THE TARGET – CD79b

The B-cell receptor (BCR) is composed of a membrane immunoglobulin (IgM) noncovalently attached to CD79.2 During B-cell development, CD79 expression precedes immunoglobulin heavy-chain gene rearrangement and CD20 expression and disappears in the plasma-cell stage of B-cell differentiation.3 CD79 functions as the signaling component of the BCR and is composed of a heterodimer of CD79a and CD79b, with each subunit containing a single extracellular immunoglobulin domain, a transmembrane domain, and an intracellular signaling domain.2 Antigen binding to the BCR initiates signaling events that include internalization of the ligand-receptor complexes and, as part of MHC class II antigen presentation by B cells, trafficking these complexes to lysosomes. Both CD79a and CD79b can induce internalization of the BCR but CD79b has the dominant role.4,5 In this manner, pola bound to CD79b is internalized and directed to lysosomal compartments, which contain proteases that can cleave the linker and release the cytotoxic payload (Figure 1).4 CD79b is an ideal target for ADC-based therapy given its high expression on most types of B-cell non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) and limited expression on normal cells (restricted to pre-B and mature B cells).1,6-8 Notably, recovery of circulating B cells was observed following administration of pola in non-human primates as CD79b is not expressed on hematopoietic stem cells.9 CD79b mutations, which occur in up to 25% of the activated B-cell (ABC) subtype of DLBCL,10 did not affect the internalization rates of pola compared with wild-type CD79b in preclinical studies.8 Targeting CD79 with unconjugated antibodies resulted in minimal antibody-dependent cell-mediated or complement-dependent cytotoxicity,4,8,9 suggesting that the main therapeutic effect of anti-CD79b ADCs is mediated by MMAE.

Based on CD79b cell-surface expression by flow cytometry, Dornan et al showed that a minimal threshold of CD79b expression was required for the in vitro activity of anti-CD79b ADC in NHL cell lines, and that the lack of CD79b expression was the primary mechanism of resistance.1 Applying this CD79b cell-surface expression threshold on 292 patient samples, 90% or more of DLBCL, FL, marginal zone lymphoma, hairy cell leukemia, and mantle cell lymphoma (MCL) cases expressed sufficient CD79b to be responsive to the ADC, compared with only 23% of CLL cases.1 Other studies showed that CD79b expression in CLL was weaker than in other closely related lymphoid malignancies such as Richter’s transformation (CLL transformation to DLBCL) and B-cell prolymphocytic leukemia.6,7,11 In the same study, Dornan et al also demonstrated that sufficient CD79b expression persisted in the majority of FL (87%) and DLBCL (77%) cases that relapsed after treatment with chemotherapy.1 Furthermore, the majority of DLBCL cases (92%, n=24) expressed CD79b by immunohistochemistry (IHC) with no significant difference in expression among the three molecular subtypes of DLBCL (germinal center B-cell (GCB), ABC, unclassifiable) based on cell-of-origin (COO) as determined by gene expression profiling (GEP).1 Overall, these findings suggested that most NHL types have sufficient CD79b expression to be susceptible for anti-CD79b ADCs.

CLINICAL TRIALS OF POLATUZUMAB

Monotherapy or in Combination with Rituximab


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The first-in-human Phase 1 clinical trial of pola comprised two dose-escalation cohorts in patients with relapsed/refractory NHL (n=34) or CLL (n=18) followed by two dose-expansion cohorts in NHL; one with pola alone (n=34) and one in combination with rituximab (R-pola, n=9) (Table 1).12 An expansion cohort in CLL was not pursued due to the lack of activity in the dose-escalation cohort. Overall, the trial included 40 patients with DLBCL, 30 with indolent NHL, 18 with CLL, and 7 with MCL. For patients with DLBCL or indolent NHL, the median age was 67 years (range, 20–81 in DLBCL and 41–86 in indolent NHL), and the majority received ≥3 prior lines of therapy (88% of DLBCL and 70% of indolent NHL) and were refractory to last therapy (78% of DLBCL and 53% of indolent NHL). Patients received pola at escalating doses of 0.1 to 2.4 mg/kg every 3 weeks until disease progression, unacceptable toxicity, or patient/physician’s decision. Only one dose-limiting toxicity was reported during dose escalation (grade 4 neutropenia at the 2.4 mg/kg dose level). Twenty-seven patients with DLBCL, 16 with indolent NHL, and 2 with MCL received the recommended Phase 2 dose (RP2D) of 2.4 mg/kg for a median of 6 cycles (range, 1–17). The most common grade 3–4 adverse events (AEs) were neutropenia (40%), anemia (11%), and peripheral neuropathy (PN) (9%). In the 9 patients treated with R-pola, grade 3–4 neutropenia and neutropenic fever occurred in 56% and 22%, respectively. Of all patients treated on trial, three patients died from treatment-related infections including lung infection, Serratia spp pneumonia and Clostridium difficile sepsis. Approximately half of the patients (51%) discontinued treatment due to AEs including PN and paresthesia in 29%. No other AE led to treatment discontinuation in more than one patient. PN occurred in 51% of the patients treated at the RP2D and was grade 1–2 in 42% and grade 3–4 in 9%. The PN was predominantly sensory except for 2 cases of motor neuropathy, had a median time to onset of 3.5 months, and resolved in 54% of the cases that required dose reductions or treatment delays/discontinuations. Notably, 17% of patients had grade 1 baseline PN prior to starting pola. In the evaluable patients treated at the RP2D, the objective response rate (ORR) was 56% in DLBCL (14/25) including complete response (CR) in 16% and 47% in indolent NHL (7/15) including CR in 20%. The two patients with MCL treated at the RP2D had a partial response. The median progression-free survival (PFS) and duration of response (DOR) were both 5 months in DLBCL, and 8 months and not reached in indolent NHL, respectively. In the 9 patients treated with R-pola (5 indolent NHL, 3 MCL, and 1 transformed FL), 7 patients (78%) had an objective response including 2 with CR (22%). The median PFS and DOR were 13 and 12 months, respectively. In CLL, the maximum tolerated dose was 1 mg/kg (two of five patients treated at 1.8 mg/kg had dose-limiting toxicities of grade 4 neutropenia and grade 4 fungal infection). None of the 18 patients with CLL had an objective response. Pola’s lack of efficacy in CLL was attributed to faster clearance and lower exposure of pola in CLL compared with NHL. There were no data on CD79b expression levels in patients with CLL or NHL, and CD79b expression was not a prerequisite for study entry.12

Table 1

The ROMULUS phase 2 clinical trial randomized patients with relapsed/refractory FL or DLBCL to rituximab plus either pola (R-pola) or pinatuzumab vedotin (Table 1).13 Pinatuzumab vedotin is a similar ADC that is composed of an anti-CD22 monoclonal antibody conjugated to MMAE. Both pola and pinatuzumab were developed by Genentech, but pola was selected for further development based on the longer duration of response achieved with R-pola in this study. Patients received rituximab plus one of the ADCs at a dose of 2.4 mg/kg every 3 weeks until disease progression or unacceptable toxicity for up to 1 year. For the 39 patients with DLBCL randomized to R-pola, median age was 68 years (range, 55–77), Eastern Cooperative Oncology Group performance status (ECOG PS) was 0–1 in 95% and 2 in 5%, median number of prior treatments was 3 (range, 2–4), 18% underwent prior autologous stem cell transplantation (SCT), and 80% were refractory to last treatment. In this cohort of patients with DLBCL, R-pola resulted in 54% ORR including 21% CR and median PFS, DOR, and overall survival (OS) of 6, 13, and 20 months, respectively. For the 20 patients with FL randomized to R-pola, median age was 67 years (range, 59–74), ECOG PS was 0–1 in 95% and 2 in 5%, no patients had bulky disease, median number of prior treatments was 2 (range, 2–4), 25% were refractory to rituximab, and 35% were refractory to last treatment. In this cohort of patients with FL, R-pola resulted in 70% ORR including 45% CR and median PFS and DOR of 15 and 9 months, respectively, whereas the median OS was not reached. None of the 6 patients (5 DLBCL, 1 FL) who crossed over to treatment with the other ADC following disease progression (including 4 patients crossing over from R-pinatuzumab to R-pola) responded, suggesting that the main mechanism of resistance was to MMAE rather than to the antibody target. The most common grade 3–4 AEs with R-pola in DLBCL were neutropenia (23%), anemia (8%), and diarrhea (8%), and in FL were neutropenia (15%) and diarrhea (10%). PN occurred in 56% of the patients with DLBCL (grade 2 in 26% and grade 3 in 10%) and 95% of the patients with FL (grade 2 in 75% and grade 3 in 5%). PN developed in a median of 2–3 months, lasted for a median of 14–17 months, and led to treatment discontinuation in 18% and 55% of the patients with DLBCL and FL, respectively. Notably, grade 1 PN was present at study entry in 39% and 25% of the patients with DLBCL and FL, respectively. The higher incidence of PN in FL compared with DLBCL was likely related to the longer duration of treatment with R-pola in FL (median of 10.5 vs 6 cycles).

Taken together, these two clinical trials showed that pola monotherapy or in combination with rituximab had encouraging activity in patients with heavily pretreated DLBCL and FL, but needed to be combined with other active agents to improve the depth and duration of response. Because PN occurred in more than half of the patients treated with pola 2.4 mg/kg and frequently led to treatment discontinuation, the maximum dose of pola in the dose-escalation portion of subsequent combination trials was set at 1.8 mg/kg.

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