Details

Autor(en) / Beteiligte

• Feng, Yang
• Lee, Jaewon
• Yang, Liping
• Hilton, Mary Beth
• Morris, Karen
• Seaman, Steven
• Edupuganti, Veera V. Shivaji R.
• Hsu, Kuo-Sheng
• Dower, Christopher
• Yu, Guojun
• So, Daeho
• Bajgain, Pradip
• Zhu, Zhongyu
• Dimitrov, Dimiter S.
• Patel, Nimit L.
• Robinson, Christina M.
• Difilippantonio, Simone
• Dyba, Marzena
• Corbel, Amanda
• Basuli, Falguni
• Swenson, Rolf E.
• Kalen, Joseph D.
• Suthe, Sreedhar Reddy
• Hussain, Myer
• Italia, James S.
• Souders, Colby A.
• Gao, Ling
• Schnermann, Martin J.
• St. Croix, Brad

Titel

Engineering CD276/B7-H3-targeted antibody-drug conjugates with enhanced cancer-eradicating capability

Ist Teil von

• Cell reports (Cambridge), 2023-12, Vol.42 (12), p.113503-113503, Article 113503

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• CD276/B7-H3 represents a promising target for cancer therapy based on widespread overexpression in both cancer cells and tumor-associated stroma. In previous preclinical studies, CD276 antibody-drug conjugates (ADCs) exploiting a talirine-type pyrrolobenzodiazepine (PBD) payload showed potent activity against various solid tumors but with a narrow therapeutic index and dosing regimen higher than that tolerated in clinical trials using other antibody-talirine conjugates. Here, we describe the development of a modified talirine PBD-based fully human CD276 ADC, called m276-SL-PBD, that is cross-species (human/mouse) reactive and can eradicate large 500–1,000-mm3 triple-negative breast cancer xenografts at doses 10- to 40-fold lower than the maximum tolerated dose. By combining CD276 targeting with judicious genetic and chemical ADC engineering, improved ADC purification, and payload sensitivity screening, these studies demonstrate that the therapeutic index of ADCs can be substantially increased, providing an advanced ADC development platform for potent and selective targeting of multiple solid tumor types. [Display omitted] •CD276 is an effective target for next-generation ADC therapy•CD276 ADCs can eradicate large 1,000-mm3 tumors in preclinical trials•Genetic and chemical engineering to reduce toxicity enhances ADC efficacy•CD276 ADCs are highly effective against HER2-negative breast cancers Off-target toxicities are a major obstacle to effective antibody-drug conjugate (ADC) therapy. By combining various genetic and biochemical approaches with payload sensitivity monitoring, Feng et al. demonstrate that the therapeutic window of talirine-based ADCs can be substantially improved, enabling the development of highly effective CD276-targeted ADCs with tumor-eradicating potential.