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Randi Hernandez was science editor at Pharmaceutical Technology from September 2014 to May 2017.
Linker technology and drug combinations play an important role in the efficacy of ADCs.
Seattle Genetics presented new data on antibody-drug conjugates (ADCs) at the 107th Annual Meeting of the American Association for Cancer Research (AACR), highlighting preclinical information on novel ADCs and presenting further evidence about the efficacy of auristatin-based ADCs when coupled with checkpoint inhibitors.
The company presented data on a Phase I preclinical molecule under investigation for the treatment of breast cancer (SGN-LIV1A) and preclinical data on a novel ADC for multiple myeloma (SGN-CD352A). SGN-CD352A is an anti-CD352 engineered cysteine monoclonal antibody (EC-mAb) that targets the antigen CD352 typically found on the surface of B cells in multiple myeloma. Two molecules of cytotoxic agent pyrrolobenzodiazepine (PBD) dimer are attached to the EC-mAb. According to AACR abstracts, SGN-CD352A demonstrated potent cytotoxic activity in human myeloma and lymphoma cell lines, even in cells that had lower expression levels of CD352-and it caused minimal damage to resting B lymphocytes, unlike many multiple myeloma treatments that kill healthy B cells in addition to cancerous B cells. "In summary, CD352 is a newly validated multiple myeloma tumor antigen and the novel PBD dimer ADC SGN-CD352A shows potent antitumor activity against cell line models of [multiple myeloma] at clinically relevant doses," the authors wrote.
According to Seattle Genetics scientists, SGN-LIV1A has already demonstrated antitumor activity alone for the treatment of breast cancer. SGN-LIV1A is an anti-LIV-1 antibody connected to a microtubule disruption agent, monomethyl auristatin E. Researchers showed that when combined with standard chemotherapeutic agents, there were "additive and synergistic effects."
Optimal PEGylation of the auristatin linker in an ADC was also explored by scientists from Seattle Genetics. Researchers tested PEG units of varying lengths in an effort to optimize drug-to-antibody ratio and enhance in vivo activity. They found an optimal PEG length for their product-and ADCs prepared with this linker have demonstrated an increase in therapeutic index compared with other monomethylauristatin E-based ADCs, they said.
Other studies presented at AACR by Seattle Genetics showed that existing FDA-approved ADC Adcetris (brentuximab vedotin)-which is directed at CD30-causes cell death through apoptosis by the disruption of the creation of tubulin. The investigators were able to measure the degree of stress induction and mimotic arrest that Adcetris caused to tumor cells, allowing them to better understand the mechanism of action through which the drug works. They concluded, “Via induction of ER stress, tumor cells killed by auristatin-based ADCs may initiate an antitumor immune response," and may provide "a rationale for exploring therapeutic strategies that combine ADCs with other immune stimulatory regimens."
Source: American Association of Cancer Research, Seattle Genetics