Carl Uli Bialucha, PhD
Cambridge, Massachusetts, United States
Our group’s focus is on developing novel antibody drug conjugates (ADCs) for the treatment of cancer. By combining the exquisite specificity and favorable pharmacokinetics of antibodies with highly-potent low-molecular weight compounds, our mission is to build an orthogonal therapeutic platform besides systemic chemotherapy and highly-targeted LMW compounds.
ADCs are modular drugs comprising an antibody molecule featuring selective binding to a cellular target of interest, a chemical linker covalently attached to the antibody and a low molecular weight compound or “payload” attached to the linker. ADCs are designed to release their potent anti-tumor compound only after receptor-mediated endocytosis following specific antigen binding on target cells.
We now understand that each of the modular components comprising an ADC can have distinguishing properties and therefore can differentially influence the behavior of the ADC in vitro and in vivo. For example, different linkers and payloads differentially affect the rate of payload release, the site of payload release and importantly the type of active metabolite generated. All of these parameters together influence both the efficacy as well as tolerability of an ADC.
One key research area for our group is to advance our understanding of the molecular determinants and pathways that influence a cancer cell’s sensitivity to ADC payloads. By taking advantage of a convergence of technologies from pooled shRNA screens to phenotypic profiling of large-scale, genomically-annotated cell line panels, we hope to characterize the key molecular players driving ADC payload sensitivity and identify novel strategies for combination treatments.
An Antibody That Locks HER3 in the Inactive Conformation Inhibits Tumor Growth Driven by HER2 or Neuregulin.
Garner AP, Bialucha CU, Sprague ER, Garrett JT, Sheng Q, Li S, Sineshchekova O, Saxena P, Sutton CR, Chen D, Chen Y, Wang H, Liang J, Das R, Mosher R, Gu J, Huang A, Haubst N, Zehetmeier C, Haberl M, Elis W, Kunz C, Heidt AB, Herlihy K, Murtie J, Schuller A, Arteaga CL, Sellers WR, Ettenberg SA.
Cancer Res. 2013 Oct 1;73(19):6024-6035.
Combination of Antibody That Inhibits Ligand-Independent HER3 Dimerization and a p110α Inhibitor Potently Blocks PI3K Signaling and Growth of HER2+ Breast Cancers.
Garrett JT, Sutton CR, Kurupi R, Bialucha CU, Ettenberg SA, Collins SD, Sheng Q, Wallweber J, Defazio-Eli L, Arteaga CL.
Cancer Res. 2013 Oct 1;73(19):6013-6023.
Functional identification of tumor-suppressor genes through an in vivo RNA interference screen in a mouse lymphoma model.
Bric A, Miething C, Bialucha CU, Scuoppo C, Zender L, Krasnitz A, Xuan Z, Zuber J, Wigler M, Hicks J, McCombie RW, Hemann MT, Hannon GJ, Powers S, Lowe SW.
Cancer Cell. 2009 Oct 6;16(4):324-35.
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