Our Science – Brechbiel Website
Martin W. Brechbiel, Ph.D.
His research interests span the array of possible uses of both diagnostic (SPECT/PET) and therapeutic radionuclides (beta and alpha emitters), paramagnetic metal ions (Gd(III) MRI), as well as applications of nanoparticles and the development of dyes suitable for use in Optical Imaging with an emphasis on combinations of imaging and therapy modalities. His research includes synthesis of novel macrocyclic polyamine molecules, synthesis of chelating agents for the sequestration of radioactive metal ions, synthesis of novel chelating agents for the creation of new chemotherapeutics, synthesis of multi-modality imaging and therapy agents multi-targeted therapy and imaging of residual intraperitoneal disease (e.g., ovarian, colorectal, pancreatic cancer), and the execution of the pre-clinical studies designed to facilitate the potential translation of all of the above into clinical trail evaluation.
Radiolabeled Monoclonal Antibodies for Diagnosis and Therapy
Tumor-associated monoclonal antibodies (mAbs), related immunoproteins, their respective engineered fragments, and receptore targeting peptides are useful therapeutic or diagnostic agents when used as selective carriers of cytotoxic and/or imaging elements. The Chemistry Section develops the chemical and physical science necessary to test and implement this concept by creating and understanding the required chemistry for 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 as well as executes the pre-clinical studies designed to facilitate their potential translation.
Cytocidal agents employed include alpha- and beta-emitting radionuclides. Chelation chemistries required to link radiometals such as Y-90, Y-86, In-111, Pb-212, Pb-203, Bi-212, Bi-213, Lu-177, and Zr-89 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 the pre-clinical studies executed by the Section and with collaborators, 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.
Current results demonstrate the exquisite therapeutic impact of targeted alpha particle therapy using Pb-212 to eliminate intraperitoneal disease. The combination of this targeted radiation therapy with chemotherapy agents, the definition of the administration scheduling and actual dosage, the targeting of multiple molecular targets with Pb-212 has culminated in the eminent filing of an IND to initiate a Phase 1 trial to treat ovarian cancer at the University of Alabama. The Section is well poised to support this effort through the execution of extensive pre-clinical studies, the manufacturing of GMP antibody conjugate, imaging methodology, extensive toxicity studies, and the performance of long-term stability studies as an active partner in this effort with AREVA.
Chelating agents produced for studies with Y-90 and other radio-lanthanides have proven useful for sequestration of the paramagnetic ion Gd(III). This fact has allowed for the initiation of an entire field of research jointly with Don Tomalia and Paul Lauterbur that demonstrated 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. The improved Gd(III) chelation conjugation chemistry result has demonstrated that the vast majority of macromolecular and Gd(III) nanoparticle MR agents are both improperly prepared and characterized; these same results demonstrate a 5-fold enhancement in sensitivity while actually decreasing the total Gd(III) injected by a factor of 2/3 to ¾, thereby greatly enhancing the toxicity and safety profile of these same agents.
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. The actual understanding of the real chemical interactions of the dye molecules themselves has provided a critical advancement tot eh use of cyanine dyes for Optical Imaging. Issues regarding actual characterization, purity, aggregation, self-quenching, and activation in vivo become far more understood when the real chemical basis of these properties are also understood.
In sum, the ongoing research of the Radioimmune & Inorganic Chemistry Section develops for human medicine purposes the necessary chemistry along with the actual understanding necessary 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. The Section is one of several groups at the NCI, CCR that is pursues research of imaging technologies and is also one of the few that creates actual therapies with the practical applications goal of translation into the clinic. This is evidenced by the marketing of commercial reagents created by the Section as well as the use of its chemistry in a commercial FDA approved therapeutic, Zevalin. The Section is also an example of multi-discipline team science that combines the skills of Inorganic, Organic, Analytical, Physical, and Radiochemistry blended with Biology, Animal Models, Molecular Biology, and all modalities of Imaging.
Collaborating on this work are and Thomas A. Waldmann, NIH; Kevin Camphousen, NIH, Deborah Citrin, NIH, Jim Mitchell, NIH, Andrew Scott, Ludwig Institute; Dan Vallera, U. Minnesota, Marty Pomper, Johns Hopkins, Ruby Meredith, University of Alabama, Birmingham; Tom Quinn, University of Missouri, Columbia, Silvia Jurisson, University of Missouri, Columbia.
This page was last updated on 6/7/2013.