NcXHF

ANTIBODY-DRUG CONJUGATES AND T-DM1
FIGURE 1. Antibody-Drug Conjugate Schematic
The drug is linked through the epsilon amino groups of lysine, through the intrastrand sulfhydryl linkages, and through genetically engineered unnatural amino acids to provide specific binding
sites and, thus, a single chemical species.
common an extreme potency and a lack of tumor selectivity,
which limits the use of the parent compounds. Dolastatin 10, the
parent molecule of the auristatins, was explored in clinical trials
in the 1990s, but exploration was terminated in 1995 when the
drug failed in a phase II trial in patients with prostate cancer. 12
The maytansinoids are exquisitely potent cytotoxic agents.
Maytansine was assessed in early clinical trials in the early 1980s.
The phase II clinical trials were disappointing, with very little
evidence of response. 13 Duocarmycins are antibiotics that alkylate
DNA in the A-T–rich regions of the double-helix minor
groove. Several duocarmycins were evaluated in clinical trials,
and dose-limiting toxicities occurred at doses too low to achieve
antitumor activity. 14,15 Calicheamicins bind in the DNA minor
grove and induce double-strand breaks, but they have narrow
therapeutic indices and serious late toxicities. 16,17 SN-38, the active
metabolite of irinotecan, is poorly bioavailable and has a
narrow therapeutic index. 18 Amatoxins, cytotoxic cyclopeptides
that target RNA polymerases, are produced by poison mushrooms.
Normal tissue toxicities of the amantins precluded their
clinical exploration. 19
ADCs are an effective method to increase the therapeutic index
of these highly potent cytotoxic agents. The drugs used in
ADCs must have suffıcient water solubility and prolonged stability
in aqueous formulations and in plasma, and they must
have a functional group that is suitable for conjugation with a
linker and that must not be readily susceptible to lysosomal enzyme
degradation. Consistent with the potent nature of the
drug, ADCs are often scheduled like cytotoxic chemotherapy in
clinical regimens, with dosing once every 3 weeks. 20-22
LINKERS
Linkers are short spacers that covalently couple the drug to
the antibody protein and must be stable in circulation (Fig.
1). Inside the cell, most linkers are labile; however, some are
stable, requiring degradation of the antibody and linker to
release the cytotoxic agent. 23,24 Many linkers react with lysine
side chains throughout the antibody or with the sulfhydryls
in the hinge regions of the antibody. Linkers in clinical use
include acid-labile hydrazone linkers that are degraded under
the low pH conditions found in lysosomes. Disulfıdebased
linkers are selectively cleaved in the cytosol in the
reductive intracellular milieu. Noncleavable thioether linkers
release the drug after degradation of the antibody in the lysosome,
and peptide linkers, such as citrulline-valine, are degraded
by lysosomal proteases in cells. Linkers using L- and
D-alanine and beta-glucuronide linkers are being explored.
Linkers with polyethylene glycol spacers have been developed
to increase the solubility of the conjugate. 25,26
Linkers can influence the circulating half-life and safety of
conjugates by minimizing the release of the drug molecule in
circulation and optimizing the delivery of the conjugate to
the target tissue. Often, during drug development, investigators
will test several linkers in safety and effıcacy assays to
select the best candidate conjugate.
ADCs
Drug-loading stoichiometry and molecular homogeneity are
important determinants of the safety and effıcacy of antibody
conjugates (Fig. 1). The goal is to develop ADCs that are sin-
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