37RI
Multi-parameter optimization of a novel anti-TROP2 MMAE Antibody-Drug-Conjugate for solid tumor therapy
Summary for 37RI
| Entry DOI | 10.2210/pdb37ri/pdb |
| Descriptor | MK6837 Heavy Chain, MK6837 Light Chain, Tumor-associated calcium signal transducer 2, ... (6 entities in total) |
| Functional Keywords | antibody-drug-conjugate, adc, trop2, mmae, solid tumors, stable linker, monoclonal antibody, hydrophobicity, avidity tuning, cell adhesion, cell adhesion-immune system complex, cell adhesion/immune system |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 6 |
| Total formula weight | 168736.56 |
| Authors | |
| Primary citation | Fayadat-Dilman, L.,Waight, A.B.,Adams, L.,Akbari, P.,Angagaw, M.,Baker, J.,Castor, M.,Chen, A.,Chen, D.,Chen, M.T.,Chien, E.,Chrencik, J.E.,Clark, D.,Dutko, J.,Derebe, M.,Goggins, A.,Griffiths, T.,Heon, M.R.,Hinton, M.C.,Hsieh, S.,Hsu, A.,Hua, Z.L.,Ibrahim, M.,Jia, M.,Johnson, R.E.,Lang, S.B.,Liu, S.Y.,Malashock, D.,Olow, A.,Oropallo, M.,Partridge, A.T.,Penaflor, V.,Boroujeni, E.R.,Ren, Z.,Sathiyamoorthy, K.,Uchida, M.,Wiswell, D.,Xia, J.,Yang, P.,Yearley, J.,Yilmaz, S.,Yu, Y.,Flygare, J.A.,Geierstanger, B.H.,Wen, J.,Seganish, W.M.,Bowman, E.P. Multi-parameter optimization of a novel anti-TROP2 MMAE antibody-drug-conjugate for solid tumor therapy. Front Oncol, 16:1915652-1915652, 2026 Cited by PubMed Abstract: TROP2 is expressed in many epithelial tumors including breast and lung cancers. It is a clinically validated ADC target based on approvals of sacituzumab govitecan for triple-negative breast cancer and datopotamab deruxtecan for HR-positive, HER2-negative breast cancer. An alternative cytotoxic approach was previously tested with PF-06664178/RN927C, an anti-TROP2 ADC with an auristatin payload, which entered clinical studies but could not be dosed efficaciously due to dose-limiting toxicities including skin rash, mucosal inflammation, and neutropenia. TroptimAb-SL-MMAE was engineered using an optimized anti-TROP2 sacituzumab antibody sequence (TroptimAb) to address issues related to hydrophobicity, non-specific uptake, and ADC developability. Sacituzumab was rehumanized and modified to enhance FcRn-mediated salvage which extended systemic half-life and potentially improving tumor distribution. Its affinity was avidity-tuned to preferentially bind cells with higher TROP2 expression to reduce on-target/off-tumor toxicity. An engineered cysteine in the Fc domain enabled generation of a homogeneous DAR2 ADC and shielded the linker-payload to reduce hydrophobicity and improve biophysical properties. Linker conjugation chemistry was also optimized to improve stability versus earlier cysteine-conjugated ADCs. We describe the preclinical profile of TroptimAb-SL-MMAE including its design, mechanism of action, anti-tumor activity, and pharmacokinetics. PubMed: 42877637DOI: 10.3389/fonc.2026.1915652 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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