Featured Image: Research Laboratory, Roche, Mannheim, Germany. Courtesy: 2020 Roche.

The European Commission’s conditional marketing authorization of polatuzumab vedotin (Polivy®; Genentech/Roche) earlier this week triggered a milestone payment which Seattle Genetics will receive from Roche.

Polatuzumab vedotin is an antibody-drug conjugate (ADC) which consists of a humanized anti-CD79b antibody that is conjugated to monomethyl auristatin E (MMAE) through engineered cysteines (THIOMABs) by a protease cleavable linker, utilizes Seattle Genetics’ proprietary technology.

Developed and commercialized by Genentech/Roche, the drug was approved in combination with bendamustine + rituximab (MabThera®; Roche for the treatment of adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), who are not candidates for a hematopoietic stem cell transplant.

Polatuzumab vedotin is a first-in-class anti-CD79b ADC currently being investigated for the treatment of several types of of non-Hodgkin lymphoma (NHL). Image courtesy Roche/Genentech.

Polatuzumab vedotin is a first-in-class anti-CD79b ADC. The CD79b protein is expressed specifically in the majority of B-cells (an immune cell impacted in some types of non-Hodgkin lymphoma (NHL), making it a promising target for the development of new therapies.[1][2]

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Polatuzumab vedotin binds to CD79b and destroys these B-cells through the delivery of an anti-cancer agent, which is thought to minimize the effects on normal cells.[3][4]

The drug is marketed in the United States by Genentech as polatuzumab vedotin-piiq, with piiq as the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the US Food and Drug Administration (FDA)

Limited treatment options
“People with relapsed or refractory diffuse large B-cell lymphoma have limited treatment options – especially those who are not candidates for hematopoietic stem cell transplant,” explained Levi Garraway, MD, Ph.D, Roche’s Chief Medical Officer and Head of Global Product Development.

Polatuzumab vedotin offers patients a new, much needed, treatment option for this aggressive disease.

“With this approval, people in the EU with relapsed or refractory diffuse large B-cell lymphoma will have the opportunity to benefit from this new Polivy combination,” Garraway further noted.

“For patients battling this aggressive disease, the prognosis is poor and few treatments are available. We are proud to bring this first-in-class treatment option to those who need it most,” he added.

Approval process
As part of their approval process, the European regulators reviewed the results from the phase Ib/II GO29365 study, the first and only clinical trial to show higher response rates and improved overall survival (OS) compared to bendamustine + rituximab in people with R/R DLBCL who are not candidates for a hematopoietic stem cell transplant. Results of the study showed that 40% of people treated with polatuzumab vedotin in combination with bendamustine + rituximab achieved a complete response (n=16/40), meaning no cancer could be detected at the time of assessment, compared to 17.5% (n=7/40) with bendamustine + rituximab alone. Complete response rates were assessed by an independent review committee.

The study also showed that polatuzumab vedotin plus bendamustine + rituximab more than doubled OS, with a median OS of 12.4 months in the polatuzumab vedotin arm, versus 4.7 months in the BR alone arm (HR=0.42). The most commonly reported adverse events in people treated with polatuzumab vedotin in combination with bendamustine + rituximab include anaemia, thrombocytopenia, neutropenia, fatigue, diarrhoea, nausea, and pyrexia.

PRIME
In 2017 the European regulators granted PRIME (PRIority MEdicines) designation to polatuzumab vedotin for the treatment of people with R/R DLBCL.

“In addition to our two marketed ADC products brentuximab vedotin (Adcetris®; Seattle Genetics) and the recently FDA-approved enfortumab vedotin-ejfv (Padcev ; , the European Commission’s approval of polatuzumab vedotin highlights the increasing importance of ADCs in the treatment of cancer,” noted Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

Today, seven ADC have been approved and are commercially available. However, more than 100 ADCs are currently in a development – from early, pre-clinical development to phase III clinical trials.

“Across our internal and collaborator pipelines, there are more than ten ADCs in clinical development employing our proprietary technology. We continue to lead in the field of ADCs with our novel linker systems, cell-killing payloads and conjugation technologies,” Siegall added.

Technology platform
Seattle Genetics’ ADC technology combines the specificity of monoclonal antibodies, innovative linker systems and potent cell-killing agents to treat cancer. The technology has been licensed to several companies, including Genentech/Roche and GlaxoSmithKline. Under the terms of these agreements, each licensee company has rights to use the technology with antibodies against specified targets.

The licensee is responsible for research, product development, manufacturing and commercialization. Seattle Genetics is entitled to receive fees, progress-dependent milestone payments and royalties on worldwide net sales of any resulting ADC products.

Clinical trials
A Study of Polatuzumab Vedotin (DCDS4501A) in Combination With Rituximab or Obinutuzumab Plus Bendamustine in Participants With Relapsed or Refractory Follicular or Diffuse Large B-Cell Lymphoma – NCT02257567

Reference
[1] Dornan D, Bennett F, Chen Y, et al. Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma. Blood. 2009;114(13):2721–2729. doi:10.1182/blood-2009-02-205500 [Pubmed]
[2] Pfeifer M, Zheng B, Erdmann T, et al. Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes. Leukemia. 2015;29(7):1578–1586. doi:10.1038/leu.2015.48 [Pubmed]
[3] Ducry L, Stump B. Antibody-drug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjug Chem. 2010;21(1):5–13. doi:10.1021/bc9002019 [Pubmed]
[4] What are antibody-drug conjugates? ADC Review | Journal of Antibody-drug Conjugates. Online. Last accesses January 19, 2020.