Our Science – Brechbiel Website

Martin W. Brechbiel, Ph.D.

Radiation Oncology Branch Head, Radioimmune Inorganic Chemistry Section Senior Investigator Building 10, Room 1B40 NCI-Bethesda Bethesda, MD 20892 Phone:   301-496-0591 Fax:   301-402-1923 E-Mail:   martinwb@mail.nih.gov

Biography

Dr. Brechbiel joined the NCI in 1983 and received his Ph.D. from American University in 1988. He has a broad range of interests that includes the synthesis of macrocyclic polyamine molecules, the synthesis of chelating agents for the sequestration of radioactive metal ions, and the synthesis of novel chelating agents for the creation of new chemotherapeutics. Dr. Brechbiel became the Section Chief of the Radioimmune & Inorganic Chemistry Section in 2001.

Research

Radiolabeled Monoclonal Antibodies for Diagnosis and Therapy

Tumor-associated monoclonal antibodies (mAbs), related immunoproteins, and their respective engineered fragments are useful therapeutic or diagnostic agents when used as selective carriers of cytotoxic or imaging elements. The Chemistry Section develops the chemical and physical science necessary to test and implement this concept by linking cytocidal or image-producing radionuclides to targeting moieties for treatment and diagnosis of malignancies in animal model systems. The Chemistry Section then creates the radiochemical protocols for preparation of pharmaceuticals for clinical trials.

Cytocidal agents employed include alpha- and beta-emitting radionuclides. Chelation chemistries required to link radiometals such as 90,86Y, 111In, 212,203Pb, 212,213Bi, and 177Lu are developed for collaborative biological studies to evaluate new chelation technology, to obtain scintigraphic or PET images of tumors, and to measure therapeutic efficacy of mAb radioconjugates. Based upon these studies, clinical trials have been initiated and continue in collaboration with the Metabolism Branch, the Molecular Imaging Program, Memorial Sloan-Kettering Cancer Center, and the Ludwig Institute.


Chelating agents produced for studies with 90Y and other radio-lanthanides have proven useful for sequestration of the paramagnetic ion Gd(III). This fact has allowed for the creation of potentially useful macromolecular dendrimeric polymer-based contrast agents for MRI applications. Polymeric dendrimers, such as the PAMAM type, allow for the precise, controlled, and reproducible chemical modification of a discrete chemical species, unlike that of linear polymeric macromolecules.

Evaluation of macromolecular chelate conjugated dendrimer-based Gd(III) MR contrast agents based on the PAMAM or DAB classes of dendrimers has revealed that these agents can be tuned for various applications by virtue of choosing generation size, core elements, conjugation with elements of polyethylene glycol, and by adjusting clearance rates with co-administration of lysine.

Current efforts target the unification of these two projects to create site specific targetable PAMAM-based agents conjugated to either intact or antibody fragments. Preliminary chemistry protocols required for this course of study has already defined methods for improving Gd(III) chelation conjugation chemistry as well as the potential for targeted imaging based on a biotin (small molecule) conjugate. Additional novel agents that combine the use of radiochemical imaging (SPECT or PET) with Optical imaging have been created and their evaluation in this arena of complementary targeted therapy and imaging are moving forward into animal model systems for evaluation.
In sum, the ongoing research of the Radioimmune & Inorganic Chemistry Section develops for human medicine purposes the necessary chemistry to allow the biomedical sciences to design diagnostic imaging protocols and rational therapies for malignancies using monoclonal antibody-mediated diagnosis and selective targeting of radiation to tumors and metastases.

Collaborating on this work are Hisataka Kobayashi, Peter Choyke, and Thomas A. Waldmann, NIH; David Scheinberg, Memorial Sloan-Kettering Cancer Center; Andrew Scott, Ludwig Institute; Ruby Meredith, University of Alabama, Birmingham; Silvia Jurisson, University of Missouri, Columbia.

This page was last updated on 9/5/2008.