Autoimmune Disorders and Transplant Rejection - The Potential of T-cells Targeted Therapeutics
Affecting as many as 5% of the population, autoimmune disease represents a major clinical problem. Ranking alongside other major conditions such as type II diabetes, in terms of prevalence this group of diseases includes a large number of different conditions of varying prevalence, associated morbidity and disability, and available clinical options. Despite the fragmentation of this market it has proved lucrative for the drug development sector with the emergence of TNF blockers, therapeutics that have now been approved for multiple indications in this market. Global sales of TNF blockers now exceed $5 billion.
Despite the success of the TNF blockers for the treatment of rheumatic diseases, inflammatory bowel disease and psoriasis, this class is rarely completely effective in these indications and some patients are unresponsive to treatment. Moreover other autoimmune diseases that have not benefited from the development of TNF blockers remain unmet markets served by the same therapeutics employed over thirty years ago. The autoimmune disease arena overlaps with the transplant sector.
Although only 0.01% of the population are transplant recipients this field represents a major focus of the drug discovery sector. Drawing less revenue than the TNF blockers, transplant therapeutics nonetheless generate global annual sales worth $2.7 billion even before figures for Cyclosporine are included. Advances over the past decades have led to improved long-term survival of patients although improvements are still required especially for the treatment of lung and intestinal transplants, and for the induction of tolerance in order to obviate life-long immunosupression.
Autoimmune Disorders & Transplant Rejection: Opportunities for the Drug Development Sector represents the most in depth analysis of these areas published for many years. Targeted towards all involved in drug development this report overviews the prevalence of the autoimmune diseases and identifies those that we believe should be prioritized by the drug development sector. Diseases highlighted are:
- Psoriasis
- Graves’ disease
- Rheumatoid arthritis
- IBD
- Type I diabetes
- Multiple sclerosis
- Lupus.
While TNF blockers target the innate immune system, considerable opportunities exist for the development of therapeutics that target T-cells. Each of these autoimmune diseases has a major T-cell component and this report describes the immunology of these indications with an emphasis on T-cell contribution. Recent research has revealed a large number of T-cell molecular targets but only a few candidates for these targets have survived late stage development. This relatively barren pipeline offers significant opportunities however selecting the most appropriate target is critical for drug development activities. This report provides a detailed evaluation of:
- CD80/86:CTLA4/CD28
- Recently identified B7 molecules: PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H3 & B7-H4
- CD40:CD154
- New TNFR family members including OX-40 (CD134) and 4-BB (CD137).
- ICOS:ICOS-L
- Adhesion molecules
Autoimmune Disorders & Transplant Rejection characterizes each of these molecular targets and provides a detailed proof of concept discussion allowing the reader to identify which targets are likely to provide most benefit for the selected indications. The report also provides a full evaluation of regulatory T-cells, a cell type that represents a major target for candidate treatments of both autoimmune disease and transplant rejection. Finally we identify some very novel and unexploited opportunities within this field including the possibility of targeting ICAM-1 to reverse established diabetes and the use of estrogen ligands to induce tolerance. The report provides in depth evaluation of preclinical and clinical data, describes the pipeline for autoimmune candidates that target T-cells, and profiles drugs in development or on the market. Profiles include sales figures for each marketed product.
The report concludes with LeadDiscovery’s analysis of T-cell therapeutics and suggests the most appropriate for further development. Some promising candidates have suffered problems in the clinic, notably the CD154 blockers and this report highlights these problems and strategies to overcome them. Other molecules such as CTLA4-Ig (eg Abatacept & Belatacept) have shown promising activity however there is room for optimization. We discuss the aims of such optimization.
In short this report represents a key tool for all involved in the autoimmune and transplant sector and offers detailed insight to those wishing to be involved in the development of next generation therapeutics.
Table of Contents
Chapter 1: A general introduction to immunology: Focus on T-cell development and regulation
- A brief introduction to specific immunity
- Antigen presentation and the MHC (HLA) system
- T-cell diversity
- T-cell differentiation following antigen binding
- Elimination of autoreactive T-cells
- Regulatory T (Treg) cells
- Regulation by T-cell co-stimulation, co-inhibition and accessory molecules binding
- Co-stimulation & co-inhibition – the major players
- CD28:B7
- CTLA4:B7
- Programmed death-1 (PD-1)
- CD40:CD154
- OX40 (CD134)
- 4-1BB (CD137)
- Accessory molecules
Chapter 2: Transplant rejection and autoimmune disease: Clinical characteristics, immunology, treatments, prevalence and markets
- Prevalence of autoimmune diseases
- Clinical characteristics and current treatments
- Psoriasis
- Autoimmune thyroid disease
- Systemic lupus erythematosus
- Rheumatoid Arthritis
- Type I diabetes
- Inflammatory bowel disease (IBD)
- Multiple Sclerosis
- Transplant rejection
- A summary of current treatments and unmet needs
Chapter 3: Targeting T-cells as an approach to autoimmune disease
- Psoriasis
- Immunology of psoriasis
- Targeting co-stimulatory molecules as an approach to psoriasis
- CD80:B7 blockade demonstrates early efficacy in psoriasis
- The development of CTLA4 mimics as a possible psoriasis treatment
- The role of CD40:CD145 in psoriasis etiology
- Targeting accessory molecules marks a breakthrough approach to psoriasis
- Landmark in psoriasis – the development of Amevive
- Landmark in psoriasis – the development of Raptiva
- Summary & recommendation for the development of psoriasis disease therapeutics
- Graves’ disease
- Immunology of Graves’ disease
- Proof of concept for developing CTLA-Ig as a treatment of Graves’ disease
- The pathophysiological role of CD40:CD154 in Graves’ disease remains unclear
- ICAM-1 has been implicated in Graves’ disease
- Summary & recommendation for the development of Graves’ disease therapeutics
- Lupus nephritis and systemic lupus erythematosus
- Immunology of lupus
- Co-stimulatory/co-inhibitory involvement in SLE
- Blockade of CD40:CD154 as an approach to lupus is questionable
- CTLA4 as a lead approach to lupus
- Combining T-cell and B-cell therapeutics for the treatment of lupus
- CD137 blockade may be of use in lupus
- Accessory/adhesion molecule involvement in lupus
- LFA-1 blockade – studies with Raptiva called for
- Summary & recommendation for the development of lupus therapeutics
- Rheumatoid arthritis
- Immunology of rheumatoid arthritis
- Landmark studies - The development of anti-TNF and anti-interleukin-1 therapeutics for the treatment of rheumatoid arthritis marks the advent of biologics
- T-Cell involvement in rheumatoid arthritis
- Exploiting CD130 to target antiarthritic T-cell therapeutics
- Co-stimulatory/co-inhibitory molecule involvement in rheumatoid arthritis
- Interrupting B7:CD28 binding as an approach to rheumatoid arthritis
- Rheumatoid arthritis landmark: Mimicking CTLA4 through the development of Orencia (CTLA4-Ig; Abatacept)
- Blockade of ICOS:ICOS-L as an alternative to disrupting CD28:B7 co-stimulation
- Investigation into the development of CD40:CD154 blockers for the treatment of rheumatoid arthritis
- Agonistic anti-CD137 monoclonal antibodies as a possible approach to rheumatoid arthritis
- Accessory molecule involvement in rheumatoid arthritis – the development of CD4 monoclonal antibodies
- Adhesion molecules
- Selectins versus integrins
- T regulatory cells in rheumatoid arthritis
- Summary & recommendation for the development of rheumatoid arthritis therapeutics
- Immunology of rheumatoid arthritis
- Type 1 Diabetes
- Immunology of type 1 diabetes
- Co-stimulatory/co-inhibitory molecule involvement in type 1 diabetes
- An etiological role for CTLA4 polymorphism
- Involvement of CD80 and CD86 in type 1 diabetes
- Targeting CD40 and CD154 may be of limited benefit in type 1 diabetes
- Blocking CD134:OX40L may be a realistic target in type 1 diabetes
- Regulatory T-cells represent a promising target for the treatment of type 1 diabetes
- Accessory/adhesion molecule involvement in type 1 diabetes
- Summary & recommendation for the development of type 1 diabetes therapeutics
- Inflammatory Bowel Disease
- Immunology of inflammatory bowel disease
- The rise of TNF blockers as treatments of IBD
- A role for T-cells in the pathology of IBD
- Co-stimulatory/co-inhibitory molecule involvement in IBD
- A key role for CD40:CD154 in the pathology of IBD
- Targeting CD28:B7 for the treatment of IBD
- Is ICOS a target for IBD therapeutics
- A role for PD-1?
- An emerging body of data supports the targeting of CD134:OX40L
- IBD represents a rational indication for therapeutics that enhance regulatory T-cell function
- Accessory molecule involvement in IBD
- The development of ICAM-1 blockers for IBD
- Tysabri offer opportunities for the treatment of Crohn’s disease
- Summary & recommendation for the development of IBD therapeutics
- Immunology of inflammatory bowel disease
- Multiple Sclerosis
- Immunology of multiple sclerosis
- Regulatory T-cells and their involvement in multiple sclerosis
- Co-stimulatory/co-inhibitory molecule involvement in multiple sclerosis
- Role of CD28:B7 in multiple sclerosis
- More recently identified members of the B7 family
- Potential for CD40:CD154 blockade for the treatment of multiple sclerosis
- CD134 - a promising target for multiple sclerosis
- Treatment with CD137 agonist antibody may prevent relapse of multiple sclerosis
- Accessory/adhesion molecule involvement in multiple sclerosis
- The rise, fall and resurrection of Tysabri
- Summary & recommendation for the development of multiple sclerosis therapeutics
- Organ Transplant Rejection
- Immunology of transplant rejection
- Co-stimulatory/co-inhibitory molecule involvement in rejection
- Blocking CD28:B7 may reduce both acute and chronic rejection – possibilities of developing combined induction/maintenance therapies
- PD-L1 may represent a new target for prevention of rejection
- CD40:CD154 targeted therapies as long-term/maintenance strategies and possibly a tolerogenic approach
- CD134 blockade offers opportunities for inducing tolerance
- ICOS blockade represents a further target for transplant protection
- Targeting regulatory T cells for long-term graft protection and tolerance
- Accessory/adhesion molecule involvement in graft rejection
- Investigation of dual LFA-1/CD40 blockade may yield new and improved approached to transplant rejection
- Summary & recommendation for the development of transplant therapeutics
- An introduction to cardiovascular disease and a role for CD40:CD154 based therapeutics
- The role of CD40:CD154 signaling in vascular inflammation and atherogenesis
- Thrombogenic activity of CD154
- The role of CD40:CD154 signaling in heart failure
- CD40:CD154 as a target for cardiovascular therapeutics?
Chapter 4: Competitive analysis and drug development recommendations for T-cell targeting
- Global sales figures for autoimmune and transplant therapeutics
- Late stage pipeline for autoimmune and transplant therapeutics
- Overall recommendations
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