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The Antibody Society

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

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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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FDA approval for caplacizumab-yhdp

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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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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.

“Antibodies to watch in 2019”

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The latest “Antibodies to watch” article is now freely accessible at mAbs! 

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, the scope of the data presented was expanded 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).

As of November 2018, a record number of antibodies (erenumab (Aimovig), fremanezumab (Ajovy), galcanezumab (Emgality), burosumab (Crysvita), lanadelumab (Takhzyro), caplacizumab (Cablivi), mogamulizumab (Poteligeo), moxetumomab pasudodox (Lumoxiti), cemiplimab (Libtayo), ibalizumab (Trogarzo), tildrakizumab (Ilumetri, Ilumya), emapalumab (Gamifant)) that treat a wide variety of diseases were granted a first approval in either the European Union (EU) or United States (US). Also as of November 2018, 4 antibody therapeutics (sacituzumab govitecan, ravulizumab, risankizumab, romosozumab) were being considered for their first marketing approval in the EU or US, and an additional 3 antibody therapeutics developed by Chinese companies (tislelizumab, sintilimab, camrelizumab) were in regulatory review in China. In addition, the data show that 3 product candidates (leronlimab, brolucizumab, polatuzumab vedotin) may enter regulatory review by the end of 2018, and at least 12 (eptinezumab, teprotumumab, crizanlizumab, satralizumab, tanezumab, isatuximab, spartalizumab, MOR208, oportuzumab monatox, TSR-042, enfortumab vedotin, ublituximab) may enter regulatory review in 2019. Notably, approximately half (18 of 33) of the late-stage pipeline of antibody therapeutics for cancer are immune checkpoint modulators or antibody-drug conjugates. Of these, 7 (tremelimumab, spartalizumab, BCD-100, omburtamab, mirvetuximab soravtansine, trastuzumab duocarmazine, and depatuxizumab mafodotin) are being evaluated in clinical studies with primary completion dates in late 2018 and in 2019, and are thus ‘antibodies to watch’. The Antibody Society looks forward to documenting progress made with these and other ‘antibodies to watch’ in the next installment of this article series.

Update: Data in “Antibodies to watch in 2019” is as of November 2018. As noted in the post below, risankizumab was approved by FDA on December 21, 2018, bringing the total number of antibody therapeutics approved in the EU or US during 2018 to 13.

First approval for ravulizumab

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On December 21, 2018, the US Food and Drug Administration approved Ultomiris (ravulizumab) injection for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH), a rare and life-threatening blood disease characterized by hemolysis of red blood cells mediated by the complement system. Developed by Alexion Pharmaceuticals, ravulizumab is a humanized mAb that inhibits complement component 5 (C5). The biologics license application for ravulizumab received a Priority Review designation. In a Phase 3 study, ravulizumab demonstrated non-inferiority to Soliris® (anti-C5 eculizumab) in complement-inhibitor treatment-naïve patients with PNH. Also developed by Alexion Pharmaceuticals, Soliris® was first approved for PNH in 2007. Ravulizumab is also undergoing regulatory review in the EU. It was granted Orphan Drug designation in both the US and EU for the treatment of patients with PNH.

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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. As of December 21, a total of 13 antibody therapeutics had been granted first approvals in either the US or EU in 2018, and marketing applications for another 3 that have not yet been approved in either the EU or US are undergoing review in these regions. Please log in to access the table in Excel format, located in the Members Only section.

Grad/PostDoc Poster Awards presented at Antibody Engineering &Therapeutics

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Congratulations to our 2018 Graduate Student and Post-doctoral Poster Award winners! An award ceremony was held on December 12th at the Society’s annual meeting, Antibody Engineering &Therapeutics, to recognize the recipients. The winners were:

Junpeng Qi (Postdoctoral Associate, The Scripps Research Institute). Poster title: Potent and selective antitumor activity of a T cell-engaging bispecific antibody targeting a membrane-proximal epitope of ROR1.

Pietro Sormanni (Borysiewicz Biomedical Sciences Fellow (postdoctoral), University of Cambridge). Poster title: Third generation antibody discovery: In silico rational design.

Madeleine Jennewein (Ph.D. candidate, Harvard University). Poster title: Trans-placental antibody transfer selects for highly functional antibodies.


Junpeng Qi – Scripps Research Institute (The Rader Lab)

“I would to thank The Antibody Society for giving me this award. It is a great opportunity, especially for a young scientist, to get the latest progress in antibody engineering and therapeutics, and to be connected with the excellent scientists in the antibody field. From this impressive annual meeting I learned that we can do amazing science with antibodies and develop fantastic antibody therapeutics benefiting patients as well.”

Pietro Sormanni – University of Cambridge (The Vendruscolo Lab)

“I am immensely grateful to The Antibody Society for selecting my application, and even more for organizing this award. This award has given me the opportunity to attend this terrific meeting, to learn about world-class research in both industry and academia, and more importantly to share and discuss my own work with leading scientists from across the world. I would like to stress the importance of the existence of awards such as this, and I call for the Society and the sponsors of the meeting to make available more of these awards and travel grants to early career researchers. Because at the end of the day, the growing community of postdoctoral researchers and graduate students is the engine that powers biomedical research, certainly in academia, and increasingly also in industry. And these travel grants provide us with the unique opportunity to get out of the lab, come to these meetings and greatly expand our research horizons, and generate new ideas. So I hope to see a bit more space dedicated to early career researchers in future editions of this meeting, thank you all for your attention, and again to The Antibody Society for this award.”

Madeleine F Jennewein – Harvard University (The Alter Lab)

Madeleine Jennewein was unexpectedly unable to join us at the meeting in San Diego, but we thank her for her participation and wish her the best with her work.