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• W2728851907 abstract "1189 Conjugation to cytotoxic drugs is one of the most promising ways to enhance the antitumor efficacy of antibodies. For example, monomethyl auristatin E (MMAE) conjugated to the chimeric anti-CD30 antibody, cAC10, is highly efficacious in scid mouse xenograft models of anaplastic large cell lymphoma (ALCL) and Hodgkin’s disease (HD). One parameter that may impact the therapeutic window of such antibody drug conjugates is toxicity due to release of drug at non-tumor sites. Unfortunately, drug liberation following conjugate catabolism appears to be the unavoidable ultimate in vivo fate of IgG drug conjugates. The use of antibody fragments for drug conjugation offers a potential way to circumvent the catabolic fate of IgG drug conjugates. This reflects that small bivalent antibody fragments target tumors efficiently but are eliminated rapidly and primarily by renal filtration which will lessen the exposure of non-tumor sites to free drug and may reduce the observed toxicity. We have created MMAE drug conjugates of various antibody fragments of cAC10, namely, diabodies, minibodies (scFv-CH3) and scFv-Fc fragments and compared their in vitro and in vivo anti-tumor activities to the corresponding IgG drug conjugate. The diabody (53 kDa), minibody (83 kDa) and scFv-Fc (105 kDa) fragments are anticipated to span a broad range of pharmacokinetic parameters allowing investigation of the impact of fragment drug conjugate clearance rate on therapeutic index. The antibody fragments were stably expressed in CHO cells, purified and site-specifically conjugated with 4 equivalents of MMAE using available or engineered cysteine residues. The cAC10 fragment MMAE conjugates and intact IgG bound comparably to CD30+ cells. Additionally, cAC10 fragment MMAE conjugates were cytotoxic against both CD30+ ALCL and HD cell lines in vitro with slight reductions in potency observed compared to the intact IgG (IgG = scFv-Fc > minibody > diabody). Administration of cAC10 fragment MMAE conjugates to scid mouse xenograft models of ALCL resulted in antitumor efficacy for each fragment format. These studies demonstrate that cAC10 antibody fragment MMAE conjugates retain the antigen binding and antitumor activity of the intact IgG conjugate. Further studies to compare the therapeutic windows of antibody fragment drug conjugates to intact IgG drug conjugates are in progress." @default.
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• W2728851907 date "2006-04-15" @default.
• W2728851907 modified "2023-10-04" @default.
• W2728851907 title "Development of antibody fragment auristatin drug conjugates for cancer therapy" @default.
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