A disease and antibody biology approach to antibody drug discovery

Transcription

1 A disease and antibody biology approach to antibody drug discovery Björn Frendéus, PhD VP, Preclinical research Presenter: Björn Frendéus Date:

2 Antibodies have revolutionized Cancer Treatment! Rituximab (Anti-CD20 mab) Molina, Ann Review Med

3 Breast cancer Unmet medical need herceptin only15-30% of patients overexpress Her2 Hematologic malignancies rituximab many blood cell cancers do not express CD20, or acquire resistance to anti- CD20 mab therapy For most types of cancer effective (curative) mab therapies are lacking Great unmet medical need also in chronic inflammatory disorders (IBD, SLE, MS) 3 We need to develop novel, more effective, antibodies!

4 How? How? 4

5 : Therapeutic antibody development mab efficacy = f (Target Biology) x f (Antibody Biology) 5

6 mab structure and function Fv 1. Modulation of ligand:receptor signalling (small molecule) 1. Target biology 2. Immunity 2. Antibody biology Innate 6 Adaptive

7 Antibody biology clinical evidence Rituximab (anti-cd20) treated NHL patients Immune Cell Cancer Cell High affinity FcgR Ab biology effect Low affinity FcgR 0.02) 7

8 Antibody biology clinical evidence Survival of herceptin (anti-her2) treated breast cancer patients Immune Cell High affinity FcgR Cancer Cell Low affinity FcgR High affinity FcgR patient Ab biology effect Figure. Adjusted Kaplan-Meier estimates of progression-free survival after herceptin treatment by FcgR3a genotype 8 Low affinity FcgR patient

9 Biologic effect Target Ab 2. Immunity Innate Adaptive 9 Park et al, 2010

10 Tumor cell death (%) mab efficacy = f (Target Biology) x f (Antibody Biology) B1 Rituximab 1F5 Ab mechanism-of-action Programmed cell death In vivo therapeutic activity Complement Cell lysis CDC Cragg & Glennie 2004 Three CD20 antibody clones (Rituximab, 1F5, B1) on same backbone (Fc) 10 similar affinities (Kd = 3-8 nm) Cragg & Glennie

11 Summary antibody biology Antibodies are highly dynamic molecules that have a unique ability to activate patient immunity Antibodies are individuals, differ greatly by efficacy and mechanism-of-action! It is not possible to predict antibody efficacy or mechanism of action merely from target specificity or target biology mab efficacy = f(target biology) x f(antibody biology) Antibodies ability to confer Fc:FcgR-dependent antitumor activity correlates with clinical and in vivo therapeutic activity 11

12 How? 12

13 13

14 1. The target specificity focused mab discovery approach IV. Preclinical & Clinical Development Source of human antibodies (n-coder, >10 10 unique mabs) I. Isolation of target specific antibodies III. In vivo PoC Lead Candidate ID Validated target Clinically Experimentally II. In vitro functional screening of target-specific mab 14

15 Limitations of target specificity-focused approaches Difficult to predict which antibody is most efficacious based on specificity Antibodies to alternative structures may show promising, sometimes unexpected, antitumor effects Cheson NEJM

16 Desired characteristics Next Gen Ab s 1. Tumor cell targeting Bind (either of several) tumor cell upregulated receptor epitopes disease-associated, functionally superior (e.g. B1 anti-cd20), activated receptor, truncated receptor etc 2. Improved anti-tumor activity Efficacy (comp gold-standard ) Activity against currently untreatable tumors Mode-of-action: FcgR-dependent anti-tumor activity Pronounced programmed cell death 3. Safe and well-tolerated 16

17 2. FIRST - a function-first approach to therapeutic antibody discovery 5. Preclinical & Clinical Development 4. In vivo PoC 1-3 Abs n-coder 1. Differential biopanning 20,000,000,000 Abs <10 Abs Patient cells 3. Target identification <100 unique Abs 2. Functional screening of target-specific mab Gold-standard 1000 s unique Abs High-throughput IgG production ICAM-1 (BI-505) s unique Abs

18 Disease Biology & mab MoA Focus Oncology Inflammation PlGF (M2 block) undisclosed (T1 diabetes) (prostate cancer) undisclosed undisclosed (breast, prostate cancer) (CLL) undisclosed (CLL) FIRST-CLL FIRST-AML undisclosed (immunology) undisclosed (CLL, MF Fc-FcgR Moa) (Myeloma, MF MoA) ICAM-1 Factor VIII oxldl (M1 block, M1->M2 skewing?) (Thrombosis, coagulation cascade) undisclosed (M1 block, M1->M2 skewing) Fc-FcgR MoA Low BioInvent expertise High 18 Myeloid cell Biology/MoA

19 Multipronged approach to development of next generation anti-cll therapeutic mab Depletion of CLL cells in proliferating centers (spleen, bone marrow) Two predefined targets strongly associated with Chronic Lymphocytic Leukaemia (undisclosed) FIRST discovery of most efficacious n-coder mab targeting CLL-upregulated surface receptor epitopes Pronounced Fc-FcgR-mediated tumor cell killing Primary patient CLL cells used throughout discovery process 19

20 CD5 In vivo CLL model A unique experimental model for evaluation of antibody-mediated depletion of CLL cells in proliferating centres in vivo Purify PBMC ~ 80% CLL cells Blood from CLL patient Inject CLL cells into immuno-deficient, irradiated mice Negative control CLL cells home to lymphoid organs IHC Human CLL cells CLL cells Proliferating human cells Human T-cells CD19 20

21 Rituximab effectively depletes solitary, but not stromal-cell associated, patient CLL cells in vivo hucll-scid mouse mab-treatment (ctrl mab or Rituximab 10mg/kg) Peritoneum Spleen 21

22 Functionally distinct subpopulations of macrophages M1 M2 22 Mosser & Edwards, Nat Rev Immunol, 2008

23 Macrophages in inflammatory diseases M1 macrophages - Classically activated Pro-inflammatory Cytotoxicity Tissue injury M2 macrophages - Alternatively activated Anti-inflammatory Tissue repair 23

24 Macrophages in cancer M2 macrophages - Alternatively activated tumor growth angiogenesis metastases immune suppression Anti-inflammatory Tissue repair M1 macrophages - Classically activated Malignant myeloid cells Pro-inflammatory Cytotoxicity Tissue injury Cause of malignancy 24

25 Hypothesis Inflammatory Diseases mabs that inhibit the M1 phenotype, or skew M1 macrophages towards M2, holds therapeutic promise. M1 M2 (includes TAMs) Cancer mabs that inhibit the M2 phenotype, or skew M2 macrophages towards M1, holds therapeutic promise. Fc-FcgR-dependent killing of cancerous myeloid cells (in, for example, AML) holds therapeutic promise. 25

26 M1/M2-associated indications Inflammatory Diseases Inflammatory bowel disease (IBD) Rheumatoid arthritis (RA) Systemic lupus erythematosus (SLE) Psoriasis Sjogren s syndrome Multiple sclerosis (MS) Type II diabetes Orphan diseases Cancer Solid cancers where frequency of infiltrating macrophages correlates with poor prognosis; for example, breast, prostate, kidney, lung and glioma. Lymphomas Acute myeloid leukemia (AML) 26

27 Summary BioInvent research strategy: Development of therapeutic mab through understanding of disease biology and antibody biology mab efficacy = f(target biology) x f(antibody biology) Disease Biology and mab MoA foci Oncology and inflammation Fc:FcgR-dependent MoA Myeloid cell biology 27

28 Q & A 28