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Web Date: March 4, 2014

Building Better Therapeutic Antibodies

Drug Delivery: Researchers develop a procedure to make antibody-drug conjugates with a consistent number of drug molecules
Department: Science & Technology | Collection: Life Sciences
News Channels: Biological SCENE, Organic SCENE
Keywords: antibody-drug conjugates, ADCs, therapeutic antibodies, glycans
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Arming Antibodies
To make an antibody-drug conjugate, researchers added galactose (purple circles) and sialic acid (blue triangles) to carbohydrate chains (open shapes) on a tumor-targeting antibody (green). After oxidizing the sialic acid to form an aldehyde, the chemists conjugated a cytotoxic drug (red star) via an amino-oxy group.
Credit: Bioconjugate Chem.
20140304lnj1-022814ADCs2
 
Arming Antibodies
To make an antibody-drug conjugate, researchers added galactose (purple circles) and sialic acid (blue triangles) to carbohydrate chains (open shapes) on a tumor-targeting antibody (green). After oxidizing the sialic acid to form an aldehyde, the chemists conjugated a cytotoxic drug (red star) via an amino-oxy group.
Credit: Bioconjugate Chem.

Antibody-drug conjugates (ADCs) are promising anti-cancer agents, consisting of a drug linked to a tumor-targeting antibody. But current approaches for attaching the drugs produce ADCs with variable numbers of drug molecules, leading to a greater risk of side effects. In a new study, researchers demonstrate a method to connect drugs to a specific site on an antibody, resulting in a more homogeneous pool of therapeutic ADCs (Bioconjugate Chem. 2014, DOI: 10.1021/bc400505q).

ADCs target certain proteins expressed at high levels by cancer cells, delivering a toxic payload directly to the tumor. The Food and Drug Administration has approved two ADCs: one for the treatment of lymphoma and the other for breast cancer. Researchers typically produce these and other ADCs by attaching drugs to either amino groups on lysine residues or to thiol groups on cysteine residues in the antibody. However, these methods are relatively nonspecific, resulting in ADCs that can contain up to 30 drug molecules.

This variability could make determining the optimal ADC dosage difficult, and if an ADC has too many drug molecules attached, it might cause toxic side effects or be cleared too rapidly from the body. So researchers led by Qun Zhou and Clark Q. Pan at Genyzme Corp., a biotechnology company in Framingham, Mass., developed a general method to add at most two drug molecules to any therapeutic antibody by attaching them to a specific site on the protein.

The two had already developed an approach to link drugs and other molecules to carbohydrates called glycans that decorate proteins (Bioconjugate Chem. 2011, DOI: 10.1021/bc1005416; Endocrinology 2013, DOI: 10.1210/en.2012-2010). So for their ADC method, the researchers picked a glycan on the tail region of all antibodies. Because the antibody tail consists of two identical protein fragments, each antibody has two of these sugar chains.

To adapt their previous method to antibodies, the researchers first had to use glycotransferase enzymes to add galactose and then sialic acid to the ends of the glycan chains. Then, they oxidized the sialic acid to produce an aldehyde that allowed them to conjugate drug molecules to the modified sugar chains via an amino-oxy group.

The team tested the method by making six ADCs—every possible combination of two cancer drugs with three different antitumor antibodies. They found that each ADC had just one or two attached drug molecules. In contrast, the same ADCs prepared with the conventional thiol conjugation method were more heterogeneous, with between one and eight attached drug molecules.

The Genzyme team administered their ADCs intravenously to mice with implanted breast tumors and found that the tumors shrunk in nine out of 10 animals. At the same amount of injected conjugate, thiol-conjugated ADCs were more potent, shrinking tumors in four animals and eliminating them in six. The increased potency is probably due to a greater average number of attached drug molecules. The team thinks they could get similar effects by injecting more of the glycan-conjugated ADCs to get more drug molecules to the tumors.

David M. Perrin of the University of British Columbia is impressed by “the level of sophistication used to generate highly specific and homogeneous ADCs.” However, he points out that the researchers will have to test the approach more to see if it can be generalized. For example, they will need to verify that the glycotransferase enzymes work on antibodies other than the ones they tested.

 
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