Cancer Research UK and Glythera, a company developing the “next-gen” antibody-drug conjugates or ADCs have agreed that Glythera receives exclusive, worldwide rights, to the charity’s novel cyclin-dependent kinases 11/ CDK11 inhibitor payload series for the development of multiple ADCs. The novel agents will be using Glythera’s proprietary PermaLink® conjugation platform.

The company’s technology involves a controlled, stable conjugation platform composed of a portfolio of linker designs, which can be used for the selective and stable functionalization and conjugation of various cytotoxic payloads to proteins and peptides.

Cyclin-dependent kinases
One of the common features of many cancer types is the over-expression and/or hyperactivation of cyclin-dependent kinases or CDKs. They are a family of protein kinases first discovered for their role in regulating the cell cycle – and binds to a regulatory protein called a cyclin.

CDKs are relatively small proteins. Their molecular weights range from 34 to 40 kDa, and they contain little more than the kinase domain. Only the cyclin-CDK complex is an active kinase, and without binding to a cyclin, a CDK has virtually no kinase activity.

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Recent research has shown that an important role in tumor cell proliferation and growth by controlling cell cycle, transcription, and RNA splicing.[1]

For example, while CDK11 has previously has not been implicated  in ovarian cancer, researchers have found  that its expression is upregulated in human ovarian cancer tissues and associated with malignant progression. Furthermore, metastatic and recurrent tumors generally have significantly higher CDK11 expression when compared with the matched, original primary tumors.

CDK activation
Each individual CDK can be activated following binding with their corresponding cyclin partner, and following binding each kinase in this family is, in a coordinated way, responsible for particular aspects of the cellular events. Aberrant expression or altered activity of distinct CDK complexes results in escape of cells from the cell cycle control, which, in turn, leads to malignant transformation.

One of the cyclin-dependent kinases, CDK11, a serine/threonine protein kinase in the family of CDKs, has a critical roles in cancer cell growth and proliferation. Scientists believe that a number of genetic and epigenetic events cause universal overexpression of CDK11 in human cancers. In turn, CDK11 interacts with numerous proteins in transcription and RNA processing (Hsp90; cyclin L1, L2, D3, CK2, etc.) and is encoded by two highly homogenous genes, CDC2L1 (CDK11B) and CDC2L2 (CDK11A) – genes that produce 3 isoforms which are associated with distinct cellular functions.

In turn, inhibition of CDK11 leads to cancer cell death and apoptosis. The available evidence suggested that CDK11 may be a novel and promising therapeutic target for the treatment of cancers.[2]

Optimizing cytotoxins
Based on the agreement, Glythera and Cancer Research UK will select and optimize a number of cytoxins from the available inhibitor payload series for development in multiple antibody-drug conjugates. Following selection, Glythera will then progress these novel ADC contructs, optimized according to cancer cell-kill profiles, for difficult-to-treat tumors.

Glythera is currently evaluating a range of clinically important antibody targets and intends to identify its first clinical antibody-drug conjugate candidate by 2019.

Successful Collaboration
This agreement between the two companies follows a successful period of collaboration during which the viability of selected low molecular weight CDK11 molecules was demonstrated in relevant ADC models.

The CDK11 inhibitor program has identified a series of low molecular weight, synthetically tractable compounds which potently inhibit and are selective against other kinase targets. The series demonstrates highly potent anti-proliferative activity in dividing and non-dividing tumour cells and represents an exciting approach for antibody-drug conjugates.

Milestone Payments
Cancer Research UK will receive an undisclosed up-front fee, milestone payments on programme success for each resulting ADC, and royalties on worldwide product sales. Glythera is responsible for the development, manufacturing and commercialization of any ADC products resulting from the agreement.

“This collaboration highlights the success of our drug discovery approach in translating the most promising early stage research into new cancer treatments,” Hamish Ryder, director of Cancer Research UK’s Therapeutic Discovery Laboratories, a wholly owned subsidiary of Cancer Research UK which pursues drug discovery research in themed alliance partnerships and delivers varied commercial partnering arrangements.

“We’re excited to work with Glythera to identify and advance the very best novel agents and develop targeted treatments for cancer patients. By continuing to bring together industry and world leading academics in this field, we hope to transform the outlook for people with cancers that are the hardest to treat,” Ryder added.

“I am delighted that Glythera is working with Cancer Research UK as we look to identify and develop CDK11 inhibitor payloads and antibody conjugates to combat difficult-to-treat solid tumours and improve the lives of patients living with cancer,” Dave Simpson, Chief Executive Officer at Glythera concluded.

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