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Polatuzumab vedotin (Drug Description)

Polatuzumab vedotin, also know as DCDS4501A or RG7596, is an investigational anti-CD79b antibody-drug conjugate or ADC being developed by Genentech/Roche. Based on its potential to selectively bind to B-cells, the trial drug is currently in clinical development (Phase I and II clinical trials).[1]

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]

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.

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]


Last Editorial Review: November 10, 2016

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