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CD79b-directed monoclonal antibody and microtubule inhibitor drug conjugate
Polatuzumab vedotin (PV) is a first-in-class CD79b-directed ADC. It is chemically engineered to destroy B cells through the targeted delivery of MMAE (vedotin), an antimitotic cytotoxin.42 PV is the fifth ADC to be FDA-approved as a chemoimmunotherapy agent and the second to carry MMAE as its payload.43,141 PV, for relapsed/refractory diffuse large B-cell lymphoma, was preceded to market by ado-trastuzumab emtansine for breast cancer (targets HER2), brentuximab vedotin for lymphomas (targets CD30), gemtuzumab ozogamicin for acute myeloid leukemia (targets CD33), and inotuzumab ozogamicin for acute lymphoblastic leukemia (targets CD22). Many other ADCs are in development,141 as are mechanistically similar antibodies, antibody fragments, and antibody-like fragment immunotoxins engineered using gene fusion techniques to deliver cytotoxic payloads (like moxetumomab pasudotox).141–143
PV was granted orphan drug status in 2016.22 Based on demonstrations of a better complete response rate (16/40 vs. 7/40) and longer 6- and 12-month durations of partial or complete response (16/25 vs. 3/10 and 12/25 vs. 2/10, respectively) for B-cell lymphomas treated with a three-drug combination of PV, bendamustine (an alkylating drug), and rituximab (a CD20-targeting monoclonal antibody) versus the two-drug combination of bendamustine and rituximab42 (NCT02257567),144 the FDA granted PV accelerated approval as a breakthrough three-drug combination regimen for adults with relapsed or refractory disease after two or more prior therapies.43 PV has been suggested as a reasonable option for patients with diffuse large B-cell lymphoma who are ineligible for, or have failed, a stem-cell transplant and also as a bridge therapy for those awaiting CD19-targeting chimeric antigen receptor (CAR) T-cell therapy.145
PV is a humanized IgG1 monoclonal antibody, produced in Chinese hamster ovary cells, that is covalently bonded to MMAE by a protease-cleavable linker (maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl [mc-vc-PAB]) using a chemical synthesis process.42 Following administration, the antibody portion of PV binds to CD79b (a B-cell receptor surface protein moderately to strongly expressed in most malignant lymphomas),146,147 and the conjugated molecule is taken up into the cell. Inside the cell the linker is cleaved by lysosomal proteases to complete the delivery of active MMAE to the cytosol. MMAE causes apoptosis by binding to microtubules and blocking tubulin polymerization in dividing cells.146
PV is administered as an intravenous infusion over 90 or 30 minutes, as tolerated, every 21 days for 6 cycles.42 The dose is 1.8 mg/kg, adjusted per the schedule published in the product labeling for treatment-related toxicities.42 Premedication with an antipyretic and antihistamine as well as prophylaxis against Pneumocystis jiroveci pneumonia and herpesvirus infections are recommended.42 PV is fetotoxic, and effective female contraception is necessary during therapy and for 3 months following therapy discontinuation.42 The terminal half-life of PV (conjugated MMAE) is approximately 12 days, and the half-life of unconjugated MMAE (vedotin) is ∼4 days.42 MMAE is a known substrate for CYP3A4 and P-gp substrate, and PV is not recommended for use in patients with moderate or worse hepatic impairment.42 Of note, MMAE is thought to be 100–1000 times more potent than doxorubicin.148 Unconjugated (free) MMAE is able to diffuse across cell membranes to cause toxicity in off-target “neighboring” cells (the “bystander effect”).141 This property makes MMAE unsuitable as a stand-alone (unconjugated) drug and worthy of special concern in patients more likely to experience increased systemic exposure (i.e., preexisting or emergent hepatic dysfunction or concomitant use of strong CYP3A4 inhibitors). Rare ocular toxicities may manifest in association with the escape of free unconjugated MMAE into the circulation triggering “bystander killing of neighboring cells.”147,149 Besides cytopenia, other particularly important adverse effects associated with PV therapy include peripheral neuropathy, infusion-related reactions, progressive multifocal leukoencephalopathy, tumor lysis syndrome, infections, and hepatotoxicity.42 Mechanisms for potential resistance to PV have been suggested.147 The cost of therapy with PV is expected to be ∼$90,000.150
Chapter 67. Pathway-Targeted Therapies: Monoclonal Antibodies, Protein Kinase Inhibitors, and Various Small Molecules
eChapter 2018: The Goodman & Gilman Year in Review New and Noteworthy FDA Approvals