Polatuzumab vedotin-piiq (Polivy™), also know as DCDS4501A or RG7596, is an anti-CD79b antibody-drug conjugate or ADC being developed by Genentech/Roche using a proprietary technology developed by Seattle Genetics. [1]
Based on its potential to selectively bind to B-cells, the drug is currently conditionally approved by the U.S. Food and Drug Administration (FDA) as a first in class antibody-drug conjugate (ADC) targeting CD79b in combination with bendamustine + rituximab (Rituxan®; Genentech/Roche) for the treatment of adults with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), an aggressive type of non-Hodgkin lymphoma that develops from the B-cells in the lymphatic system, who have received at least two prior therapies.
Mechanism of action
Polatuzumab vedotin contains a humanized monoclonal antibody (mAb) targeting B-cell antigen receptor complex-associated protein beta chain (CD79b) conjugated to the synthetic dolastatin 10 analog microtubule-disrupting monomethyl auristatin E (MMAE) through engineered cysteines (THIOMABs) by a protease-cleavable peptide linker (valine–citrulline; Maleimidocaproylvaline-citrulline-p-aminobenzoyloxycarbonyl or MC-VC-PABC). The advantage of the citrulline-valine (VC) linker is that it is highly stable in plasma.[1][2]
Polatuzumab vedotin-piiq has an approximate molecular weight of 150kDa. An average of 3.5 molecules of MMAE are attached to each antibody molecule.Polatuzumab vedotin has an approximate molecular weight of 150kDa. The drug has an average drug-to-antibody ration (DAR) of 3.5 molecules of MMAE attached to each antibody molecule and is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, while the small molecule components are produced by chemical synthesis.
MMEA, the cytotoxic payload used, has the potential antineoplastic activity similar to that of vincristine, a drug commonly used in the treatment of Non-Hodgkin Lymphoma (NHL).
Upon administration, polatuzumab vedotin selectively binds to CD79b, a protein which is abundantly expressed on the surface of B-cells. Following internalization and proteolytic cleavage, MMAE binds to tubulin and inhibits its polymerization, resulting in G2/M phase arrest and tumor cell apoptosis.[3][4]
Receptor signaling
CD79b is a transmembrane protein expressed on the surface of B-cells as part of the B-cell receptor complex. As a component of the B-cell receptor (BCR), CD79b plays a key role in B-cell receptor signaling and is expressed on the surface of almost all types of malignant B-cells. In preclinical in vitro models, data have shown polatuzumab vedotin to effectively and selectively kill cells expressing CD79b.[4]
Clinical trials
Polatuzumab vedotin is being investigated in Phase I and Phase II clinical trials. The Phase I trial investigates the drug in B-cell Non-Hodgkin lymphoma while the Phase II trials investigates the trial drug for the treatment of patients with relapsed or refractory follicular or diffuse large B-Cell Lymphoma.
The accelerated approval was based on a multicenter, open-label study of polatuzumab vedotin (DCDS4501A or RG-7596) administered by intravenous (IV) infusion in combination with standard doses of bendamustine (B) and rituximab (R) or obinutuzumab (G) in patients with relapsed or refractory follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL). The study comprises two stages: a Phase Ib dose-escalation stage and a Phase II stage. The anticipated time on treatment is 18-24 weeks.Basis for conditional approval
The accelerated approval of polatuzumab vedotin was based on the results from the Phase Ib/II GO29365 study, a global, phase Ib/II randomised study evaluating the safety, tolerability and activity of polatuzumab vedotin in combination with bendamustine and rituximab or obinutuzumab (Gazyva®; Genentech/Roche) in relapsed or refractory (R/R) follicular lymphoma or diffuse large B-cell lymphoma (DLBCL). (NCT02257567).
This study is the first and only randomized pivotal clinical trial to show higher response rates over bendamustine + rituximab in people with R/R DLBCL who are ineligible for a hematopoietic stem cell transplant.
The results of the study showed that 40% of people treated with polatuzumab vedotin plus bendamustine + rituximab achieved a complete response (n=16/40; 95% CI: 25-57), meaning no cancer could be detected at the time of assessment, compared to 18% with bendamustine + rituximab alone (n=7/40; 95% CI: 7-33).
Complete response rates were assessed by independent review committee. The study also showed that 45% of people on polatuzumab vedotin plus bendamustine + rituximab achieved an objective response at the end of treatment (n=18/40; 95% CI: 29-62), compared to 18% of people treated with bendamustine + rituximab alone (n=7/40; 95% CI: 7-33).
Of the people treated with polatuzumab vedotin plus bendamustine + rituximab who achieved a complete or partial response, 64% (n=16/25) had a duration of response (DOR) lasting at least six months as compared to 30% (n=3/10) of people treated with bendamustine + rituximab alone.
Additionally, 48% (n=12/25) of people treated with polatuzumab vedotin plus bendamustine + rituximab had a DOR lasting at least a year as compared to 20% (n=2/10) of people treated with bendamustine + rituximab alone.
Adverse reactions occurring in at least 20% of patients, and at least five percent more frequently in patients treated with polatuzumab vedotin plus bendamustine + rituximab compared to bendamustine + rituximab alone, included low white blood cell count, low platelet levels, low red blood cell count, numbness, tingling or pain in the hands and feet, diarrhea, fever, decreased appetite and pneumonia.
Polatuzumab vedotin-piiq (Polivy™) PackagingCurrent regulatory status
The Food and Drug Administration (FDA) has granted accelerated approval to Polivy (polatuzumab vedotin-piiq; Genentech), in combination with bendamustine plus rituximab (BR), for the treatment of adults with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who have received at least 2 prior therapies.
How supplied
Polatuzumab vedotin-piiq is supplied as a sterile, white to grayish-white, preservative-free, lyophilized powder, which has a cake-like appearance,for intravenous infusion after reconstitution and dilution. After reconstitution with 7.2mL of Sterile Water for Injection, USP, the final concentration is 20 mg/mLwith a pH of approximately 5.3. Each single-dose vial delivers 140 mg of polatuzumab vedotin-piiq, polysorbate-20(8.4mg), sodium hydroxide (3.80 mg), succinic acid (8.27mg), sucrose (288mg). See Highlights of Prescribing Information.
References:
[1] Hofland P. Phase I Study Supports Therapeutic Potential of Polatuzumab Vedotin in non-Hodgkin Lymphoma. ADC Review / Journal of Antibody-drug Conjugates, April 30, 2015 [Article]
[2] Polson AG, Yu SF, Elkins K, et al. Antibody-drug conjugates targeted to CD79 for the treatment of non-Hodgkin lymphoma. Blood. 2007;110:616-623. [Article]
[3] Nyborg B. Polatuzumab Vedotin and Pinatuzumab Vedotin + Rituximab Generally Well-tolerated With Similar Toxicity Profiles. ADC Review / Journal of Antibody-drug Conjugates, December 9, 2014 [Article]
[4]Dornan D, Bennett F, Chen Y, Dennis M, Eaton D, Elkins K, French D, et al. Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma. Blood. 2009 Sep 24;114(13):2721-9. doi: 10.1182/blood-2009-02-205500. Epub 2009 Jul 24.[Article]
Editorial Review: November 10, 2016
Last Editorial Review and Update: June 12, 2019
