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Most read from mAbs, May-June 2019

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The Antibody Society is pleased  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 11.4 (May-June 2019)

Combining the best of two worlds: highly flexible chimeric antigen receptor adaptor molecules (CAR-adaptors) for the recruitment of chimeric antigen receptor T cells.

In this review, Darowski et al. summarize emerging approaches that aim to further evolve CAR-T cell therapy based on combinations of so-called universal or modular CAR-(modCAR-)T cells, and their respective adaptor molecules (CAR-adaptors), which mediate the crosslinking between target and effector cells. The activity of such modCAR-T cells is entirely dependent on binding of the respective CAR-adaptor to both a tumor antigen and to the CAR-expressing T cell. Contrary to conventional CAR-T cells, where the immunological synapse is established by direct interaction of CAR and membrane-bound target, modCAR-T cells provide a highly flexible and customizable development of the CAR-T cell concept and offer an additional possibility to control T cell activity.

Efficient tumor killing and minimal cytokine release with novel T-cell agonist bispecific antibodies.

Using a sequence-based discovery platform, Trinklein et al. identified new anti-CD3 antibodies from humanized rats that bind to multiple epitopes and elicit varying levels of T-cell activation. In T-BsAb format, 12 different anti-CD3 arms induce equivalent levels of tumor cell lysis by primary T-cells, but potency varies by a thousand-fold. The lead CD3-targeting arm stimulates very low levels of cytokine release, but drives robust tumor antigen-specific killing in vitro and in a mouse xenograft model. This new CD3-targeting antibody underpins a next-generation T-BsAb platform in which potent cytotoxicity is uncoupled from high levels of cytokine release, which may lead to a wider therapeutic window in the clinic.

Sym021, a promising anti-PD1 clinical candidate antibody derived from a new chicken antibody discovery platform.

In this study by Gjetting et al., the Symplex antibody discovery platform was adapted to chicken immunoglobulin genes and combined with high-throughput humanization of antibody frameworks by “mass complementarity-determining region grafting”. Wild type chickens were immunized with an immune checkpoint inhibitor programmed cell death 1 (PD1) antigen, and a repertoire of 144 antibodies was generated. The PD1 antibody repertoire was successfully humanized, and the authors found that most humanized antibodies retained affinity largely similar to that of the parental chicken antibodies. The lead antibody Sym021 blocked PD-L1 and PD-L2 ligand binding, resulting in elevated T-cell cytokine production in vitro. Detailed epitope mapping showed that the epitope recognized by Sym021 was unique compared to the clinically approved PD1 antibodies pembrolizumab and nivolumab. Moreover, Sym021 bound human PD1 with a stronger affinity (30 pM) compared to nivolumab and pembrolizumab, while also cross-reacting with cynomolgus and mouse PD1. This enabled direct testing of Sym021 in the syngeneic mouse in vivo cancer models and evaluation of preclinical toxicology in cynomolgus monkeys. Preclinical in vivo evaluation in various murine and human tumor models demonstrated a pronounced anti-tumor effect of Sym021, supporting its current evaluation in a Phase 1 clinical trial.

“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.

Antibody immune checkpoint modulators in the clinic

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The treatment of cancer via antibody therapeutics that modulate immune responses is the focus of substantial research and development by the biopharmaceutical industry. To date, 6 monoclonal antibodies (mAbs) that function by modulating immune checkpoints have been approved in the US: ipilimumab (anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA4)); pembrolizumab and nivolumab (anti-programmed death receptor 1 (PD-1)); durvalumab, avelumab, and atezolizumab (anti-programmed death ligand 1 (PD-L1)). Cemiplimab, another anti-PD-1 mAb, is currently undergoing regulatory review. Antibody immune checkpoint modulators can be used to treat many types of cancer,[1] which makes them highly attractive for biopharmaceutical development. For example, the approved products, which target only 3 of the many proteins involved in either stimulating or inhibiting immune responses, are used to treat melanoma, non-small-cell lung cancer, head and neck cancer, Hodgkin’s lymphoma, bladder cancer, gastric/gastroesophageal junction adenocarcinoma, renal cell cancer, hepatocellular cancer, Merkel cell carcinoma and colorectal cancer. [2]

More than 80 antibody immune checkpoint modulators sponsored by commercial firms are in clinical development, and they comprise ~ 24% of the clinical pipeline of antibody therapeutics for cancer. Most are in early development, with 50 and 28 antibody immune checkpoint modulators undergoing evaluation in Phase 1 and Phase 2 clinical studies, respectively. Seven (IBI308, BCD-100, PDR001, tislelizumab, camrelizumab, utomilumab, and tremelimumab) are undergoing evaluation in late-stage studies.[3]

Despite the fact that 5 antibodies targeting the PD-1 pathway are already marketed, PD-1 and PD-L1 remain popular as targets for antibodies in development. Of the antibody immune checkpoint modulators currently in the clinic, 21 molecules target PD-1, including five in late-stage clinical studies, and 9 antibodies target PD-L1. Other popular antigens for antibodies in clinical development include glucocorticoid-induced tumor necrosis factor receptor (GITR; target of 7 antibodies); CD40, LAG-3 and OX40 (each the target of 6 antibodies); as well as T-cell immunoglobulin and mucin-domain-containing molecule (TIM-3), T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) and CTLA4 (each the target of 4 antibodies). In addition, two bispecific antibodies (anti-PD-1, LAG-3 MGD013; anti-PD-L1, CTLA-4 AK104) targeting these immune checkpoints are in clinical studies; to avoid double counting, these two were excluded from the totals given above.

Over 100 antibody immune checkpoint modulators have entered commercially sponsored clinical studies since 2000, but ~60% of the molecules first entered such studies in the past 3 years. The ultimate fates (approval or termination) for most of the molecules are thus not yet known, but the available data is sufficient to calculate a Phase 1 to 2 transition rate, which is 74%. This rate compares favorably with that for all antibody therapeutics (75%) and anti-cancer antibody therapeutics (69%). The current data suggest that antibody immune checkpoint modulators, as a group, has a notably higher Phase 2 to 3 transition rate compared with all antibody therapeutics. This result, however, is based on outcomes for relatively few molecules. It should be noted that clinical studies may be terminated for business reasons, as well as safety or efficacy issues. For example, although PD-1 and PD-L1 are well-validated targets, the market for anti-PD-1 and anti-PD-L1 antibodies in the future may not be sufficient to justify continued development of all such antibodies in the current pipeline. Termination of molecules at Phase 2 for business reasons would decrease the Phase 2 to 3 transition rate. To date, no antibody immune checkpoint modulators have been terminated during regulatory review; the transition rate at that phase is thus 100%.

The Antibody Society has partnered with Hanson Wade to track trends in the clinical development of innovative cancer therapies, with a focus on immune checkpoint modulators and antibody-drug conjugates. As the date for ICI Boston 2018 (March 19-21) approaches, Hanson Wade has prepared a comprehensive e-book that provides insights into combination strategies involving immune checkpoint inhibitors, which can be downloaded here. Members of The Antibody Society qualify for a 20% discount to ICI Boston 2018. Please contact us at membership@antibodysociety.org for the code.

  1. Torphy RJ, Schulick RD, Zhu Y. Newly Emerging Immune Checkpoints: Promises for Future Cancer Therapy. Int J Mol Sci. 2017; 18(12). pii: E2642. doi: 10.3390/ijms18122642.
  2. Iwai Y, Hamanishi J, Chamoto K, Honjo T. Cancer immunotherapies targeting the PD-1 signaling pathway. J Biomed Sci 2017; 24:26. doi.org/10.1186/s12929-017-0329-9.
  3. Kaplon H, Reichert JM. Antibodies to watch in 2018. MAbs. 2018 Jan 4:1-21. doi: 10.1080/19420862.2018.1415671.

The Antibody Society tracks the progress of commercially sponsored antibody therapeutics in clinical development on a continuous basis. We collect information, including molecular composition (e.g., format, isotype, target), phase of development and indications studied, from publicly available sources (e.g., press releases, company websites, meeting abstracts, published literature, clinicaltrials.gov, regulatory agency websites). Our data are cross-checked against databases generously provided by our corporate partners, including Hanson Wade’s Beacon Targeted Therapies and the Therapeutic Antibody Database. It should be noted that companies may not publicly disclose all information for all molecules in the pipeline, especially those in the early stages of development. The numbers of molecules discussed above should thus be considered minimums, as targets have not been disclosed for all the molecules we are tracking. We look forward to reporting additional trends and metrics for antibody therapeutics development in the future.

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