Highlights on ADCs from Interviews with The Experts

On October 27th and 28th, Boston, MA will be host city for the World ADC Summit, sponsored by Biorbis. SAFC will be in attendance as a featured Exhibitor. Several posts on this blog (1, 2, 3) detail SAFC's new facilities and capabilities to support ADC manufacturing and other high-potency APIs.

 

As a preview to the Conference, Biorbis has posted 4 interviews with industry experts on antibody drug conjugation (ADC) on its registration site.  The interviews are free to download and I'd encourage you to read them in their entirety to whet your appetite for the conference. However, I'd like to highlight some of the content here from interviews with the following experts: Dr. Jay Tibbitts at Genentech, Dr. Thomas Davis at Celldex Therapeutics, Dr. Alejandro Ricart at Pfizer, and Dr. Beverly Teicher at Genzyme.

 The appeal of ADCs is they provide the chance for a targeted therapy directed to a cancer cell rather than treat with a systemic chemotherapeutic agent for example. This is made possible by the antibody's specificity and afinity for cell surface targets. Unfortunately, not all cancers are amenable to the ADC approach.

The target protein must be expressed abundantly on the target cell surface and have very limited expression on normal cells. The target protein must also be internalized when it is bound by the antibody. That is how the toxic payload attached to the antibody is delivered within the cell. Right now, there are relatively few therapeutic target proteins that fulfill these criteria - so this approach can't be used with every cancer.

Some of the big improvements that have been made with ADCs include some of the following advances:

• Better availability of linker molecules that are stable in circulation and release their drug conjugate inside cells - deliver more drug where its needed
• Ability to make more human variants of monoclonal antibodies
• Genetically engineered antibodies with specific or selective binding sites for linker-drug attachments
• Antibody fragment technology gives molecules of smaller size, potential for better cellular penetration, and better PK characteristics
• Improved analytic testing allows monitoring your antibody, your drug conjugate, and the impact of the linker and its stability - allows measurement of antibody and free drug levels

 Areas of potential improvement of course still exist.  Some of the areas where more work is needed:

• More work is needed toward discovery of suitable tumor-associated antigens - proteomics may be used to help here
• Very important to develop diagnostic/biomarker tests alongside most ADCs to help define best patient populations for these potent drugs
• Newer, more stable linkers are still needed
• Exploration of 'bystander killing' - that is killing of other tumor cells near your target that may not express the target specific antigen. This is mediated through release of the toxin from dead tumor cells after they been killed.
• The regulatory space outside the US FDA is years behind - education with these regulators will be required as this technology moves forward

 ADCs are a relatively high COG therapeutics.  They require expertise in protein production, small molecule production and reproducible conjugate production.  In some cases, it has required collaborations between three or more companies, not counting manufacturing contractors, to bring a single ADC to clinical trial. SAFC does perform contract manufacturing of ADCs - performing the conjugations steps with specialized facilities to handle high potency drugs.

At present, the industry is watching T-DM1 and SGN-35 closely. If these ADCs in clinical investigation are successful therapeutics, other ADCs will become much more widely applied to cell surface targets that fit the necessary criteria.

Posted by Bruce Lehr Sepember 22nd 2010.

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