < 0.025; **P = 0.0151 24 4 Steidler et al., 2000. Science.
STRATEGY BUILDS ON STRONG FOUNDATION OF PRIOR RESEARCH Oral L. lactis Secreting anti-TNF Demonstrate Efficacy in Chronic Colitis5 Superior efficiency of oral vs systemic Purified anti-TNF *P < 0.05 compared to mock & LL-pTREX1 • Assessment of oral L. lactis anti-TNF and purified anti- 6.0 5.6 © 2019 ActoBio Therapeutics, Inc. All rights reserved. 7.0 5.4 5.5 TNF (oral and systemic) for efficacy in established 6.0 4.4 chronic enterocolitis Histological Score 5.0 3.1 4.0 • Proof of concept demonstrated in mouse colitis 3.0 models with oral ActoBiotics : 2.0 1.0 • Superior efficacy versus purified anti-TNF (oral and 0.0 systemic): ActoBiotics represents a nearly ~50% LL-MT1-MT1 PBS MT1-MT1 LL-pTREX1 Mock MT1-MT1-AR1 decrease in intestinal inflammation versus ~25% and ~5% with oral and systemic purified anti-TNF, respectively • No immunogenicity issues in contrast with systemic purified anti-TNF Oral Treatment Systemic Treatment • Activity restricted to intestine - No interference with LL-pTREX1: L. lactis Empty Vector Control LL-MT1-MT1: L. lactis-Secreting Anti-mTNF systemic bacterial infections MT1-MT1(-AR1): Purified Anti-mTNF (50mg/kg oral; 25mg/kg systemic) 25 5 Vandebroucke et al., Mucosal Immunol. 2010
© 2019 ActoBio Therapeutics, Inc. All rights reserved. ActoBiotics® in Inflammatory Bowel Disease Case Study 26
AG020 – MULTIPLE EFFECTORS IN INFLAMMATORY BOWEL DISEASE DISEASE SNAPSHOT CURRENT TREATMENT PARADIGM GLOBAL MARKET SIZE/EPIDEMIOLOGY • Risk Factors: • Current Treatment Pathway: • Complex interactions between • Aminosalicylates genetics, environment and gut • Corticosteroids © 2019 ActoBio Therapeutics, Inc. All rights reserved. microbiota • Immunomodulators (AZA, 6-MP, anti-TNF, etc.) • Symptoms: • Disadvantages of Current Treatments: • Vary depending on the location and 2019 Addressable Population: • Systemic administration with risks for severity of inflammation, but may infections, cancer, immunogenicity include diarrhea, bleeding ulcers, US: 52,000 (UC) / 44,000 (CD) • Lack of full remission and loss of EU: 94,00 (UC) / 62,000 (CD) abdominal pain, weight loss, anemia response Japan: 8,600 (UC) / 2,800 (CD) and extra-intestinal manifestations • Unmet Need: • Efficacious drugs or drug combinations without side-effects and more convenient administration 1L Mild / Moderate CD Target Patient Demographic 2L Mild / Moderate UC 27
AG020 – MULTIPLE EFFECTORS IN INFLAMMATORY BOWEL DISEASE • ActoBiotics® demonstrated therapeutic efficacy in animal models of IBD. • When orally delivered by ActoBiotics, the anti-inflammatory cytokine IL-10, mucosal healing trefoil factors (TFF) 1, 2 and 3, and antibodies against TNFα, each individually showed an initial level of reduction of inflammation in mice models of disease. • ActoBiotics® have also been demonstrated to be safe and tolerated in human Phase 1 clinical trials. © 2019 ActoBio Therapeutics, Inc. All rights reserved. • Seek to improve upon these positive results by combining multiple treatments in a single dosage, targeting established as new disease pathways identified by recent research. Development strategy based on: • Oral therapy • High efficacy through topical delivery • Novel mechanisms/combination approaches to improve efficacy • Superior efficacy/safety to systemic biologicals • Favorable safety/cost profile allows for sustained treatment over years vs. days/weeks • Test this multiple effector approach in validated animal disease models and then enter human clinical trials. 28
A unique delivery platform precisely tailored for specific disease modification ACTOBIOTICS®, MICROBE-BASED Specifically designed to target disease areas with high unmet need BIOPHARMACEUTICALS Rapid development of new candidates for expression and local delivery of therapeutics at Targeted delivery via oral capsule, oral rinse or topical solution disease sites including the intestine, the mouth and © 2019 ActoBio Therapeutics, Inc. All rights reserved. Demonstrated safety and tolerability the nasopharynx Robust and scalable manufacturing process Feel free to contact us for more information: communications@actobio.com Our factsheet can be downloaded in the investors section on actobio.com 29
KEY PUBLICATIONS Clinical • Limaye SA, et al. Phase 1b, multicenter, single blinded, placebo-controlled, sequential dose escalation study to assess the safety and tolerability of topically applied AG013 in subjects with locally advanced head and neck cancer receiving induction chemotherapy. Cancer. 2013;119(24):4268-4276. • Braat H, et al. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease. Clinical Gastroenterology and Hepatology. 2006;4:754-759. Preclinical • Takiishi T, et al. Reversal of diabetes in NOD mice by clinical-grade proinsulin and IL-10-secreting Lactococcus lactis in combination with low-lose anti-CD3 depends on the Induction of Foxp3- Positive T cells. Diabetes. 2017;66(2):448-459. © 2019 ActoBio Therapeutics, Inc. All rights reserved. • Robert S, et al. Oral delivery of glutamic acid decarboxylase (GAD)-65 and IL10 by Lactococcus lactis reverses diabetes in recent-onset NOD mice. Diabetes. 2014;63(8):2876-2887. • Takiishi T, et al. Reversal of autoimmune diabetes by restoration of antigen- specific tolerance using genetically modified Lactococcus lactis in mice. Journal of Clinical Investigation. 2012 May 1;122(5):1717-25 • Caluwaerts S, et al. AG013, a mouth rinse formulation of Lactococcus lactis secreting human Trefoil Factor 1, provides a safe and efficacious therapeutic tool for treating oral mucositis. Oral Oncology. 2010 Jul;46(7):564-70. • Vandenbroucke K, et al. Orally administered L. lactis secreting an anti-TNF Nanobody demonstrate efficacy in chronic colitis. Mucosal Immunology. 2010 Jan;3(1):49-56. • Huibregtse IL, et al. Induction of antigen-specific tolerance by oral administration of Lactococcus lactis delivered immunodominant DQ8-restricted gliadin peptide in sensitized nonobese diabetic ABo DQ8 transgenic mice. Journal of Immunology. 2009 Aug 15;183(4):2390-6. • Vandenbroucke K, et al. Active delivery of trefoil factors by genetically modified Lactococcus lactis prevents and heals acute colitis in mice. Gastroenterology. 2004;127:502-513. Platform • Rottiers P, De Smedt T and Steidler L. Modulation of gut-associated lymphoid tissue functions with genetically modified Lactococcus lactis. International Reviews of Immunology. 2009;28:465- 486. • Huibregtse IL, et al. Induction of ovalbumin-specific tolerance by oral administration of Lactococcus lactis secreting ovalbumin. Gastroenterology. 2007;133:517-528. • Steidler L, et al. Biological containment of genetically modified Lactococcus lactis for intestinal delivery of human interleukin 10. Nature Biotechnology. 2003;21:785-789. • Steidler L, et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science. 2000;289:1352-1355. • Steidler L, et al. Mucosal delivery of murine interleukin-2 (IL-2) and IL-6 by recombinant strains of Lactococcus lactis co-expressing antigen and cytokine. Infection and Immunity. 1998;66:3183-3189. • Steidler L, et al. Secretion of biologically active murine interleukin-2 by Lactococcus lactis subsp. lactis. Applied and Environmental Microbiology. 1995;61(4):1627-1629. 30
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