Ernesto Freire received his PhD from the University of Virginia. He is a professor in the Department of Biology and holds a joint appointment in the Department of Biophysics and Biophysical Chemistry at JHMI. 

The ultimate goal of biomedical research is to cure disease. Drug development is a key endeavor towards that goal.  Two different types of drug molecules are being developed in the pharmaceutical industry: 1) Small molecule drugs; and, 2) Biologics, i.e. proteins as drug molecules, especially monoclonal antibodies.

1) Fundamental research in this laboratory has resulted in the development of a thermodynamic platform for small molecule drug discovery and optimization. This platform is permanently improved and simultaneously applied to the discovery and optimization of novel drugs against important diseases for which no successful therapies are available. The optimization platform is aimed at achieving extremely high binding affinity and selectivity as well as appropriate pharmacokinetics.

2) Currently monoclonal antibodies are the fastest growing segment in the pharmaceutical industry.  Our research has developed new experimental approaches to evaluate and predict the long-term stability of mAbs.  These approaches have resulted in thermodynamic algorithms to identify the most stable variants of a mAb or the best formulation for a specific mAb.

3)  Thermodynamics of Proteins and their Interactions.  Development of new analytical methods, algorithms and their associated software for the analysis of differential scanning calorimetry (DSC), isothermal titration calorimetry (ITC) and isothermal calorimetry (IC) data.  Application of those methods to the study of the structural stability of monoclonal antibodies (mAbs), antibody drug conjugates (ADCs) and other antibody constructs.

A. Schön. In a Leidos sponsored collaboration with VRC/NIH we are characterizing antibody binding to targets associated with several serious infectious diseases, especially malaria. This research has played a key role in the identification of broadly neutralizing human monoclonal antibodies against the major surface protein expressed on the malaria parasite Plasmodium falciparum. Lately, our research has been expanded to involve studies of antibody binding to the spike protein of SARS-CoV-2, the virus that causes Covid-19.

Publications 2017 - 2021

1. Afanador, G. A., Guerra, A. J., Swift, R. P., Rodriguez, R. E., Bartee, D., Matthews, K. A., Schon, A., Freire, E., Freel Meyers, C. L., and Prigge, S. T. (2017) A novel lipoate attachment enzyme is shared by Plasmodium and Chlamydia species, Mol Microbiol 106, 439-451.
2. Herschhorn, A., Gu, C., Moraca, F., Ma, X., Farrell, M., Smith, A. B., 3rd, Pancera, M., Kwong, P. D., Schon, A., Freire, E., Abrams, C., Blanchard, S. C., Mothes, W., and Sodroski, J. G. (2017) The beta20-beta21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions, Nature Commun 8, 1049.
3. Pancera, M., Lai, Y. T., Bylund, T., Druz, A., Narpala, S., O'Dell, S., Schon, A., Bailer, R. T., Chuang, G. Y., Geng, H., Louder, M. K., Rawi, R., Soumana, D. I., Finzi, A., Herschhorn, A., Madani, N., Sodroski, J., Freire, E., Langley, D. R., Mascola, J. R., McDermott, A. B., and Kwong, P. D. (2017) Crystal structures of trimeric HIV envelope with entry inhibitors BMS-378806 and BMS-626529, Nature Chem Biol 13, 1115-1122.
4. Schon, A., Clarkson, B. R., Jaime, M., and Freire, E. (2017) Temperature stability of proteins: Analysis of irreversible denaturation using isothermal calorimetry, Proteins 85, 2009-2017. 265.       
5. Kisalu, N. K., Idris, A. H., Weidle, C., Flores-Garcia, Y., Flynn, B. J., Sack, B. K., Murphy, S., Schon, A., Freire, E., Francica, J. R., Miller, A. B., Gregory, J., March, S., Liao, H. X., Haynes, B. F., Wiehe, K., Trama, A. M., Saunders, K. O., Gladden, M. A., Monroe, A., Bonsignori, M., Kanekiyo, M., Wheatley, A. K., McDermott, A. B., Farney, S. K., Chuang, G. Y., Zhang, B., Kc, N., Chakravarty, S., Kwong, P. D., Sinnis, P., Bhatia, S. N., Kappe, S. H. I., Sim, B. K. L., Hoffman, S. L., Zavala, F., Pancera, M., and Seder, R. A. (2018) A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite, Nat Med 24, 408-416
6. Alsahafi, N., Anand, S. P., Castillo-Menendez, L., Verly, M. M., Medjahed, H., Prevost, J., Herschhorn, A., Richard, J., Schon, A., Melillo, B., Freire, E., Smith, A. B., 3rd, Sodroski, J., and Finzi, A. (2018) SOSIP changes affect human immunodeficiency virus (HIV-1) envelope glycoprotein conformation and CD4 engagement, J Virol.  92, 1-14
7.  Clarkson, B.R,, Chaudhuri, R., Schon, A., Cooper, J.W., Kueltzo, L. and Freire, E. (2018) Long term stability of a HIV-1 neutralizing monoclonal antibody using isothermal calorimetry.  Analytical Biochemistry  554, 61-69
8.  Li, Y., Lock, L. L., Wang, Y., Ou, S. H., Stern, D., Schon, A., Freire, E., Xu, X., Ghose, S., Li, Z. J., and Cui, H. (2018) Bioinspired supramolecular engineering of self-assembling immunofibers for high affinity binding of immunoglobulin G, Biomaterials 178, 448-457.
9.  Clarkson, B. R., and Freire, E. (2018) Isothermal calorimetry of a monoclonal antibody using a conventional differential scanning calorimeter, Anal Biochem 558, 50-52
10.  Freire, E. Can calorimetry provide accurate estimates of long-term stability for monoclonal antibodies? (2019) European Pharmaceutical Review 24, 1-4
11.  Schon, A. and Freire, E. (2020) Binding Thermodynamics to Intrinsically Disordered Protein Domains, Methods in Molecular Biology, 2141, 449-462
12. LT Wang, LS Pereira, Y Flores-Garcia, J O'Connor, BJ Flynn, A Schön, NK Hurlburt, M Dillon, ASP Yang, A Fabra-Garcia, AH Idris, BT Mayer, MW Gerber, R Gottardo, RD Mason, N Cavett, RB Ballard, NK Kisalu, A Molina-Cruz, J Nelson, R Vistein, C Barillas-Mury, R Amino, D Baker, NP King, RW Sauerwein, M Pancera, IA Cockburn, F Zavala, JR Francica, RA Seder, A. (2020) Potent Anti-Malarial Human Monoclonal Antibody Targets Circumsporozoite Protein Minor Repeats and Neutralizes Sporozoites in the Liver, Immunity, 53 733-744 e738.
13. T Zhou, Y Tsybovsky, J Gorman, M Rapp, G Cerutti, GY Chuang, PS Katsamba, JM Sampson, A Schön, J Bimela, JC Boyington, A Nazzari, AS Olia, W Shi, M Sastry, T Stephens, J Stuckey, IT Teng, P Wang, S Wang, B Zhang, RA Friesner, DD Ho, JR Mascola, L Shapiro, PD Kwong. (2020) Cryo-EM Structures of SARS-CoV-2 Spike without and with ACE2 Reveal a pH-Dependent Switch to Mediate Endosomal Positioning of Receptor-Binding Domains, Cell Host Microbe, 28 867-879 e865.
14. Schon, E. Freire, (2021) Reversibility and irreversibility in the temperature denaturation of monoclonal antibodies, Analytical Biochem, 626 114240.

Research Scientist

Arne Schon

Undergraduate Student

Maru Jaime

Technicians/Staff

Victoria Kholodenko