RGD Reference Report - Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. - Rat Genome Database

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Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index.

Authors: Junutula, JR  Raab, H  Clark, S  Bhakta, S  Leipold, DD  Weir, S  Chen, Y  Simpson, M  Tsai, SP  Dennis, MS  Lu, Y  Meng, YG  Ng, C  Yang, J  Lee, CC  Duenas, E  Gorrell, J  Katta, V  Kim, A  McDorman, K  Flagella, K  Venook, R  Ross, S  Spencer, SD  Lee Wong, W  Lowman, HB  Vandlen, R  Sliwkowski, MX  Scheller, RH  Polakis, P  Mallet, W 
Citation: Junutula JR, etal., Nat Biotechnol. 2008 Aug;26(8):925-32. doi: 10.1038/nbt.1480. Epub 2008 Jul 20.
RGD ID: 7364774
Pubmed: PMID:18641636   (View Abstract at PubMed)
DOI: DOI:10.1038/nbt.1480   (Journal Full-text)

Antibody-drug conjugates enhance the antitumor effects of antibodies and reduce adverse systemic effects of potent cytotoxic drugs. However, conventional drug conjugation strategies yield heterogenous conjugates with relatively narrow therapeutic index (maximum tolerated dose/curative dose). Using leads from our previously described phage display-based method to predict suitable conjugation sites, we engineered cysteine substitutions at positions on light and heavy chains that provide reactive thiol groups and do not perturb immunoglobulin folding and assembly, or alter antigen binding. When conjugated to monomethyl auristatin E, an antibody against the ovarian cancer antigen MUC16 is as efficacious as a conventional conjugate in mouse xenograft models. Moreover, it is tolerated at higher doses in rats and cynomolgus monkeys than the same conjugate prepared by conventional approaches. The favorable in vivo properties of the near-homogenous composition of this conjugate suggest that our strategy offers a general approach to retaining the antitumor efficacy of antibody-drug conjugates, while minimizing their systemic toxicity.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
ovarian cancer treatmentIDA 7364774 RGD 
ovarian cancer treatmentISOMUC16 (Homo sapiens)7364774; 7364774 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Muc16  (mucin 16, cell surface associated)

Genes (Mus musculus)
Muc16  (mucin 16)

Genes (Homo sapiens)
MUC16  (mucin 16, cell surface associated)


Additional Information