China says Japan-developed drug Avigan works against coronavirus. Nikkei Asian Review. Data for antibody therapeutics that were first approved in either the US or EU during , as well as several products first approved in Russia or India, were provided.
Antibody therapeutics undergoing regulatory review by the Food and Drug Administration or the European Medicines Agency as of November were also discussed. Brief summaries of antibody therapeutics in late-stage clinical study that may progress to regulatory review in late or , based on public disclosures by the sponsoring companies, were included. In concluding, Dr. Reichert noted that the late-stage clinical pipeline is robust, and she anticipated that more antibody therapeutics will be in late-stage studies in than any year previously documented.
Remarkably, compared to , the number of antibody therapeutics currently in late-stage studies has nearly tripled to 75 antibody therapeutics. These topics will be discussed, along with trends observed in the burgeoning early-stage pipeline. Popular formats and mechanisms of action, as well as popular and obscure targets, for antibody therapeutics that recently entered the clinical pipeline will be included.
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. Data for antibody therapeutics that entered clinical study recently, in Excel format, may be downloaded from the Members Only area.
We have identified 17 antibody therapeutics for which an application to start clinical study was filed or a Phase 1 study was started in , and an additional 11 antibody therapeutics with clinical studies not yet recruiting patients, as listed on clinicaltrials. The trend toward development of antibodies as treatments for cancer is also quite similar. 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 , as nearly three-quarters of the antibody therapeutics currently in the cohort fit in one or more of the 3 categories. More to come! Throughout , 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 or so far in Data will be updated throughout Not a member?
Please join! 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. Antibodies to watch in Solanezumab caused a slight improvement in cognitive function but did not reduce beta-amyloid plaques.
Bapineuzumab, crenezumab, and gantenerumab did not improve cognitive function or reduce beta-amyloid plaques. Aducanumab, bapineuzumab, and gantenerumab lowered tau cerebrospinal fluid levels, with the caveat that tau levels were not measured in participants who were given crenezumab or solanezumab or data were not available.
Results from brain imaging showed that aducanumab, bapineuzumab, and gantenerumab raised the risk of ARIA, while solanezumab did not. Data on ARIA risk with use of crenezumab were not available.
Patients received mosunetuzumab at dose levels from 0. The ORR was The median duration of response DOR was Patients with aggressive or indolent NHL were included. Three-weekly doses from 1. After a median of 6. In the frontline setting, mosunetuzumab is being assessed either as a monotherapy or in combination with chemotherapy.
Treatment was continued up to a maximum of 17 cycles. The median age was 84 range: 67— years. After this, fortnightly maintenance dosing is given.
Median DOR was 7. The dose was administered weekly for two day cycles, fortnightly for four cycles and then four-weekly thereafter. Data on duration of response are not yet available. Two patients have discontinued treatment whilst six have continued on therapy. No drug limiting toxicity or severe adverse events were reported in the patients treated to date. Identifying patients at high risk of adverse events and implementing management strategies is important to reduce toxicities and maximising the utility of bsAb.
Adverse events are common in patients receiving bsAbs, with the majority of patients experiencing grade 3 or higher adverse events Table 1 [ 11 , 19 ]. Overlapping toxicities are seen with conventional chemotherapy, including fatigue, cytopenias, infections, diarrhea and elevated liver enzymes [ 10 , 13 , 20 , 22 , 23 ].
Tumour lysis syndrome has been reported due to their potent activity, including fatal outcomes [ 24 ]. Prophylaxis should be employed for patients at increased risk with high tumour burden, circulating disease, elevated LDH and impaired renal function. Grade 5 adverse events are rare [ 21 , 22 ]. AE—adverse event. PD—progressive disease. NR—not reported. Gpt—Obinutuzumab pre-treatment. Rates of neutropenia not reported.
CRS is a common systemic inflammatory response seen in response to antibody and adoptive T-cell therapies, resulting from immune activation and release of inflammatory cytokines [ 25 ]. IL-6 is the predominant cytokine most consistently found to be elevated in CRS patients, with high levels correlating with severe CRS [ 26 , 27 ].
Fever within 24 h is the hallmark symptom, with significant variability in other aspects of the clinical presentation. Mild features include fatigue, headache, rash, arthralgia and myalgia. Severe CRS is a medical emergency and can present with circulatory shock, respiratory dysfunction, neurotoxicity and disseminated intravascular coagulation [ 25 ].
Intercurrent illnesses and toxicity can complicate the diagnosis. Patients receiving bsAbs are also at risk of sepsis and infection must be investigated and empirically treated in most patients presenting with CRS symptoms. Haemophagocytic lymphohistiocytosis or macrophage activation syndrome, tumour lysis syndrome and hypersensitivity reactions also present with overlapping clinical and laboratory features [ 30 , 31 ].
A number of disparate grading systems for CRS have been developed [ 25 , 33 , 34 , 35 , 36 ]. The consensus grading system allows better comparison of safety data across different immune effector cell engaging therapies and facilitates the development of optimal and consistent grade-directed management strategies. Patient, disease and therapy-related factors influence the risk of developing severe CRS. Patients with high disease burden are more likely to experience severe CRS [ 37 , 38 , 39 , 40 ].
Other risk factors for CRS include the administered dose of therapy, circulating disease and the presence of a pre-existent state of inflammation with either active infection, high ferritin or high C-reactive protein CRP [ 37 , 42 , 43 , 44 , 45 ].
Mitigation strategies to reduce severe CRS are commonly used with bsAbs. Premedications are regularly employed with steroids, antihistamines and acetaminophen or paracetamol [ 8 ]. Step-up dosing reduces the risk of severe CRS and this approach has been incorporated into ongoing clinical trials of bsAbs in NHL patients [ 11 , 46 , 47 ].
A novel approach is the use of obinutuzumab 7 days before the first dose of glofitamab [ 48 ]. Obinutuzumab partially occupies CD20 antigen epitope targets of glofitamab and profoundly depletes B-cells in the peripheral blood and secondary lymphoid organs, thereby reducing T-cell activation and cytokine release.
Subcutaneous administration of mosunetuzumab has shown reduced IL-6 peak levels and preliminary data show an association with only mild CRS events [ 17 ].
Management of CRS follows a grade-adapted strategy. Mild grade 1 CRS is managed with supportive therapy including infusion discontinuation, intravenous fluids, antipyretics and antihistamines. Prolonged or severe CRS requires close monitoring of organ function, generally within an intensive care unit. A clinical response is generally seen within a few hours and repeated doses can be given if significant improvement does not occur within 8 to 12 h. Tocilizumab does not efficiently penetrate the blood—brain barrier and so corticosteroids are used in cases with significant neurotoxicity or co-existing ICANS [ 25 ].
Otherwise, corticosteroids are used as second line treatment for severe or refractory CRS. Corticosteroids have widespread downregulatory effect on immune activation, raising theoretical concerns of dampening the immune anti-tumour effect [ 39 , 50 ].
However, tocilizumab and corticosteroid administration to treat CRS do not appear to negatively affect response rates to T-cell engaging therapies [ 51 , 52 ]. Inhibition of other cytokines implicated in CRS can be considered in refractory cases. ICANS is commonly associated with CRS and its pathophysiology similarly arises from an enhanced release of proinflammatory cytokines and neurotoxic substances. Endothelial activation and disruption of the blood-brain barrier also plays a critical role in the syndrome [ 54 , 55 ].
The toxicity appeared to be dose-dependent and lead to frequent treatment discontinuation Table 1. ICANS generally develops within the first seven days of therapy [ 3 ]. Headache and tremor are the most common symptoms. Whilst the clinical presentation can vary, it often follows a stereotypic evolution [ 30 ].
Tremor, dysgraphia, expressive and nominal dysphasia, impaired attention, apraxia and lethargy are early manifestations. Global aphasia, akinesia, seizures and obtundation are late and severe manifestations. Headache is a non-specific symptom, whereas expressive dysphasia is a specific symptom of ICANS and a good predictor of severe neurotoxicity [ 55 ]. ICANS grade is determined by the most severe event not attributable to any other cause. High tumour burden, thrombocytopenia, high ferritin and pre-existing neurological co-morbidities are also risk factors [ 54 , 56 , 57 ].
Management of ICANS involves thorough and serial investigations with EEG, fundoscopic examination and neuroimaging to exclude other causes of neurotoxicity and to identify further complications. Pharmacological treatment is with high dose corticosteroids e. Tocilizumab is not used for ICANS management due to its limited ability to cross the blood-brain-barrier, although it is often administered due to the common co-occurrence with CRS [ 36 ].
Tumour flare is a well described immune reaction in NHL, particularly with exposure to immunomodulators such as thalidomide and lenalidomide [ 59 , 60 ]. A similar phenomenon is seen with T-cell engaging therapies whereby an influx of T-cells into the tumour sites shortly after first administration leads to fevers, tumour pain, lymphocytosis and rash. Other clinical features will vary depending on anatomical location and the size of the tumour.
Mass effect can occur on vital structures such as airways, blood vessels and other vital organs. Radiological imaging may show pseudoprogression [ 61 , 62 ]. Dose-limiting tumour flare has been reported with glofitamab when used in combination with atezolizumab, an anti-PD-L1 inhibitor [ 22 ].
Prophylactic preventative intervention should be considered in patients with tumors involving critical locations such as the oropharynx and mediastinum. Pain associated with tumour flare can be managed with non-opioid and opioid analgesia, with high dose corticosteroids reserved for persistent or severe cases.
The off-the-shelf preparation to provide cell-specific immune engagement has provided a new therapeutic option and, based on early clinical development described in this review, combinatorial and monotherapy bsAb therapy is being tested from frontline through to heavily pre-treated patients, including those who progressed after CAR T-cell therapy.
This review has highlighted some of the mechanistic differences between bsAbs in advanced stage clinical development for lymphoma. Preclinical and biomarker studies including pharmacokinetics and cytokine assays will assist understanding as to the different treatment responses, tumour kinetics and AE profiles of bsAbs.
The AE profile is distinct from non-cellular therapies, but relatively uniform to the class and once familiarity with CRS identification, classification and management is achieved, clinicians are well poised to implement the use of bsAbs into widespread clinical practice as safety and efficacy endpoints are met and the likely pathway to approval achieved. Conceptualization, methodology, investigation, writing— original draft preparation, review and editing by R.
All authors have read and agreed to the published version of the manuscript. National Center for Biotechnology Information , U. Journal List J Pers Med v. J Pers Med. Published online Apr Gregory 1, 2. Find articles by Jeremy Ong. Gareth P. Stephen Opat, Academic Editor. Author information Article notes Copyright and License information Disclaimer. Received Mar 1; Accepted Apr This article has been cited by other articles in PMC.
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