The Antibody Society

the official website of the antibody society

The Antibody Society

An international non-profit supporting antibody-related research and development.

Antibody therapeutics in early-stage clinical studies

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The popular “Antibodies to watch” articles aim to update members of The Antibody Society, as well as the broader scientific community, on progress in the late-stage clinical development of innovative antibody therapeutics. Data for these molecules (60 as of March 22, 2019) are made available in the Members Only area of The Antibody Society’s website. We are pleased to announce that we are expanding our coverage of the commercial clinical pipeline to include data for antibody therapeutics that have recently entered clinical study. Two factors motivated us: 1) the remarkable increase in the number entering clinical study annually (to ~120 in 2018); and 2) the remarkable focus on antibodies developed for cancer (~80% of the total in 2018). Data for antibody therapeutics that entered clinical study recently, in Excel format, may be downloaded from the Members Only area.

The biopharmaceutical industry’s intense focus on the development of antibody therapeutics, and particularly those for cancer, is unabated in 2019, according to the data available by mid-March. We have identified 17 antibody therapeutics for which an application to start clinical study was filed or a Phase 1 study was started in 2019, and an additional 11 antibody therapeutics with clinical studies not yet recruiting patients, as listed on clinicaltrials.gov. The rate of clinical entry for antibody therapeutics so far in 2019 is thus similar to that observed in 2018 (~10 per month). The trend toward development of antibodies as treatments for cancer is also quite similar. Of the 2019 cohort so far identified, 22 of 28 (79%) are for cancer.

The commercial clinical pipeline of cancer therapies has become increasingly dominated by 3 categories of antibodies: 1) immune checkpoint modulators; 2) antibody-drug conjugates (ADCs); and 3) bispecific antibodies (see figure for details).

Our data so far suggests that this trend will continue in 2019, as nearly three-quarters of the antibody therapeutics currently in the 2019 cohort fit in one (or more) of the 3 categories. Examples of antibodies that fit more than 1 category include TG-1801 (TG Therapeutics, Inc., Novimmune SA), a bispecific antibody targeting the immune checkpoint CD47 as well as CD19, and  INBRX-105 (Inhibrx, Inc.), a bispecific antibody targeting the immune checkpoints PD-L1 and 4-1BB. TG-1801, a human IgG1 designed to target and deplete B-cells, is undergoing evaluation in a Phase 1 study (NCT03804996) of patients with B-cell lymphoma. INBRX-105 is undergoing evaluation as a treatment for hematological and solid tumors in a Phase 1 study (NCT03809624).

More to come! Throughout 2019, we will track and report on the development of all antibody therapeutics that enter clinical study during the year.

Attention members! Please log in to access our data for all antibody therapeutics that entered clinical study during 2018 or so far in 2019. After logging in, click on ‘Antibodies in early-stage studies’ in the Members Only dropdown menu. Data will be updated throughout 2019.

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Marketing application submitted for brolucizumab, an anti-VEGF-A antibody for macular degeneration

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The European Medicines Agency’s March 2019 summary of applications for new human medicines under evaluation by the Committee for Medicinal Products for Human Use indicates that an application for brolucizumab as a ophthalmological is undergoing review.

Brolucizumab, a humanized scFv that targets all isoforms of vascular endothelial growth factor-A, has been evaluated in clinical studies as a treatment for neovascular age-related macular degeneration (nAMD). In October 2018, Novartis released 96-week results from the Phase 3 HAWK (NCT02307682) and HARRIER (NCT02434328) studies that reaffirmed positive 48-week findings. The two studies included more than 1,800 patients in comparing the efficacy and safety of intravitreal injections of 6 mg brolucizumab or 3 mg brolucizumab (HAWK study only) versus 2 mg aflibercept in patients with nAMD. The primary efficacy endpoint of the studies, non-inferiority to aflibercept (EYLEA®) in mean change in best-corrected visual acuity (BCVA) at week 48, was met. The 96-week results indicate patients administered brolucizumab maintained robust visual gains, with mean change in BCVA of 5.9 letters for brolucizumab 6 mg versus 5.3 letters for aflibercept in the HAWK study, and 6.1 letters versus 6.6 letters, respectively, in the HARRIER study. Superior reductions in retinal fluid and central subfield thickness (CST) demonstrated at 48 weeks were reaffirmed at 96 weeks. The percentage of patients with nAMD that had intra-retinal fluid and/or sub-retinal fluid was 24% for brolucizumab 6 mg vs. 37% for aflibercept in HAWK (p=0.0001) and 24% vs. 39%, respectively, in the HARRIER study (P<0.0001). Absolute reductions in CST from baseline were -175 µm for brolucizumab 6 mg versus -149 µm for aflibercept in HAWK (p=0.0057) and -198 µm versus -155 µm, respectively, in the HARRIER study (P<0.0001).

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The Antibody Society maintains a comprehensive table of approved mAb 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. Information about other antibody therapeutics that may enter regulatory review in 2019 can be found in ‘Antibodies to watch in 2019’.

Biologics license application submitted for eptinezumab, an anti-CGRP antibody for migraine prevention

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Alder BioPharmaceuticals has submitted a biologics license application (BLA) for eptinezumab, a humanized IgG1 monoclonal antibody that targets calcitonin gene-related peptide (CGRP), for migraine prevention. If the US Food and Drug Administration grants approval, Alder will be on track to launch the drug in Q1 2020. The BLA included data from the PROMISE 1 and PROMISE 2 studies, which evaluated the effects of eptinezumab in episodic migraine patients (n=888) or chronic migraine patients (n=1,072), respectively.  In PROMISE 1, the primary and key secondary endpoints were met, and the safety and tolerability were similar to placebo, while in PROMISE 2, the primary and all key secondary endpoints were met, and the safety and tolerability was consistent with earlier eptinezumab studies.

Alder announced one-year results from the PROMISE 1 study in June 2018, which indicated that, following the first quarterly infusion, episodic migraine patients treated with 300 mg eptinezumab experienced 4.3 fewer monthly migraine days (MMDs) from a baseline of 8 MMDs, compared to 3.2 fewer MMDs for placebo from baseline (p= 0.0001). At one year after the third and fourth quarterly infusions, patients treated with 300 mg eptinezumab experienced further gains in efficacy, with a reduction of 5.2 fewer MMDs compared to 4.0 fewer MMDs for placebo-treated patients.  In addition, ~31% of episodic migraine patients achieved, on average per month, 100% reduction of migraine days from baseline compared to ~ 21% for placebo. New 6-month results from the PROMISE 2 study were also released in June 2018.  These results indicated that, after the first quarterly infusion, chronic migraine patients dosed with 300 mg of eptinezumab experienced 8.2 fewer MMDs, from a baseline of 16 MMDs, compared to 5.6 fewer MMDs for placebo from baseline (p <.0001). A further reduction in MMDs was seen following a second infusion; 8.8 fewer MMDs for patients dosed with 300 mg compared to 6.2 fewer MMDs for those with placebo. In addition, ~ 21% of chronic migraine patients achieved, on average, 100% reduction of MMDs from baseline compared to 9% for placebo after two quarterly infusions of 300 mg of eptinezumab.

If approved, eptinezumab would become the fourth antibody therapeutic for migraine prevention on the US market, following the approval of erenumab-aooe (Aimovig; Novartis), galcanezumab-gnlm (Emgality; Eli Lilly & Company) and fremanezumab-vfrm (Ajovy; Teva Pharmaceuticals) in 2018.

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The Antibody Society maintains a comprehensive table of approved mAb 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.

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

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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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The Antibody Society maintains a comprehensive table of approved mAb 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.

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Most read from mAbs, Feb/March 2019

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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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