Antibody-Drug Conjugates for Cancer Therapy

O RIGINAL A RTICLES

Antibody-Drug Conjugates for Cancer Therapy Paul J.Carter,PhD,and Peter D.Senter,PhD

Abstract:The antibody-drug conjugate(ADC)concept is to use an antibody to deliver a cytotoxic drug selectively to a target such as a tumor-associated antigen.Such conjugates represent a broadly ap-plicable approach to enhance the antitumor activity of antibodies and improve the tumor-to-normal tissue selectivity of chemotherapy. Critical parameters for ADC development include target antigen selection,conjugate internalization by tumor cells,drug potency and stability of the linker between drug and antibody.Other important considerations include the conjugation methods,drug-to-antibody ratio,and the effects of drug conjugation on antibody properties. Highly potent drugs with more stable linkers have been attached to a new generation of antibodies to create conjugates with pronounced antitumor activities in preclinical studies and encouraging results in early stage clinical trials.This review details these advances,dis-cusses some of the remaining challenges,and overviews ADCs currently in clinical trials for cancer therapy.

Key Words:antibody,immunoconjugate,targeted therapy (Cancer J2008;14:154–169)

A ntibody-based therapeutics are of growing signi?cance

for cancer therapy as evidenced by12such drugs ap-proved for oncologic indications since1995,including9in the United States.1However,these antibody therapeutics are seldom curative,encouraging numerous approaches to en-hance ef?cacy.2–5Two of the most promising strategies to enhance the antitumor activity of antibodies are antibody-drug conjugates(ADCs)—the focus of this review—and Fc optimization to augment secondary immune functions.5 ADCs comprise an antibody,usually in IgG format, conjugated to a cytotoxic drug via a chemical linker(Fig.1). The therapeutic concept of ADCs is to use an antibody as a vehicle to deliver a cytotoxic drug to a tumor cell by means of binding to a target cell surface antigen(Fig.1).ADCs are prodrugs requiring drug release for activation,commonly after ADC internalization into the target cell.Numerous preclinical ef?cacy studies show that ADCs have signi?cant potential for enhancing the antitumor activity of“naked”antibodies and reducing the systemic toxicity of the conju-gated drugs.3,6Moreover,clinical demonstration of the ADC concept has been provided by gemtuzumab ozogamicin(My-lotarg),a humanized anti-CD33antibody conjugated to cali-cheamicin approved in the United States for the treatment of acute myeloid leukemia(AML).7

The concept of arming antibodies by conjugation to protein toxins dates back to1970,8and was followed a few years later by antibody conjugates with cytotoxic drugs. Antibody therapeutics have come of age in the intervening decades with the advent of hybridoma technology to develop murine monoclonal antibodies(MAb),9chimerization and humanization to address the shortcomings of murine MAb as therapeutics,and more recently with direct routes to human antibodies using phage display or transgenic mice.2The clinical potential of ADCs has been greatly enhanced by im-proved choices of targets,10more potent drugs in conjunction with linkers of improved stability6,11and greatly expanded knowledge of ADC cell biology32and pharmacology.13ADCs are reviewed here from a design perspective from target selec-tion,through ADC lead identi?cation,optimization,and preclin-ical development to clinical experience(Fig.2).Other payload-ing strategies for antibodies,as well as for alternative delivery vehicles,have been extensively reviewed elsewhere3,11,12,14and are outside the scope of this article.Of these,radioimmunocon-jugates stand out,with the approval of2different anti-CD20 radioimmunoconjugates for the treatment of non-Hodgkin lym-phoma:ibritumomab tiuxetan(Zevalin,90Y conjugate)and131I tositumomab(Bexxar).15

TARGET SELECTION

The de novo identi?cation and validation of cell surface targets as candidates for ADCs is beyond the scope of this article and is reviewed elsewhere.10Target selection from a candidate pool is a critical?rst step in generating ADCs(Fig.2).Expres-sion pro?ling is a key aspect of target selection in that tumor-associated antigen expression is presumed to be one of the necessary criteria for successful targeting with an ADC,whereas little or no normal tissue expression is desirable and may be necessary to achieve an adequate therapeutic index.

Immunohistochemistry allows semi-quantitative analy-sis of protein expression in tissue samples and is often the most direct and consequently preferred method for evaluating potential ADC targets.The advent of tissue microarrays16 facilitates high-throughput expression pro?ling—hundreds to thousands of samples—with greater standardization.17A lim-itation of immunohistochemistry is the high variability of data with different reagents,protocols and samples17—resolvable if concordant data are obtained using multiple antibodies.An additional challenge with immunohistochem-istry is that data may be dif?cult to interpret if the antigen is

From Seattle Genetics,Inc.,Bothell,Washington98021.

Reprint requests:Paul J.Carter or Peter D.Senter,Seattle Genetics,Inc.,

2182330th Drive SE,Bothell,WA98021.E-mail:pcarter@ace3230cbb68a98271fefa23

or psenter@ace3230cbb68a98271fefa23.

Copyright?2008by Lippincott Williams&Wilkins

ISSN:1528-9117/08/1403-0154

The Cancer Journal?Volume14,Number3,May/June2008 154

located inside the cell as well as on the cell surface.Flow cytometry is also used for protein expression pro?ling,particu-larly for hematologic tumors.This method provides more quan-titative information than immunohistochemistry and can dem-onstrate the accessibility of a target to an antibody.Limitations of ?ow cytometry include the limited availability of suitable patient samples,and the need to disaggregate solid tumor sam-p …… 此处隐藏：59937字，全部文档内容请下载后查看。喜欢就下载吧 ……