A LM AC SC I E NC E
COVER STORY
CAREFUL HANDLING
have limited use of the drug. Operator works For now, “conjugates in an isolator are a niche that has been to dry, weigh, and package explored a lot, but there highly potent is no certainty that this compounds. technology will work,” says Enrico T. Polastro, vice president and senior industry specialist with Arthur D. Little Benelux. Others, however, see Mylotarg as proof of the concept, and several drug companies are working on improving conjugation technologies (C&EN, Sept. 25, 2006, page 51).
FILLING A HIGHLY POTENT NICHE Drug companies want to CREATE CONJUGATES of potent drugs and biological molecules, and custom manufacturers are complying ANN M. THAYER, C&EN HOUSTON
LIKE ANY GOOD PAIRING, an antibodydrug conjugate (ADC) is intended to be greater than the sum of its parts. Drug developers hope the yin and yang of linked biological and small-molecule parts will make for a highly effective therapy. In creating anticancer conjugates, drug innovators play with the pros and cons of both cytotoxic drugs and targeted delivery molecules. A cytotoxic drug will kill everything in its path—cancer cells and innocent bystanders alike. Monoclonal antibodies, on the other hand, are extremely discriminating for their targets but sometimes therapeutically ineffective on their own. Through an ADC coupling, the antibody harnesses the potent cytotoxic agent and delivers it by binding selectively to receptors on the target cell. Once bound there, the drug is released from the conjugate to do its work only where it is needed. Through this drug delivery route, nasty systemic side effects associated with chemotherapy can be avoided. Drugs once
considered entirely too toxic for use are in the running, and old drugs can find new life in ADCs. Meanwhile, antibodies can find wider use as cancer-cell-specific messengers. But matchmaking the right antibody and drug pair, and finding the linker to wed them, is a complicated development challenge. Just how challenging is evident in the large and rapidly growing oncology marketplace. Although scientists have worked on ADCs for decades, only one has been approved, and that was in 2000. Wyeth’s Mylotarg combines the cytotoxic agent calicheamicin with an antibody that binds to leukemia cells. But toxicity and dosage issues stemming from an unstable linker
INDEED, many candidates are in development. Some use new compounds that are at least 100 to 1,000 times more cytotoxic than traditional anticancer agents. Specialized handling skills and containment facilities, along with safety and quality controls, are required to synthesize these highly potent compounds and conduct the conjugation step that readies them for action. Alert to this opportunity, a few custom chemical manufacturers that can handle highly potent compounds have been expanding their conjugation capabilities. Compared with standard active pharmaceutical ingredient (API) manufacturing, these services promise many times the profit potential, although they also require expensive equipment and lots of time and labor. For now, higher premiums are justified by rising demand and a limited number of suppliers. Within the conjugation area, not all custom chemical suppliers offer the same capabilities. While they all have the contained equipment needed for making highly potent APIs and carrying out the conjugation, they don’t all provide linker technology or the biological component. Often the customer will supply a specially designed antibody and possibly the linker or small-molecule drug. Due to their confidentiality agreements with drug developers, custom manufacturers don’t offer details on what they are making. “Some conjugates are moving pretty far into the clinic and are generat-
“Conjugates are a niche that has been explored a lot, but there is no certainty that this technology will work.”
WWW.C E N- ONLI NE .ORG
28
J UNE 16, 20 0 8
*EFBTGPSUIF FOFSHJ[JOH TJEFPGMJGF
8IFSFWFSEBOHFSMVSLTXIFOTQBSLTÛZ &WPOJLEFÚFTDPOWFOUJPOBM UIJOLJOHXJUI4FQBSJPO BOFYDFQUJPOBMJOOPWBUJPO5IJTDFSBNJD TFQBSBUPSNBLFTJUQPTTJCMFUPCVJMEMBSHFMJUIJVNJPOCBUUFSJFTGPSNPUPS WFIJDMFTPSXJOEUVSCJOFTUIBUBSFTBGFS NPSFFGÚDJFOUBOENPSFFDP OPNJDBMUIBODPOWFOUJPOBMCBUUFSJFT4FQBSJPOJTPOFFYBNQMFPG UIFNBOZJOOPWBUJPOTUIBUNBLF&WPOJL GPSNFSMZLOPXOBT%FHVTTB UIFDSFBUJWFGPSDFJOTQFDJBMUZDIFNJDBMT 8FDSFBUFHSPVOECSFBLJOHTPMVUJPOTBUPVSNPSFUIBOSFTFBSDIBOE EFWFMPQNFOUTJUFTXPSMEXJEF JOTQJSJOHDVTUPNFSTXJUIPVSJEFBTJO TVDIEJWFSTFNBSLFUTBTBVUPNPUJWF DPBUJOHT DPTNFUJDT QMBTUJDTBOE QIBSNBDFVUJDBMT4FFGPSZPVSTFMGXXXFWPOJLDPNJEFBT
REQUEST MORE AT ADINFONOW.ORG
COVER STORY
“Many of our customers are not willing to make the capital investment necessary to build facilities.” ing positive results,” says David Feldker, SAFC Pharma’s vice president for manufacturing and U.S. operations. “The number of customers that we have knocking at the door just for this service is definitely a sign that people are focused in this area.” SAFC Pharma, the custom drugmanufacturing arm of Sigma-Aldrich, just started up a 600-sq-ft high-potency API conjugation suite in St. Louis that meets standards for current Good Manufacturing Practices (cGMP). “We have product being manufactured in there right now,” Feldker says. “Hopefully, business demand will dictate that we keep adding on there as well.” Because ADCs are targeted, potent, and used at low dosages, commercial quantities may be only kilograms per year and therefore don’t call for large production
facilities. SAFC, for example, can produce early-stage clinical amounts, or about 200–250 g of material per batch, in its new facility and has the potential to expand to commercial-scale multikilogram batches. Along with cytotoxics production, SAFC can make the linkers, Feldker says. Biologic compounds have their own set of handling and quality-control measures and regulatory standards, he points out, which SAFC has incorporated at some of its sites. SAFC doesn’t manufacture antibodies, “but we are looking at bringing on that kind of capability,” Feldker adds. A customer may have millions of dollars invested in the antibody side of the equation. “That’s typically the intellectual property a biopharmaceutical or pharmaceutical company will bring to the table.” Feldker says. “They need to
send it to someone who is going to do the conjugation to the potent compound, and it really comes down to having the capability to handle the biologics and meet expectations.” The work requires conducting chemistry under high-containment conditions and also capabilities in protein handling, peptide chemistry, and linker engineering, explains R. Ananthanarayanan, president of Piramal Pharma Solutions, the custom manufacturing business at India’s Piramal Healthcare. The business offers highpotency, linker, and conjugation services but doesn’t manufacture monoclonal antibodies, he says. Piramal Healthcare recently finished building a cGMP conjugation suite in Grangemouth, Scotland, that can be used to produce ADC batches of a few 100 g and up to 50 kg per year. It joins five other suites for manufacturing highly potent APIs, some of which are outfitted for conjugation as well. “We are excited about the initial response we have had and the current projects at hand and believe that there might be a need for further expansion in 2008,” Ananthanarayanan says. Interest is coming from large pharmaceutical companies as well as small and midsized biotechnology companies, he and others point out. The Swiss chemical and biotechnology company Lonza focuses on the different linker technologies that pharmaceutical customers are using, says Iwan Bertholjotti, head of potent compound production for Lonza’s exclusive synthesis business sector. The company recently built a small-scale and a large-scale potent compound conjugation unit to supply clinical-trial and commercial quantities and says it has already produced cGMP batches. LINKERS HAVE TO ensure product sta-
R EQUEST MO RE AT A DINFO NOW.O RG
bility during handling and storage, as well as when the conjugate is circulating in the blood, but then must release the cytotoxic payload once inside a tumor cell. Early linkers were pH dependent, but better ones now use enzyme-labile constructs such as thioethers, disulfide bonds, or peptides. In addition to linker technology, Lonza is well positioned with its biopharmaceutical capabilities. “We have the ability to produce monoclonal antibodies and the cytotoxic drugs,” Bertholjotti explains. WWW.C E N- ONLI NE .ORG
30
J UNE 16, 20 0 8
PRO DUCT P I P E L I NE
Drug Conjugates Advance In Clinical Trials Phase I studies for nonHodgkin’s lymphoma and other B-cell hematological malignancies using a CD19targeting monoclonal antibody and DM4. ImmunoGen has its own conjugates under development. IMGN901 uses DM1 and targets the CD56 antigen in multiple myeloma (in Phase I trials) and small-cell lung cancer (in Phase II) and has shown preclinical potential against ovarian cancer. And IMGN242, which has shown evidence of activity in Phase II testing, uses DM4 and targets an antigen found on gastrointestinal tumors. Other ultrapotent agents being investigated as conjugates include analogs of the bacterial natural product CC-1065, which selectively binds and alkylates double-stranded DNA. And Seattle Genetics is developing auristatins that inhibit microtubule assembly. Its SGN-35, now in Phase I trials, uses an auristatin and an antibody against the cell-surface protein CD30 to target Hodgkin’s lymphoma and other hematologic malignancies. In preclinical work, SGN-75 has been found to deliver an auristatin payload into CD70expressing solid tumors. Likewise, CuraGen has moved its CR011-vcMMAE into Phase II trials for treating advanced melanoma. The agent is an antibody against glycoprotein NMB, which plays a role in how cancer cells invade and metastasize, attached to an auristatin using Seattle Genetics’ technology.
WWW.C E N- ONLI NE .ORG
ON TARGET Knowledge, experience, integrity, and results – that’s what Arch Pharmalabs brings to your small molecule API and drug intermediate goals! From early development to commercial launch, Arch Pharmalabs stands with you, singularly focused on hitting your milestones. Together, we can efficiently transform your molecules into products, reducing costs and growing your profitability.
INGREDIENTS FOR SUCCESS Skilled, customer-centric teams State-of-the-art process R&D capabilities Flexible, cGMP, FDA-inspected assets in India Custom synthesis for pre-clinical studies, Phase I-III trials and launch Complete IP security and compliance To learn more, call our North America office at +1 707 938 1247
Transforming Chemistry. Synthesizing Success. www.archpharmalabs.com
31
J UNE 16, 20 0 8
R EQUEST MO RE AT A DINFO NOW.O RG
Many new therapies combining a highly potent drug compound and delivery molecule are targeting cancer. As was evident at the recent American Society of Clinical Oncology meeting in Chicago, several such conjugates are showing promise as they advance in development. Wyeth—which sells the only marketed drug conjugate, Mylotarg, for treating myeloid leukemia—now has a second conjugate called CMC-554 in Phase II and Phase III clinical studies. It too uses the cytotoxic agent calicheamicin, which causes breaks in cancer cell DNA, but couples it to an antibody with affinity for the CD22 antigen on lymphoma cells. Genentech, having licensed technology from ImmunoGen, is developing trastuzumab-DM1, which uses the antibody in its breast cancer drug Herceptin. The conjugate adds the cytotoxic power of ImmunoGen’s DM1, a maytansinoid compound that’s 1,000 times more potent then traditional anticancer agents. It’s the first clinical candidate in Genentech’s antibody-drug conjugate program, and the company is expected to make a decision this year about whether it will pursue Phase III studies. Sanofi-Aventis has licensed two conjugates from ImmunoGen that are both in Phase I studies. Like Mylotarg, AVE9633 targets myeloid leukemia with a CD33 antibody. But it is bound to another maytansinoid, DM4. Meanwhile, the conjugate designated SAR3419 is a potential treatment in
COVER STORY
vice president for commercial operations. antibodies, it can handle them. “And we “We definitely see a positive view from “More recently, we have developed techdevelop the linking technology with the customers that we are backward integratnology for conjugating small molecules customer and scale it up because there ed in all elements.” and synthetic peptides to recombinant can be a lot of problems taking a linker Besides monoclonal antibodies, other proteins.” from the lab to commercial scale,” he biological structures such as peptides and adds. The typical ADC combines polymers can be used to make about four drug molecules with conjugates and improve drug CONJUGATED SET one antibody. delivery. Cambrex, for example, Linker ties a cytotoxic drug, such as the maytansine DM1, Although new cytotoxic manufactures conjugates for to a monoclonal anitbody. drugs are being developed, customers using polymers and drugmakers see an opportunity peptides, says Eric P. Neuffer, DM1 Linker to extend the patent life on vice president for sales and busisome of the older products by ness development. And Swiss O O O making new conjugates, Grifcustom manufacturer Sochinaz S N Antibody N S fiths explains. “Working with collaborates with its parent, the H O CH3 O a known drug already on the peptide maker Bachem, to make O CH3 Cl market may make things move cytotoxic peptide conjugates. N CH3O a little quicker in the regulatory Similarly, Almac Sciences approval arena.” combines its abilities in peptide O CH3O These are some of the shortand potent-molecule synthesis N O term dynamics in the industry. to make conjugates. “We have H HO 3–4 “Many of our customers are a number of technologies that not willing to make the capital allow us to conjugate active speinvestment necessary to build facilities cies to synthetic peptides, either using Meanwhile, Carbogen-Amcis is workfor these products,” Griffiths adds. “So we protected peptide chains or directly using ing on several projects in the conjugation see a big opportunity there for the custom unprotected linear or folded synthetic area, says Chief Executive Officer Mark manufacturing market.” ■ peptides,” says David Moody, Almac’s Griffiths. Although the firm doesn’t make
Business Unit Sales Director:
[email protected] United States:
[email protected] Japan:
[email protected] England:
[email protected] Germany:
[email protected] www.isochem.fr
R EQUEST MO RE AT A DINFO NOW.O RG
ISOCHEM: The key solution provider ISOCHEM designs the most creative and accurate solutions for your needs in fine chemical custom synthesis. It offers the skill and competence required for the success of your valued project.
> Visit us at CHEMSPEC Europe June 18-19, 2008 Booth 470 - Hall 4
Pharmaceuticals
Cosmetics
Agro & Specialty Chemicals
A total focus on fine chemicals
WWW.C E N- ONLI NE .ORG
32
J UNE 16, 20 0 8
