Martin W. Brechbiel, Ph.D.
Dr. Brechbiel is a leading authority on the development of the chemistry required for effective targeted radiation therapy and imaging chemistry. His studies have led to initiation of multiple clinical trials, including those employing α-emitters 213Bi and 212Pb. Basic coordination chemistry studies have also addressed the synthesis and in vivo validation of novel agents that have been translated through from pre-clinical studies to clinical use onwards to commercial products for both imaging and therapy of cancer.
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 Radioimmune and Inorganic Chemistry Section developed 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 created the radiochemical protocols for preparation of pharmaceuticals for clinical trials as well as executed the pre-clinical studies designed to facilitate their potential translation. Cytocidal agents employed included α- and β-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 were 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 were initiated in collaboration with the Metabolism Branch, the Molecular Imaging Program, Memorial Sloan-Kettering Cancer Center, and the Ludwig Institute. Results demonstrated the exquisite therapeutic impact of targeted α-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, and the targeting of multiple molecular targets with Pb-212 culminated in the filing of an IND to initiate a Phase 1 trial to treat ovarian cancer at the University of Alabama.
The Section supported 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 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.
Efforts targeted 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 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 demonstrated that the vast majority of macromolecular and Gd(III) nanoparticle MR agents are both improperly prepared and characterized; these same results demonstrated a 5-fold enhancement in sensitivity while actually decreasing the total Gd(III) injected by a factor of 2/3 thereby greatly enhancing the toxicity and safety profile of these same agents.
Additional novel agents that combined the use of radiochemical imaging (SPECT or PET) with optical imaging were created and their evaluation in the area of complementary targeted therapy and imaging is moving forward into animal model systems for evaluation. The actual understanding of the real chemical interactions of the dye molecules themselves provided a critical advancement in the 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 research of the Radioimmune and Inorganic Chemistry Section developed 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 was one of several groups at the NCI, CCR that pursue research of imaging technologies and was also one of the few that created 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-disciplinary 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.
Collaborators in this work: Thomas A. Waldmann, NCI; Kevin Camphousen, NCI; Deborah Citrin, NCI; Jim Mitchell, NCI; Andrew Scott, Ludwig Institute; Dan Vallera, University of Minnesota; Marty Pomper, Johns Hopkins University; Ruby Meredith, University of Alabama, Birmingham; Tom Quinn, University of Missouri, Columbia; and Silvia Jurisson, University of Missouri, Columbia.
Selected Key Publications
Synthesis of 1-(p-Isothiocyanatobenzyl) derivatives of DTPA and EDTA: Antibody labeling and tumor-imaging studies.Inorg Chem. 25: 2772, 1986. [ Journal Article ]
Stereochemical influence on the stability of radio-metal complexes in vivo. Synthesis and evaluation of the four stereoisomers of 2-(p-nitrobenzyl)-trans-CyDTPA.Bioorg. Med. Chem. 5: 1925-34, 1997. [ Journal Article ]
- Blood. 100: 1233-9, 2002. [ Journal Article ]
- Clin Cancer Res. 10: 7834-41, 2004. [ Journal Article ]
(212)Pb-radioimmunotherapy induces G(2) cell-cycle arrest and delays DNA damage repair in tumor xenografts in a model for disseminated intraperitoneal disease.Mol. Cancer Ther. 11: 639-48, 2012. [ Journal Article ]
Dr. Brechbiel joined the NCI in 1983 and received his Ph.D. from American University in 1988. He was appointed Acting Section Chief of the Radioimmune and Inorganic Chemistry Section in 1997. Dr. Brechbiel became the tenured Section Chief of the Radioimmune and Inorganic Chemistry Section in 2001. 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 pre-clinical studies designed to facilitate the potential translation of all of the above into clinical trial evaluation.