in focus | Sartorius

mAb linked to an antimitotic agent. It is approved for enabling cross-linking and simultaneous activation of classical Hodgkin lymphoma, systemic anaplastic large tumor and effector cells. For example, catumaxomab, cell lymphoma, and other CD30-expressing T-cell lym- which now has FDA orphan drug status for EpCam posi- phomas. For the treatment of HER2-positive metastatic tive gastric and ovarian tumors, binds EpCAM, CD3 on breast cancer, ado-trastuzumab-emtansine targets HER2 T cells, and the Fc portion recruits immune cells. and consists of the monoclonal antibody trastuzumab Bispecific antibodies pose several challenges for devel- covalently linked to cytotoxic agent DM1. opment. It is necessary to determine which Fab inter- faces may be combined without compromising function ENGINEERING FOR ENHANCED or affinity of either arm, and their specificity toward CYTOTOXICITY multiple targets necessitates substantial characteriza- Monoclonal antibodies contain an antigen-binding tion to ensure efficacy. In addition to binding affinity and fragment (Fab) and a crystallizable fragment (Fc). specificity, assays are necessary to determine target cell Many mAbs exert their effects through immune cell lysis by effector cells activated by the mAb. recruitment, which relies on the interaction between the Fc domain and its receptors. Fc engineering confers IN-DEPTH INSIGHTS FOR NEXT- greater affinity for immune effector cells, resulting GENERATION ANTIBODY in greater cytotoxicity and phagocytosis. Glycoengi- DEVELOPMENT neering and site mutagenesis methods modulate the Developing novel next-generation antibodies is a com- Fc-FcγR (Fc region of IgG) and FcRn (neonatal Fc plex process that requires in-depth analysis and char- receptor) interactions. One such example is obintu- acterization of candidate molecules to identify optimal zumab, a glycoengineered mAb FDA approved for use candidates. Often, this is achieved with time-consuming in combination with bendamustine and obinutuzumab assays to assess phenotype, activation, cytotoxicity, cell THE NEXT GENERATION OF MONOCLONAL monotherapy for patients with follicular lymphoma. It health, etc. New technology has improved the speed and is a successor to the type I CD20 antibody, rituximab, accuracy of analyses to identify candidates with the de- ANTIBODY THERAPEUTICS FOR CANCER and demonstrates enhanced binding affinity to the sired biological outcome based on multiple parameters. The discovery and development of next-generation monoclonal antibodies for cancer FcγRIII receptor on immune effector cells. The IntelliCyt iQue3 with ForeCyt® software enables immunotherapy relies on rapid, information-rich solutions that offer deeper biological Antibody modifications achieved through Fc en- simultaneous analysis of cell-mediated cytotoxicity, cell insights than current strategies. gineering can have significant effects on activity and health, function, activation, and more in each microplate specificity. Several assays are essential in the develop- well. The ability to multiplex assays (such as ADCC and ngoing research investigating new therapeu- ANTIBODY-DRUG CONJUGATES ment of Fc engineered antibodies to assess antibody- bead-based assays to measure secreted cytokines), as well tics continues to improve survival rates and DELIVER POTENT AGENTS receptor binding affinity as well as Fc-mediated as rapidly analyse antibody specificity and EC50 mea- quality of life for cancer patients. The use Antibody-drug conjugates (ADCs) consist of a mAb immune effector function. FcRn and FcγR binding surements, dramatically increases throughput. Offering O of therapeutic antibodies as immunotherapy attached to a biologically active drug with a linker that are frequently assessed via ELISA and flow cytometry improved speed and greater biological insights, Sarto- for hematologic cancers and solid tumors has shown is stable in the circulation. The highly selective mAb methods. ADCC and antibody-dependent cellular rius solutions accelerate next-generation mAb therapy promise as an effective treatment strategy. This is due, in targets tumor-associated antigens, enabling delivery phagocytosis (ADCP) assays, along with complement- discovery and development. part, to the greater specificity of monoclonal antibodies of chemotherapeutic agents, some of which have high dependent cytotoxicity (CDC) assays provide insight (mAbs) compared to other treatments. There are hun- systemic toxicity. Upon binding, the ADC is internalized into the mechanism of action. dreds of clinical trials underway to examine the efficacy and the cytotoxic agents are released by lysosomal deg- of mAbs for treating various forms of cancer. Next-gen- radation. ADC development is complex, as it is crucial to IMMUNE CELL RETARGETING WITH eration antibodies including antibody-drug conjugates ensure rapid internalization to prevent systemic release BISPECIFIC mAbs (ADCs), engineered antibodies, and bispecific antibodies, of cytotoxic agents, however this may dampen antibody- The first description of bispecific antibodies dates are a key area of research and development, with poten- dependent cell-mediated cytotoxicity (ADCC). As such, back to the 1960s, when they were developed with the tially significant clinical implications. However, prior to it is necessary to evaluate internalization and ADCC, in hybridoma technique. Unlike a monospecific antibody, entering the clinical setting, mAb development begins addition to other cell health and phenotypic parameters that has two identical antigen-binding sites, bispecific an- with significant pre-clinical research. Successful mAb during development. tibodies have two unique antigen-binding sites. Bispecific discovery and development relies on information-rich Several ADCs have been approved by the Food and mAbs are capable of binding a CD3 receptor to activate To learn more about Sartorius solutions for technologies for rapid identification and characterization Drug Administration (FDA) for various indications. cytotoxic T lymphocytes on one antigen-binding site, mAb therapy discovery and development, of candidate molecules. Among them, brentuximab vedotin is a CD30-specific and a tumor antigen (CD20, HER2, etc.) on the other, visit: www.sartorius.com/mab-oncology