Antibody-drug conjugates or ADCs combine the cytotoxic potential of chemotherapeutic drugs with the specificity of monoclonal antibodies.  One of the critical parameters effecting the efficacy, therapeutic window, and toxicity profile of ADCs is the selection of the an appropriate target.

Novel targets of antibody-drug conjugates have typically been selected by identifying transmembrane antigens that are highly expressed in tumors but are low or absent in normal, healthy, tissues.

However, the number of potential targets meeting these requirements is limited.  Scientists have long hypotesised that this may be caused because the expression of these targets in a specific tumor is not high enough for optimal efficacy, or, in contrast, the expression of the target in normal, healthy, tissues is too high, leading to unexeptable toxicity.

One alternative, Probody™ Drug Conjugates (PDCs),  being developed by CytomX Therapeutics, an oncology-focused biopharmaceutical company pioneering a novel class of investigational antibody therapeutics, are designed to take advantage of the unique conditions of a tumor’s microenvironment.

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PDCs remain inactive until proteolytically activated in the tumor microenvironment and may have the potential to enable targeting of more desirable tumor antigens with higher, more persistent and more homogeneous expression in tumors, while limiting toxicity due to interaction with these antigens in normal tissues. In essence, Probody-drug conjugates mask use a masking peptide designed to limit binding to healthy tissue, thereby minimizing toxicities.

While the tumor-targeting features of an antibody are thus enhanced, the drug activity in healthy tissue is reduced.  As a result, probody therapeutics bind selectively to tumors and avoid binding to healthy tissue, to minimize toxicity and potentially create safer, more effective therapies.

Desirable target
Transferrin receptor 1 (TfR1), also known as CD71, which is ubiquitously expressed on the surface of dividing, normal or healthy cells as well as a number of solid and hematologic malignant cancer cells, mediates the uptake of transferrin-iron complexes (required for cell division and cannot be down regulated by tumors) is an example of a highly desirable antibody-drug conjugate target. [1]

One of the reasons is the well-characterized ability of CD71 to efficiently internalize and deliver a payload intracellularly. Another reason is that CD71 is expressed homogeneously in high levels (3+ expression by IHC) in almost all tumor types, including in metastatic disease.

But because CD71 is also expressed on multiple normal, healthy, cell types, including many progenitor hematological cells, scientists have had doubts about the possibility to develop a CD71-targeted antibody-drug conjugate since this expression in normal dividing cells prohibits development of a traditional antibody-drug conjugate.

To enable targeting of CD71, scientists at CytomX therapeutics developed an anti-CD71 Probody-drug Conjugate or PDC, which can be activated by multiple proteases in the tumor microenvironment. However, while activated in the tumor microenvironment, the anti-CD71 probody-drug conjugate remains in a relatively inactive form while in circulation and in normal tissues.

In mouse models of lymphoma, breast cancer and lung cancer the novel anti-CD71 prosody-drug conjugate produces complete tumor regressions at therapeutic doses.

Consistent with their hypothesis that it would be difficult to develop an anti-CD71 antibody-drug conjugate, treatment of cynomolgus monkeys with an anti-CD71 antibody-drug conjugate at doses that were efficacious in mouse tumor models caused life-threatening depletion of CD71-expressing hematopoietic cells, including neutrophils, lymphocytes and red blood cells (RBCs).

In contrast, these toxicities were not observed in monkeys treated with the same dose of the anti-CD71 probody-drug conjugate, consistent with the Probody therapeutic avoiding interaction with these normal cells.

During the 2016 annual meeting of the American Association for Cancer Research (AACR), being held April 16 – 20 in New Orleans, researchers presented data from preclinical studies showing that probody drug conjugates can safely and effectively target attractive tumor antigens like CD71 which have been difficult to address with traditional antibody-drug conjugates (Poster #2975).

The presented data also supported the development potential of Probody therapeutics directed against CD71 in multiple different cancers, demonstrating that these novel drugs can safely and effectively target tumor antigens.

Collaboration
Following the AACR meeting, CytomX Therapeutics and Abbie, a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories, announced that they have entered have entered into a collaboration to co-develop and co-commercialize probody-drug conjugates against CD71.

“We believe that the Probody platform provides a differentiated opportunity to combine with our strength in antibody drug conjugates,” noted Steve Davidsen, Ph.D., vice president, oncology drug discovery at AbbVie.

“We are encouraged by the promising preclinical data that CytomX has generated for their probody-drug conjugate programs to-date and look forward to working closely with their team. This collaboration will enable us to expand our innovative pipeline in antibody drug conjugates and leverage our strength in that area to previously unexplored targets,” Davidsen explained.

“This collaboration is another important step toward achieving CytomX’s vision of transforming lives with safer, more effective therapies and allows us to further advance our broad pipeline of Probody therapeutics,” said Sean McCarthy, D.Phil., president and chief executive officer at CytomX.

“AbbVie has demonstrated leadership in developing antibody drug conjugates and we look forward to collaborating with their team to realize the full potential of our CD71 Probody drug conjugate program and additional oncology targets,” he continued.

Agreement
Under the terms of the agreement, CytomX and AbbVie will co-develop a probody-drug conjugate against CD71, with CytomX leading pre-clinical and early clinical development. AbbVie will lead later development and commercialization, with global late-stage development costs shared between the two companies.

CytomX will receive an upfront payment of $30 million and is eligible to receive up to $470 million in development, regulatory and commercial milestones, pending the achievement of pre-determined outcomes. AbbVie will lead global commercial activities with CytomX eligible to receive a profit share in the U.S. and tiered double-digit royalties on net product sales outside of the U.S. CytomX retains an option to co-promote in the U.S.

AbbVie also receives exclusive worldwide rights to develop and commercialize probody-drug conjugates against up to two additional, undisclosed targets.  According to a statement of the companies, should AbbVie pursue these targets, CytomX is eligible to receive additional milestone and royalty payments per target on any resulting products.

CytomX’s lead probody-drug conjugates, CX-2009, directed at CD166, is currently in the IND-enabling stage. Other probody-drug conjugates programs are being assessed for advancement into clinical investigation.

In addition to the established partnership with AbbVie, CytomX has also established partnerships with Pfizer and ImmunoGen for multiple therapeutic targets and programs.

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