Autoimmune Disorders & Transplant Rejection The Potential Of T-cells Targeted Therapeutics

Published by: LeadDiscovery

Published: Dec. 1, 2005 - 83 Pages

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

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

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

Abstract

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.

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