Bristol-Myers Squibb has received acceptance of the Investigational New Drug application (IND) from the U.S. Food and Drug Administration (FDA) for a CTLA-4-directed Probody™ therapeutic.

Cytotoxic T lymphocyte Associated Antigen 4, also known as CTLA-4, the clinically validated target of the Bristol-Myers Squibb checkpoint inhibitor ipilimumab (Yervoy®)*, is the first target to advance into the clinic under a strategic collaboration with CytomX Therapeutics formed in May 2014.

CytomX Therapeutics a clinical-stage biopharmaceutical company developing a pipeline of investigational Probody™ therapeutics, which are designed to exploit unique conditions of the tumor microenvironment to more effectively localize antibody binding and activity while limiting activity in healthy tissues.

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The IND acceptance results in a $10 million milestone payment to CytomX.

“Immune checkpoint inhibitors are making a profound impact in the treatment of people with cancer,” noted Sean McCarthy, D.Phil., president and chief executive officer of CytomX Therapeutics.

“By localizing antibody binding and therapeutic activity to the tumor microenvironment, our goal with Probody therapeutics is to deliver the same or potentially greater potency as first-generation checkpoint inhibitors, while reducing unwanted side effects. We are excited to see the CTLA-4 Probody advancing into the clinic and look forward to additional progress in our foundational alliance with Bristol-Myers Squibb,” he explained.

Solving a problem
Traditional antibodies bind to unique antigens that exist in abundance on diseased tissue. However, antibody may also target the same antigens found on healthy tissue, creating a critical challenge for drug development focusing on highly potent next-generation antibody therapies such as immunotherapy combinations, antibody-drug conjugates, T-cell engaging bispecific antibodies and CAR-NK cell therapies.

Using a masking peptide, CytomX Therapeutics’ Probody therapeutic solves this problem by only binding to diseased tissue.

A recombinant, proteolytically-activated antibody prodrugs, Probody therapeutics are engineered to remain inert until activated locally by tumor-associated proteases. In normal, healthy tissue, protease activity is tightly controlled and minimal.

But in cancer cells, protease activity is dysregulated. Hence, these novel, innovative Prodrug therapeutics exploit the fundamental dysregulation of extracellular protease activity that exists in tumors relative to healthy tissue.[1]

In healthy tissue the target-binding region of the Probody therapeutic remains masked and unable to bind.[1]

This results in minimizing toxicities. The technology also offers improved target selectivity allowing the development of novel drugs for previously inaccessible targets, and to expand the therapeutic index of existing, validated targets.

Collaboration
In March 2017, Bristol-Myers Squibb and CytomX Therapeutics expanded their 2014 worldwide collaboration to discover, develop and commercialize novel therapies using CytomX‘s proprietary Probody platform taking total upfront payments to CytomX to $275 million. The collaboration provides Bristol-Myers Squibb with the opportunity to select up to ten oncology targets and two non-oncology targets.

To date, Bristol-Myers Squibb has selected five oncology targets under the collaboration, including CTLA-4. CytomX is eligible to receive additional preclinical payments and development, regulatory and sales milestone payments totaling up to $4.7 billion across all 12 collaboration targets, as well as tiered royalties from mid-single digit to low-double digits on net sales of each product commercialized by Bristol-Myers Squibb.

Other agreements
Earlier this year CytomX advanced CX-2029, a Probody drug conjugate (PDC) targeting CD71 and being developed in collaboration with AbbVie, into GLP toxicology studies, a key step on the path to filing an Investigational New Drug (IND) application which is expected in 2018. As part of of their strategic oncology collaboration agreement signed in 2016, CytomX received a $15 million milestone payment from AbbVie following the start of the GLP toxicology study.

In October CytomX and Amgen announced their strategic collaboration to co-develop a CytomX Probody™ T-cell engaging bispecific against the Epidermal Growth Factor Receptor (EGFR), a highly validated oncology target expressed on multiple human cancer types.


* Ipilimumab (Yervoy®; Bristol-Myers Squibb) is indicated for the treatment of unresectable or metastatic melanoma in adults and pediatric patients (12 years and older) and for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy. For more information please review the highlights of prescribing information.


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