Histiocytosis - Monoclonal Antibody Development

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Histiocytosis - Monoclonal Antibody Development


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Monoclonal Antibody Development for Diagnosis and Treatment of LCH

Langerhans cell histiocytosis (LCH) is a rare disorder affecting children and adults for which the incidence has been estimated to be approximately 5 to 10 patients per million persons(i). LCH is characterized by the clonal proliferation (ii) of phenotypically immature (iii), CD1a positive cells (iv) that are similar to Langerhans cells, which are important in the regulation of the immune system.

Clinical signs and symptoms range from isolated eosinophilic granuloma (v) of bone or limited skin involvement to multi-organ dysfunction and fatal disseminated (vi) disease.

Current approaches to the treatment of patients with LCH include a variety of chemotherapeutic and immunosuppressive agents as well as radiation therapy and sometimes bone marrow transplantation. Despite aggressive treatment, there is a high incidence of recurrent disease and significant morbidity (vii) as well as mortality in patients with disease that is unresponsive to treatment. The identification of mutations in the BRAF1 gene in 50% to 60% of patients has provided another potential approach of treatment that needs careful testing. Also, the development of resistance to targeted therapies is commonly observed, and combination therapies are likely to be important to further test. More effective approaches for imaging disease status as well as novel treatment modalities for patients with LCH are thus still needed and would represent an important advance.

The development of cell surface protein targeted (viii) monoclonal antibodies (MAB) (ix) to treat patients with autoimmune disorders and cancer has resulted in multiple examples of the utility of immunotargeted therapy. Such antibodies represent what the famous Dr. Ehrlich in the early 20th century called ‘magic bullets’ to fight disease. We have thus developed a fully human MAB with high specificity and affinity for a native, external epitope of CD1a that internalizes upon binding to surface CD1a and can also induce significant and selective in vitro and in vivo anti-tumor cytotoxicity. This work has been based on the important findings of work from the United Kingdom using a mouse monoclonal antibody.

While no treatment is likely to be without some possible side effects, monoclonal antibodies have been exceptional agents in terms of the low degree of adverse effects and their ability to be highly selective for the target tumor cells. The figure schematically demonstrates how monoclonal antibodies can selectively eradicate tumor cells as well as identify them in patients with specialized radiology imaging methods.

Our hope is that we can now develop this immunotherapeutic and immunodiagnostic approach for patients with LCH. The need is to produce and test sufficient amounts of the monoclonal antibody under clinical grade conditions so that it can be tested in patients with a feasibility trial. If successful, we would like to develop it as a single ‘one stop’ diagnostic scan that would selectively identify LCH in patients, thus potentially reducing the number of different types of scanning. Such antibody scans could also be used to detect responses of LCH in patients undergoing other types of conventional and new treatments. In addition, we would hope that the monoclonal antibody could also provide benefit as a treatment alone or in combination with other therapies to patients with LCH.


(i) Because of the rare occurrence of LCH, government in the United States has dubbed it an “orphan disease.” This means that they do not provide funds to research orphan diseases, although they do encourage pharmaceutical companies to do research involving orphan diseases through tax incentives.
(ii) clonal proliferation- growth of cells in a genetically identical manner
(iii) phenotypically immature- cells that are visibly immature due to their genetic makeup interacting with the environment
(iv) CD1a positive cells- cells that test positive for the CD1a gene
(v) eosiniphilic granuloma- synonymous with “Histiocytosis X” or “Langerhans Cell Histiocytosis.” A specific type of white blood cell, also part of the immune system, that becomes grainy in form
(vi) disseminated- widespread, distributed
(vi) morbidity- illness
(viii) cell surface protein targeted- The protein on the cell’s surface is the key in this process that unlocks the cell to allow this therapy in. Our hope is that this will deactivate the targeted cells, therefore prohibiting them from reproducing.
(ix) monoclonal antibodies (MAB)- antibodies that come from a single clone.

If you prefer to donate by check, please mail checks to:
Attn: Bonnie Morgan
Phoenix Children's Hospital Foundation
2929 E Camelback Rd, Suite 122
Phoenix, AZ 85016

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