Dataset Information

Rapid tissue prototyping with micro-organospheres.

ABSTRACT: In vitro tissue models hold great promise for modeling diseases and drug responses. Here, we used emulsion microfluidics to form micro-organospheres (MOSs), which are droplet-encapsulated miniature three-dimensional (3D) tissue models that can be established rapidly from patient tissues or cells. MOSs retain key biological features and responses to chemo-, targeted, and radiation therapies compared with organoids. The small size and large surface-to-volume ratio of MOSs enable various applications including quantitative assessment of nutrient dependence, pathogen-host interaction for anti-viral drug screening, and a rapid potency assay for chimeric antigen receptor (CAR)-T therapy. An automated MOS imaging pipeline combined with machine learning overcomes plating variation, distinguishes tumorspheres from stroma, differentiates cytostatic versus cytotoxic drug effects, and captures resistant clones and heterogeneity in drug response. This pipeline is capable of robust assessments of drug response at individual-tumorsphere resolution and provides a rapid and high-throughput therapeutic profiling platform for precision medicine.

SUBMITTER: Wang Z

PROVIDER: S-EPMC9481922 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Rapid tissue prototyping with micro-organospheres.

Wang Zhaohui Z Boretto Matteo M Millen Rosemary R Natesh Naveen N Reckzeh Elena S ES Hsu Carolyn C Negrete Marcos M Yao Haipei H Quayle William W Heaton Brook E BE Harding Alfred T AT Bose Shree S Driehuis Else E Beumer Joep J Rivera Grecia O GO van Ineveld Ravian L RL Gex Donald D DeVilla Jessica J Wang Daisong D Puschhof Jens J Geurts Maarten H MH Yeung Athena A Hamele Cait C Smith Amber A Bankaitis Eric E Xiang Kun K Ding Shengli S Nelson Daniel D Delubac Daniel D Rios Anne A Abi-Hachem Ralph R Jang David D Goldstein Bradley J BJ Glass Carolyn C Heaton Nicholas S NS Hsu David D Clevers Hans H Shen Xiling X

Stem cell reports 20220818 9

In vitro tissue models hold great promise for modeling diseases and drug responses. Here, we used emulsion microfluidics to form micro-organospheres (MOSs), which are droplet-encapsulated miniature three-dimensional (3D) tissue models that can be established rapidly from patient tissues or cells. MOSs retain key biological features and responses to chemo-, targeted, and radiation therapies compared with organoids. The small size and large surface-to-volume ratio of MOSs enable various applicatio ...[more]

PMID: 35985334

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Project description:Multispecific antibody-like molecules have the potential to advance the standard-of-care in many human diseases. The design of therapeutic molecules in this class, however, has proven to be difficult and, despite significant successes in preclinical research, only one trivalent antibody, catumaxomab, has demonstrated clinical utility. The challenge originates from the complexity of the design space where multiple parameters such as affinity, avidity, effector functions, and pharmaceutical properties need to be engineered in concurrent fashion to achieve the desired therapeutic efficacy. Here, we present a rapid prototyping approach that allows us to successfully optimize these parameters within one campaign cycle that includes modular design, yeast display of structure focused antibody libraries and high throughput biophysical profiling. We delineate this approach by presenting a design case study of MM-141, a tetravalent bispecific antibody targeting two compensatory signaling growth factor receptors: insulin-like growth factor 1 receptor (IGF-1R) and v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ErbB3). A MM-141 proof-of-concept (POC) parent molecule did not meet initial design criteria due to modest bioactivity and poor stability properties. Using a combination of yeast display, structured-guided antibody design and library-scale thermal challenge assay, we discovered a diverse set of stable and active anti-IGF-1R and anti-ErbB3 single-chain variable fragments (scFvs). These optimized modules were reformatted to create a diverse set of full-length tetravalent bispecific antibodies. These re-engineered molecules achieved complete blockade of growth factor induced pro-survival signaling, were stable in serum, and had adequate activity and pharmaceutical properties for clinical development. We believe this approach can be readily applied to the optimization of other classes of bispecific or even multispecific antibody-like molecules.

Dataset Information

Rapid tissue prototyping with micro-organospheres.

Publications

Rapid tissue prototyping with micro-organospheres.

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