Tuesday, November 20, 2012

White Paper: The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma

Today, we feature a white paper from Peter Senter, Ph.D., Vice President, Chemistry, Seattle Genetics, Inc. who will be a keynote presenter at the Antibody Therapeutics Conference.  The event will take place December 2-6, 2012 in San Diego, California. For more information, download the agenda.

The concept of targeting cancer cells with ADCs has roots that can be traced back more than a century, when the German immunologist Paul Ehrlich (Fig. 1) proposed that if toxic molecules could be selectively delivered to disease-causing cells, it would be possible to develop therapeutic modalities with specificities that were otherwise unattainable 1.

For treating cancer, this would require a targeting agent that selectively binds to tumor cell surface antigens, coupled with a cytotoxic drug that could kill the cells once delivered. Antibodies that have been selected to distinguish between tumor and non-tumor cells are ideally suited for this purpose because they are readily available, biologically compatible, minimally immunogenic and may circulate in the body for extended periods of time. The adaptation of antibodies to Ehrlich’s vision is schematically represented in Figure 2, which shows how ADCs can elicit specific tumor cell killing either through receptor-mediated endocytosis 2–4 or extracellular drug release 5. Target cells are killed if sufficient drug is selectively delivered, ideally sparing normal tissues from chemotherapeutic damage.

Whereas early ADC research was undertaken with available targeting reagents such as polyclonal antibodies to human tumor antigens 6, it was not until the development of monoclonal antibody (mAb) technology by Kohler and Milstein (Fig. 1) in 1975 7 that tumor targeting became technologically feasible. Soon afterward, several pharmaceutical and biotech companies actively developed ADC programs for treating cancer, with an emphasis on proof-of-principle experiments using conventional anticancer drugs targeted to tumor types for which the drugs had been already approved. Unfortunately, advanced agents from this work, such as KS1/4–desacetylvinblastine hydrazide 8 (Eli Lilly; Indianapolis) in patients with metastatic adenocarcinomas, and BR96–doxorubicin (Adriamycin) 9 (Bristol-Myers Squibb; New York) in patients with metastatic breast cancer proved to be clinically unsuccessful. Shortcomings became evident, stemming from conjugate immunogenicity, low drug potency, antigen expression on normal tissues and instability of the linkers that joined the drugs to the mAbs.

Read the full white article here.

1. Schwartz, r.S. Paul Ehrlich’s magic bullets. N. Engl. J. Med. 350, 1079–1080 (2004).
2. Senter, P.D. Potent antibody drug conjugates for cancer therapy. Curr. Opin. Chem. Biol. 13, 235–244 (2009).
3. Carter, P.J. & Senter, P.D. Antibody-drug conjugates for cancer therapy. Cancer J. 14, 154–169 (2008).
4. Wu, A.M. & Senter, P.D. Arming antibodies: prospects and challenges for immunoconjugates. Nat.Biotechnol. 23, 1137–1146 (2005).
5. Bernardes, G.J. et al. A traceless vascular-targeting antibody-drug conjugate for cancer therapy. Angew. Chem. Int. Edn Engl. 51, 941–944 (2012).
6. Arnon, r. & Sela, M. In vitro and in vivo efficacy of conjugates of daunomycin with anti-tumor antibodies. Immunol. Rev. 62, 5–27 (1982).
7. K√∂hler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495–497 (1975).
8. Petersen, B.H., DeHerdt, S.v., Schneck, D.W. & Bumol, t.F. the human immune response to KS1/4-desacetylvinblastine (LY256787) and KS1/4-desacetylvinblastine hydrazide (LY203728) in single and multiple dose clinical studies. Cancer Res. 51, 2286–2290 (1991).
9. tolcher, A.W. et al. randomized phase II study of Br96-doxorubicin conjugate in patients with metastatic breast cancer. J. Clin. Oncol. 17, 478–484 (1999).

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