Cytotoxicity of the anti-CD22 immunotoxin HA22 (CAT-8015) against paediatric acute lymphoblastic leukaemia.

Acute lymphoblastic leukaemia (ALL) remains the most frequent cause of cancer-related mortality in paediatrics and outcome is poor for patients who have high-risk ALL or relapse. HA22 (CAT-8015) is an immunotoxin composed of an anti-CD22 variable fragment linked to a 38 kDa truncated protein derived from Pseudomonas exotoxin A. Using a bone marrow mesenchymal cell culture assay to support ALL cell viability, we investigated the in vitro cytotoxicity of HA22 against ALL blasts from newly diagnosed (n = 13) and relapsed patients (n = 22). There was interpatient variability in sensitivity to HA22. Twenty-four of 35 patient samples tested were sensitive (median 50% lethal concentration 3 ng/ml, range 1-80 ng/ml). Blasts from the other 11 patients were not killed by 500 ng/ml HA22. The median 50% lethal concentration was 20 ng/ml for all patients. There was no significant difference in HA22 sensitivity between diagnosis and relapse samples but peripheral blood ALL blasts were more sensitive to HA22 than those from bone marrow (P = 0.008). Thus, HA22, at concentrations achievable in patients, is highly cytotoxic to B-lineage ALL cells. These results provide a strong rationale for clinical testing of this agent in children with drug-resistant ALL and offers the potential to reduce morbidities of treatment while improving outcome.

Antibody-onconase conjugates: cytotoxicity and intracellular routing.

Onconase, a member of the pancreatic ribonuclease A superfamily, is currently in Phase III clinical trials for treatment of unresectable malignant mesothelioma. The anticancer effect of onconase may relate to its intracellular target, a non-coding RNA. Some non-coding RNAs are aberrantly expressed in cancer cells. This discovery is creating new interest in drugs that target RNA. Conjugating onconase to agents that recognize tumor associated molecules further increases its potency and specificity. Analysis of onconase activity when directed to two different internalizing and one non-internalizing receptor reveals that the ideal targeting agents would rapidly enter lysosomal compartments before onconase escaped to the cytosol. Antibody-onconase conjugates are effective in preclinical models, cause little non-specific toxicities in mice and have favorable formulation properties. Understanding the reason for their potency coupled with understanding novel RNA-based mechanisms of tumor cell death will lead to improved variations of targeted onconase.

Emerging biological therapies in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a prototypic inflammatory autoimmune disorder characterized by multisystem involvement and fluctuating disease activity. Symptoms range from rather mild manifestations such as rash or arthritis to life-threatening end-organ manifestations such as glomerulonephritis or thrombosis. Virtually every organ system is subject to potential damage. Symptoms typically wax and wane over the course of the disease; yet unfortunately, many patients will experience a slow decline in their health because of the ongoing systemic inflammation. Effective treatment must be individualized and is often based on the specific manifestations that are seen in each patient. In a similar manner, prognosis is also dependent on the severity and the specific organ systems involved.

Emerging drugs for chronic lymphocytic leukaemia.

Although the philosophy of management of patients with chronic lymphocytic leukaemia (CLL) has been altered with the advent of fludarabine-based therapies, impact on long-term survival is unclear and a significant proportion of patients will develop resistance to fludarabine. Similar to other haematological malignancies, a potential for 'cure' is likely to be achieved only if 'high-quality' complete remissions (CRs) are achieved. Treatment options for patients who develop resistance to fludarabine continue to be limited, with only a proportion obtaining a response (usually not CRs) with salvage therapies. This review summarises novel therapies that are being evaluated in patients with CLL, specifically those targeting the antiapoptotic Bcl-2 family of proteins and receptors (e.g., CD40, CD80, HLA-DR) involved in mediating survival signals from the microenvironment.