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New antibody-drug conjugate, polatuzumab vedotin, enters FDA review

February 20, 2019 by Janice Reichert

Roche’s biologics license application (BLA) for polatuzumab vedotin in combination with bendamustine plus Rituxan® (rituximab) (BR) for the treatment of people with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) has been accepted and granted a priority review by the US Food and Drug Administration. A decision on approval of the BLA is expected by August 19, 2019. Developed in collaboration with Seattle Genetics, polatuzumab vedotin is composed of a humanized anti-CD79b IgG1 antibody conjugated to the antimitotic agent monomethyl auristatin E. The antibody’s target is highly expressed on B cells of patients with lymphoma. Polatuzumab vedotin was granted FDA’s Breakthrough Therapy designation, the European Medicines Agency (EMA)’s PRIME designation, and US and EU Orphan Drug designations for DLBCL. A marketing application for polatuzumab vedotin is undergoing review by EMA.

The BLA is based on positive clinical data from a randomized Phase 1/2 study (NCT02257567/GO29365), which evaluated polatuzumab vedotin administered by IV infusion in combination with standard doses of BR or obinutuzumab in patients with R/R follicular lymphoma (FL) or DLBCL. Study results indicated that median overall survival was over one year in people with R/R DLBCL not eligible for a hematopoietic stem cell transplant who received the combination of polatuzumab vedotin and BR, and less than 5 month for those in the BR arm of the study (12.4 vs. 4.7 months, hazard ratio (HR)=0.42; 95% CI 0.24-0.75). In addition, polatuzumab vedotin plus BR increased median progression-free survival (PFS) and led to a 66% reduction in risk of disease worsening or death compared to BR alone (median PFS: 7.6 months vs. 2.0 months; HR=0.34; 95% CI 0.20-0.57), and patients treated with polatuzumab vedotin plus BR showed a longer time between first response to treatment and disease worsening than those receiving BR alone (investigator assessed median duration of response: 10.3 months vs. 4.1 months; HR=0.44).

The combination of polatuzumab vedotin with R-CHP protocol (rituximab, cyclophosphamide, doxorubicin and prednisone) versus R-CHOP (rituximab-cyclophosphamide, doxorubicin, vincristine and prednisone) in DLBCL patients is currently being investigated in the Phase 3 POLARIX (NCT03274492) study. The primary endpoint is PFS. Secondary outcome measures include PFS, compete response and overall survival. The estimated primary completion date of the study is December 2019.

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Most read from mAbs, Feb/March 2019

February 15, 2019 by Janice Reichert

The Antibody Society is pleased and proud to be affiliated with mAbs, a multi-disciplinary journal dedicated to advancing the art and science of antibody research and development. We hope you enjoy these summaries based on the abstracts of the most read papers published in a recent issue. All the articles are open access; PDFs can be freely downloaded by following the links below.

Issue 11.2 (February/March 2019)

Antibodies to watch in 2019.
For the past 10 years, the annual ‘Antibodies to watch’ articles have provided updates on key events in the late-stage development of antibody therapeutics, such as first regulatory review or approval, that occurred in the year before publication or were anticipated to occur during the year of publication. To commemorate the 10th anniversary of the article series and to celebrate the 2018 Nobel Prizes in Chemistry and in Physiology or Medicine, which were given for work that is highly relevant to antibody therapeutics research and development, Kaplon and Reichert expanded the scope of the data presented to include an overview of all commercial clinical development of antibody therapeutics and approval success rates for this class of molecules. The data indicate that:
1) antibody therapeutics are entering clinical study, and being approved, in record numbers;
2) the commercial pipeline is robust, with over 570 antibody therapeutics at various clinical phases, including 62 in late-stage clinical studies; and
3) Phase 1 to approval success rates are favorable, ranging from 17–25%, depending on the therapeutic area (cancer vs. non-cancer).

Ion channels as therapeutic antibody targets.
In this review, Hutchings et al evaluate the technical challenges of raising antibodies to membrane-spanning proteins together with enabling technologies that may facilitate the discovery of antibody therapeutics to ion channels. They also discuss the potential targeting opportunities in the anti-ion channel antibody landscape, along with a number of case studies where functional antibodies that target ion channels have been reported. Antibodies currently in development and progressing towards the clinic are highlighted.

Influence of N-glycosylation on effector functions and thermal stability of glycoengineered IgG1 monoclonal antibody with homogeneous glycoforms.
The separation of various glycoforms to investigate the biological and functional relevance of glycosylation is a major challenge, and the individual contributions of each glycoform is usually not considered when evaluating mAbs with highly heterogeneous distributions. In this study, Wada et al used chemoenzymatic glycoengineering incorporating an endo-β-N-acetylglucosaminidase (ENGase) EndoS2 and its mutant with transglycosylation activity to generate mAb glycoforms with highly homogeneous and well-defined N-glycans to better understand and precisely evaluate the effect of each N-glycan structure on Fc effector functions and protein stability. They demonstrated that the core fucosylation, non-reducing terminal galactosylation, sialylation, and mannosylation of IgG1 mAb N-glycans impact not only on FcγRIIIa binding, antibody-dependent cell-mediated cytotoxicity, and C1q binding, but also FcRn binding, thermal stability and propensity for protein aggregation.

Co-engaging CD47 and CD19 with a bispecific antibody abrogates B-cell receptor/CD19 association leading to impaired B-cell proliferation.
In this report, Hatterer et al describes the generation of a CD47xCD19 bispecific antibody (biAb) to target and deplete B cells via multiple antibody-mediated mechanisms. Interestingly, the biAb, constructed of a CD19 binding arm and a CD47 binding arm, inhibited BCR-mediated B-cell proliferation with an effect even more potent than a CD19 monoclonal antibody (mAb). The inhibitory effect of the biAb was not attributable to CD47 binding because a monovalent or bivalent anti-CD47 mAb had no effect on B cell proliferation. Fluorescence resonance energy transfer analysis demonstrated that co-engaging CD19 and CD47 prevented CD19 clustering and its migration to BCR clusters, while only engaging CD19 (with a mAb) showed no impact on either CD19 clustering or migration. The lack of association between CD19 and the BCR resulted in decreased phosphorylation of CD19 upon BCR activation. Furthermore, the biAb differentially modulated BCR-induced gene expression compared to a CD19 mAb. Taken together, this unexpected role of CD47xCD19 co-ligation in inhibiting B cell proliferation illuminates a novel approach in which two B cell surface molecules can be tethered, to one another in order, which may provide a therapeutic benefit in settings of autoimmunity and B cell malignancies.

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FDA approval for caplacizumab-yhdp

February 6, 2019 by Janice Reichert

On February 6, 2019, the US Food and Drug Administration approved caplacizumab-yhdp (Cablivi), in combination with plasma exchange and immunosuppressive therapy, for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP). During episodes of this rare, life-threatening blood clotting disorder, microclots can form, leading to low platelet counts, ischemia and organ dysfunction in aTTP patients. Approval was based on positive results from a study of 145 patients with an acute episode of aTTP who were randomized 1:1 to receive either caplacizumab or placebo in addition to standard-of-care treatment, which was daily plasma exchange and immunosuppression. Caplacizumab was granted its first approved in the European Union (EU) on August 31, 2018. The mAb was granted Fast Track designation in the US and Orphan Drug designations in the US and EU for the treatment of aTTP.

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Most read from mAbs, January 2019

January 21, 2019 by Janice Reichert

Issue 11.1 (January 2019)

Evolution of a comprehensive, orthogonal approach to sequence variant analysis for biotherapeutics.
As discussed by Lin et al., a cross-functional team of Pfizer colleagues from the Analytical and Bioprocess Development departments worked closely together for over 6 years to formulate and communicate a practical, reliable sequence variant (SV) testing strategy with state-of-the-art techniques that did not necessitate more resources or lengthen project timelines. The final SV screening strategy relies on next-generation sequencing and amino acid analysis as frontline techniques to identify mammalian cell clones with genetic mutations and recognize cell culture process media/feed conditions that induce misincorporations, respectively. Once an industry-wide challenge, sequence variation is now routinely monitored and controlled at Pfizer (and other biopharmaceutical companies) through increased awareness, dedicated cross-line efforts, smart comprehensive strategies, and advances in instrumentation/software, resulting in even higher product quality standards for biopharmaceutical products.

The first World Health Organization International Standard for infliximab products: A step towards maintaining harmonized biological activity.
In this Brief Report, Metcalfe et al. present a collaborative study designed to assess the suitability of the first international standard (IS) for infliximab to serve as an IS for the in vitro biological activity of infliximab. The IS was developed by the UK’s National Institute for Biological Standards and Control (NIBSC). The study involved participants using in vitro cell-based bioassays (TNF neutralization, antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity) and binding assays. The results of this study showed that the candidate preparation, coded 16/170, is suitable as an IS for infliximab bioactivity. This infliximab IS from NIBSC, is intended to support in vitro bioassay calibration and validation by defining international units of bioactivity

Anti-PD1 ‘SHR-1210ʹ aberrantly targets pro-angiogenic receptors and this polyspecificity can be ablated by paratope refinement.
Finlay et al. report that the combination of receptor proteome screening and optimization of the antibody binding interface succeeded in generating novel, higher-potency, specificity-enhanced therapeutic IgGs from a single, clinically sub-optimal progenitor. They show that highly-specific off-target binding events might be an under-appreciated phenomenon in therapeutic antibody development, but that these unwanted properties can be fully ameliorated by paratope refinement.

Deamidation and isomerization liability analysis of 131 clinical-stage antibodies.
As discussed by Lu et al., knowledge of the chemical stability characteristics of clinical-stage therapeutic monoclonal antibodies (mAbs) is fragmented and lacks comprehensive comparative assessment. To address this knowledge gap, the authors produced 131 mAbs with amino acid sequences corresponding to the variable regions of clinical-stage mAbs, subjected these to low and high pH stresses and identified the resulting modifications at amino acid-level resolution via tryptic peptide mapping. Among this large set of mAbs, relatively high frequencies of asparagine deamidation events were observed in CDRs H2 and L1, while CDRs H3, H2 and L1 contained relatively high frequencies of instances of aspartate isomerization.

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First approval for romosozumab

January 10, 2019 by Janice Reichert

Japan’s Ministry of Health, Labor and Welfare has granted a marketing authorization for romosozumab (EVENITY) for the treatment of osteoporosis in patients at high risk of fracture. Developed by Amgen and UCB, romosozumab is a humanized IgG2 monoclonal antibody that targets sclerostin. The approval in Japan is based on results from the Phase 3 FRAME and BRIDGE studies, which included 7,180 postmenopausal women with osteoporosis and 245 men with osteoporosis, respectively.

A biologics license application (BLA) for romosozumab as a treatment of osteoporosis in postmenopausal women at high risk for fracture was submitted to the U.S. Food and Drug Administration (FDA) in July 2016, but additional safety and efficacy data was requested in the FDA’s complete response letter, as announced by Amgen and UCB in July 2017. In July 2018, Amgen and UCB announced that the BLA had been resubmitted. In addition to data from early-stage clinical studies, the original BLA included data from the Phase 3 FRAME study. The resubmitted BLA includes results from the more recent Phase 3 ARCH study, an alendronate-active comparator trial including 4,093 postmenopausal women with osteoporosis who experienced a fracture, and the Phase 3 BRIDGE study. The FDA’s Bone, Reproductive and Urologic Drugs Advisory Committee is scheduled to review data supporting the BLA for romosozumab at a meeting on January 16, 2019.

The European Medicines Agency is also currently reviewing a marketing application for romosozumab.

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The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. Please log in to access the table, which is located in the Members Only section and can be downloaded in Excel format.