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1. Introduction
2. (1) Introduction to antibody engineering
3. IgG antibodies as therapeutic agents
4. IgG is the preferred class
5. Antibody modes of action
6. Human IgG Fc receptors
7. IgG-FcRIII crystal structure
8. The IgG receptor FcRn
9. Immunoglobulin frame system
10. Humanisation of Campath-1G
11. Effector functions of human Ig isotypes
12. Mechanism of action of Campath antibodies
13. Human IgG1 was effective in therapy
14. (2) Engineering of functions
15. Case study: FMAIT
16. A protective antibody for use in FMAIT?
17. Ideal properties of a protective antibody in FMAIT
18. Engineered antibody to inhibit cell killing?
19. Effector functions of human IgG subclasses
20. Human IgG subclasses - similarity in sequence
21. Transferring motifs between human subclasses
22. Sequences of modified constant regions
23. Summary of terminology of modified antibodies
24. Schematic of G1-delta-a
25. Schematic of G1-delta-b/c
26. Schematic of G1-delta-ab/ac
27. Target antigen systems for modified antibodies
28. CD52 target antigen system
29. RhD target antigen system
30. Engineering of functions - (2a) - complement
31. Complement-mediated lysis of mononuclear cells
32. Inhibition of complement-mediated lysis
33. (2b) Results for high affinity FcRI binding (CD64)
34. Binding of modified antibodies to FcRI
35. Titration of binding to FcRI
36. Chemiluminescent response of human monocytes
37. Inhibition of chemiluminescent response
38. Inhibition of chemiluminescence to clinical sera
39. (2c) Results for FcRII low affinity receptors (CD32)
40. Immunocomplex binding to low affinity receptors
41. Binding to FcRIIa (131R allotype)
42. Binding to FcRIIa (131H allotype)
43. Binding to FcRIIb
44. Comparison of binding to IIa and IIb receptors
45. (2d) Results for FcRIII receptors (CD16)
46. Binding to FcRIIIb receptor
47. Activity in ADCC to RBC
48. Inhibition of ADCC to RBC
49. Inhibition of ADCC by anti-RHD
50. (2e) Summary of results
51. Mutations effect is not predicted by WT functions
52. Comparison of delta-b and delta-c mutations
53. Summary of activities of modified antibodies
54. (3) Clinical volunteer study with selected mutations
55. Volunteer study with mutated and WT RhD Abs
56. Study with mutated and WT RhD Abs - results
57. Antibodies with modified Fc regions inhibit killing
58. (4) Mutations that enhance activity
59. Sequences of IgG antibodies in the CH2 region
60. Human IgG1-FcR model
61. Positions of differences in FcRIIa and FcRIIb
62. Position of the Fc 268 mutation
63. Position of the FcRII 131 polymorphism
64. Summary of the position 268 modifications
65. Binding of 268 mutants to FcRIIb
66. ADCC with 268 mutants
67. Summary of 268 mutant activities
68. Proposed applications of G1-delta-e
69. Other examples of Fc engineering
70. Summary
71. Acknowledgements
72. References

Topics Covered

• IgG structure and modes of action
• Human IgG Fc receptors
• Structural interactions
• Engineering strategy
• Selection of subclasses and effector functions
• Manipulation of functions
• Case study: FMAIT
• Design and engineering of inhibitory Fc mutants
• Functional properties
• Complement mediated lysis
• FcR binding
• Monocyte activation
• ADCC
• Clinical volunteer study
• Activatory mutations
• Enhanced binding to FcR
• Increased ADCC
• Possible applications

Links

Series:

• Monoclonal Antibodies as Therapeutic Agents

Categories:

• Immunology
• Methods

Therapeutic Areas:

• Immunology & Inflammation

Talk Citation

Publication History

• Published on October 1, 2007

Financial Disclosures

• Requested.