On September 10, 2022 BeiGene (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global, science-driven biotechnology company focused on developing innovative and affordable medicines to improve treatment outcomes and access for patients worldwide, reported that updates from its solid tumor development program for cornerstone PD-1 antibody tislelizumab at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 in Paris (Press release, BeiGene, SEP 10, 2022, View Source [SID1234619361]).

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Results from the Phase 3 RATIONALE 301 trial of tislelizumab versus sorafenib as first-line treatment in patients with unresectable hepatocellular carcinoma were accepted as a late-breaking abstract (LBA36) and presented at an oral session on Saturday, September 10. In the final analysis of 674 patients enrolled from Asia, Europe, and U.S., RATIONALE 301 met its primary endpoint of overall survival (OS) non-inferiority, with a median OS of 15.9 months for tislelizumab compared with an OS of 14.1 months for sorafenib (HR: 0.85 [95.003% CI: 0.712, 1.019]); superiority was subsequently tested, which was not met. OS data were consistent across all pre-specified subgroups, including regions.

In the RATIONALE 301 trial, tislelizumab was associated with a higher objective response rate (ORR) (14.3% vs. 5.4%) and more durable responses (median duration of response (DoR) 36.1 months vs. 11.0 months) compared with sorafenib. Median progression-free survival (PFS) for tislelizumab versus sorafenib was 2.1 months vs. 3.4 months respectively; HR: 1.11 [95% CI: 0.92, 1.33].

The safety profiles for tislelizumab and sorafenib treatments were consistent with previous studies, and tislelizumab demonstrated a comparatively favorable profile versus sorafenib with lower incidence rates of grade >3 adverse events (AEs) and AEs leading to discontinuation (48.2% vs 65.4% and 10.9% vs 18.5% respectively). AEs leading to death were low across both tislelizumab (4.4%) and sorafenib (5.2%) arm.

"The RATIONALE 301 study results confirm a durable overall survival benefit of single agent tislelizumab and we are pleased that the safety profile for tislelizumab is consistent with previous studies. While targeted therapies can be an important treatment modality for advanced hepatocellular cancer, the safety and tolerability profile remain an important consideration," said Mark Lanasa, M.D., Ph.D, Chief Medical Officer, Solid Tumors, at BeiGene. "We’re pleased to share the data at ESMO (Free ESMO Whitepaper) today and to engage with leading oncology researchers about our expansive clinical development program for tislelizumab in solid tumors."

In addition to the late-breaking Phase 3 RATIONALE 301 results, BeiGene shared posters demonstrating a consistent response for tislelizumab across pre-specified subgroups in a Phase 3 trial and indications of anti-tumor activity and tolerable safety profile in a Phase 1 trial with tislelizumab in combination with chemotherapy and investigational anti-TIGIT antibody ociperlimab:

Abstract 1031P – RATIONALE 303 (NCT03358875): Tislelizumab demonstrated favorable OS, PFS, DoR, and ORR compared with docetaxel, regardless of subgroup, in a prespecified analysis of Asian versus non-Asian patients in the global RATIONALE 303 study of tislelizumab versus docetaxel as second- or third-line therapy in previously treated patients with locally advanced non-small cell lung cancer (NSCLC) Lower rates of treatment-emergent adverse events were reported for tislelizumab versus docetaxel (41.1% vs 75.2% of Asian patients and 45.9% vs 72.9% of non-Asian patients, respectively).
Abstract 1017P –AdvanTIG-105 (NCT04047862): Ociperlimab and tislelizumab plus chemotherapy demonstrated antitumor activity in cohorts 1 and 2 of this Phase 1b dose-expansion study and the recommended Phase 2 dose showed a manageable safety profile in patients with metastatic squamous and non-squamous NSCLC.
BeiGene also shared posters describing the trial design for ongoing tislelizumab combination clinical trials:

Abstract 1194TiP – AdvanTIG-205 (NCT05014815): Phase 2 trial of ociperlimab + tislelizumab + chemotherapy in first line treatment of patients with locally advanced, unresectable, or metastatic NSCLC.
Abstract 1187TiP – BGB-A317-Sitra-301 (NCT04921358): Phase 3 study of tislelizumab with sitravatinib versus chemotherapy in patients with locally advanced/metastatic NSCLC previously treated with chemo and an anti-programmed cell death protein 1/ligand 1 antibody.
About Tislelizumab

Tislelizumab is a humanized IgG4 anti-PD-1 monoclonal antibody specifically designed to minimize binding to Fc-gamma (Fcγ) receptors on macrophages, helping to aid the body’s immune cells to detect and fight tumors. In pre-clinical studies, binding to Fcγ receptors on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells.

Tislelizumab is the first investigational medicine from BeiGene’s immuno-oncology biologics program and is being evaluated in solid tumor and hematologic malignancies, as monotherapy and in combination.

The global tislelizumab clinical development program includes more than 11,000 subjects enrolled to-date in 30 countries and regions. More information on the tislelizumab development program, including clinical trials and regulatory submissions, can be found on the Tislelizumab Fact Sheet in our corporate press kit.

About RATIONALE 301

RATIONALE 301 (NCT03412773) is a global, Phase 3, randomized, open-label study of tislelizumab compared with sorafenib as a first-line treatment in adult patients with unresectable HCC. The primary endpoint of the study is non-inferiority of OS between the two treatment groups. The key secondary endpoint is ORR, as assessed by Blinded Independent Review Committee (BIRC) per RECIST v1.1. Other secondary endpoints include other efficacy assessments such as PFS, DoR, and Time to Progression per BIRC, as well as measures of health-related quality of life, and safety and tolerability.

BeiGene Oncology

BeiGene is committed to advancing best- and first-in-class clinical candidates internally or with like-minded partners to develop impactful and affordable medicines for patients across the globe. We have a growing R&D and medical affairs team of approximately 3,300 colleagues dedicated to advancing more than 100 clinical trials that have involved more than 16,000 subjects. Our expansive portfolio is directed predominantly by our internal colleagues supporting clinical trials in more than 45 countries and regions. Hematology-oncology and solid tumor targeted therapies and immuno-oncology are key focus areas for the Company, with both mono- and combination therapies prioritized in our research and development. BeiGene currently has three approved medicines discovered and developed in our own labs: BTK inhibitor BRUKINSA in more than 50 markets including the U.S., China, the European Union, Great Britain, Canada, Australia, and South Korea; and the non-FC-gamma receptor binding anti-PD-1 antibody, tislelizumab, as well as the PARP inhibitor, pamiparib, in China.

BeiGene also partners with innovative companies who share our goal of developing therapies to address global health needs. We commercialize a range of oncology medicines in China licensed from Amgen, Bristol Myers Squibb, EUSA Pharma and Bio-Thera. We also plan to address greater areas of unmet need globally through our other collaborations including with Mirati Therapeutics, Seagen, and Zymeworks.

In January 2021, BeiGene and Novartis announced a collaboration granting Novartis rights to co-develop, manufacture, and commercialize BeiGene’s anti-PD1 antibody, tislelizumab, in North America, Europe, and Japan. Building upon this productive collaboration, BeiGene and Novartis announced an option, collaboration, and license agreement in December 2021 for BeiGene’s TIGIT inhibitor, ociperlimab, that is in Phase 3 development. Novartis and BeiGene also entered into a strategic commercial agreement through which BeiGene will promote five approved Novartis Oncology products across designated regions of China.

On September 10, 2022 Spectrum Pharmaceuticals, Inc. (NasdaqGS: SPPI), a biopharmaceutical company focused on novel and targeted oncology therapies, reported data from a poster presentation titled: High Activity of Poziotinib in G778_P780dup HER2 Exon 20 Insertion Mutations in Non-Small Cell Lung Cancer (NSCLC) (Press release, Spectrum Pharmaceuticals, SEP 10, 2022, View Source [SID1234619359]). The data show that poziotinib is highly active in G778 mutations in both treatment naïve and previously treated patients with NSCLC.

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The poster titled "High Activity of Poziotinib in G778_P780dup HER2 Exon 20 Insertion Mutations in Non-Small Cell Lung Cancer (NSCLC)" is being presented by Xiuning Le, M.D., Ph.D., Assistant Professor, The University of Texas MD Anderson Cancer Center on September 12, 2022. A poster with the data is available to registered participants at the European Society for Medical Oncology Congress (ESMO) (Free ESMO Whitepaper) 2022 taking place in Paris from September 9-13, 2022.

"The G778 mutation is one of the frequent HER2 exon 20 insertion mutations and patients with these tumors have a poor prognosis," said Francois Lebel, M.D., Chief Medical Officer of Spectrum Pharmaceuticals. "These findings demonstrate the high activity of poziotinib in both treatment naïve and heavily pre-treated patients."

Results for Poziotinib in this Patient Group

The findings are based on an assessment of the activity of poziotinib in patients with the G778_P780dup HER2 exon 20 insertion mutation in a population of previously treated (Cohort 2) and treatment-naïve (Cohort 4) patients with NSCLC from the ZENITH20 clinical trial. Patients (n=90) in Cohort 2 (C2) received 16 mg of poziotinib once a day (QD) and patients (n=80) in Cohort 4 (C4) received 16 mg QD or 8 mg twice a day (BID). The primary endpoint was objective response rate (ORR). Fourteen patients had the HER2 G778 insertion (C2, n=7; C4, n=7) mutation.

12 of 14 patients were evaluable and all had partial response, resulting in an ORR of 85.7% (95% CI, 57.2, 98.2) and a median DOR of 5.5 months (range 2.9-14.1). The ORR was 100% in the previously treated C2 patients, and 71.4% in the treatment naïve C4 patients. Median DOR was 5.3 months for the C2 patients and 8.9 months for those in C4. The frequency of adverse events (AEs) was consistent with prior reports and overall AEs were similar to the TKI class.

The poster will be available for viewing by registered participants during the conference via the ESMO (Free ESMO Whitepaper) website beginning on September 10, 2022. It will also be available on the Investor Relations section of the company’s website at View Source

About Poziotinib

Poziotinib is a novel, oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) that inhibits the tyrosine kinase activity of EGFR as well as HER2 and HER4. Importantly this, in turn, leads to the inhibition of the proliferation of tumor cells that overexpress these receptors. Mutations or overexpression/amplification of EGFR family receptors have been associated with a number of different cancers, including non-small cell lung cancer (NSCLC), breast cancer, and gastric cancer. HER2 exon 20 insertion mutations are a rare subset accounting for approximately 2-4% in NSCLC. There is no approved therapy specifically for either treatment-naïve or previously treated NSCLC with HER2 exon 20 insertion mutations. The company holds an exclusive license from Hanmi Pharmaceutical to develop, manufacture, and commercialize poziotinib worldwide, excluding Korea and China.

On September 10, 2022 Exact Sciences Corp. (Nasdaq: EXAS), a leading provider of cancer screening and diagnostic tests, reported data from a multi-cancer early detection (MCED) biomarker validation study was presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (Press release, Exact Sciences, SEP 10, 2022, View Source [SID1234619358]). The study rigorously assessed the performance of four distinct biomarker classes found in the blood and known to signal the presence of cancer regardless of its location in the body.

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"Cancer releases a diverse set of biomarkers into the blood that can be harnessed to detect the devastating disease at earlier stages," said Tom Beer, M.D., F.A.C.P., chief medical officer and vice president, multi-cancer early detection, Exact Sciences. "These data demonstrate in a large, well-designed case-control study that combining different cancer biomarkers improves cancer detection, especially in stages I and II, when treatment may be more effective for patients. This is a major step forward in our mission to detect cancer earlier before signs and symptoms appear."

Four biomarker classes, discovered through years of collaboration with Johns Hopkins and Mayo Clinic and analyzed together for the first time in this study, demonstrated the ability to detect cancer signal from 15 organ sites with a mean sensitivity of 61% and mean specificity of 98.2%. The multi-biomarker approach, including aneuploidy, proteins, and DNA methylation and mutations, provided encouraging cancer detection in stages I and II, with a combined sensitivity of 38.7%.

Sensitivities by Cancer Stage for Four-Biomarker Class Set

The retrospective, case-control study included cancers from 11 organ sites with no recommended screening option today and 15 organ sites and tissue in total, including breast, bladder, colon, esophageal, kidney, liver, lung, multiple myeloma, myelodysplastic syndrome, non-Hodgkin’s lymphoma, ovarian, pancreatic, prostate, stomach, and uterine. The non-cancer control cohort included age-matched, presumably healthy individuals and samples from individuals with non-cancer diseases to represent the intended use population more effectively.

Many cancers can be cured if detected early and treated effectively.i Yet cancer remains the second leading cause of death worldwide, accounting for approximately 1 in every 6 deathsii, with no recommended screening tests available for 70 percent of cancer diagnoses.

"Being able to screen patients for multiple cancers with a blood test, especially those that don’t have a current screening option, is extremely exciting," said Anne Marie Lennon M.B.B.Ch., Ph.D. Director, Division of Gastroenterology and Hepatology and Professor of Medicine at Johns Hopkins Medicine. "Robust studies like this one are important in understanding the potential effectiveness of a multi-biomarker approach to MCED. This study shows encouraging signs that cancers, including early-stage cancers, can be detected, providing us the opportunity to improve patient outcomes by treating the disease when it is typically most responsive to therapy."

The study presented at ESMO (Free ESMO Whitepaper) builds on the insights and experience gained from earlier versions of the MCED test used in the DETECT-A study. DETECT-A, the first and only prospective, interventional study of 10,000 women to screen for multiple cancers, demonstrated the ability of an MCED test to more than double the number of screening-detected cancers compared to standard-of-care screening methods alone.iii

A larger case-control study is underway to further validate the results shared at ESMO (Free ESMO Whitepaper) and determine the final design of the MCED test. Exact Sciences will then begin recruiting patients for the FDA registrational Study Of All comeRs(SOAR) trial in MCED during 2023. The SOAR trial will be the largest prospective, interventional MCED trial ever conducted in the United States. Exact Sciences plans to leverage its leading presence in primary care and cancer screening to accelerate the availability of MCED and deliver this powerful innovation to patients in need.

On September 10, 2022 Anaveon, a clinical-stage immuno-oncology company, reported that updated clinical data from the ongoing Phase I/II study of ANV419 in patients with solid tumors, as well as new pre-clinical data further elucidating the mode of action of this powerful and selective interleukin-2 (IL-2) agonist, in poster presentations at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022, taking place in Paris, September 9 – 13, 2022 (Press release, Anaveon, SEP 10, 2022, View Source [SID1234619357]).

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26 patients in 9 dosing cohorts with different cancers progressing after standard therapy, received ANV419 once every 14 days at doses up to 243 µg/kg in two-week cycles as an intravenous infusion over 15 minutes without pre-medication. ANV419 is well tolerated, and all drug related events were reversible and responsive to supportive care therapy.
The most common drug related AEs were low grade (G1 or G2) fever, chills, vomiting and fatigue. No patients have withdrawn from the study due to AEs and no dose limiting toxicities have been observed up to and including 243 µg/kg. Dosing is ongoing in the 364 µg/kg cohort.

Pharmacodynamic evaluation of ANV419 on day 4 post-dosing (cycle 1 and 2) showed a selective and dose dependent proliferation of CD8+ T and NK cells, with a lower increase of proliferating Tregs.

In this heavily pre-treated population, 5 patients continue to receive ANV419 treatment. At ANV419 doses ≥108 µg/kg, 75% of patients achieved at least disease stabilization (5 SD, 1 PR). One patient who is still on ANV419 treatment, had a partial response after two weeks of ANV419 treatment, with 31% shrinkage of tumour mass and a sustained and deepening response with 56% shrinkage at 3 months of ANV419 treatment.

Dr. Elena Garralda at the Hospital Universitari Vall d’Hebron in Barcelona, and lead investigator on the study said, "These early data are encouraging and I believe ANV419 has the potential to be a clinically important therapy for patients with different tumor types, both as monotherapy and in combination."

Preclinical data for ANV419 in combination with checkpoint inhibitors were also presented at ESMO (Free ESMO Whitepaper). These demonstrate broad activity of ANV419 on effector cells, supporting the initiation of Phase II studies assessing ANV419 treatment in indications in which CD8 T cells and NK cells are involved in tumor resolution as well as supporting combination studies with checkpoint inhibitors and treatments acting through antibody-dependent cellular cytotoxicity.

"We are very excited by the safety, selectivity and preliminary efficacy of ANV419 which builds on the data that we presented at AACR (Free AACR Whitepaper) earlier this year," added Christoph Bucher, MD, Chief Medical Officer of Anaveon. "At doses equivalent to high dose IL-2, ANV419 maintains a safety and pharmacokinetic profile which will enable us to select the most effective dose level without incurring the side effects seen by other IL-2 therapies. We will now initiate our Phase II program investigating the efficacy of ANV419 in Melanoma and Multiple Myeloma and look forward to demonstrating the full therapeutic potential of ANV419 for patients."

Abstracts are available on the ESMO (Free ESMO Whitepaper) website and the accompanying posters will be available in the publications section of Anaveon’s website.

Details of the poster presentations are:

Abstract Title: "ANV419, a selective IL-2R-beta-gamma targeted antibody-IL-2 fusion protein, in patients with advanced solid tumors, a phase I/II study"
Presentation Number: 479P (pdf)
Location: Poster Area Hall 4
Authors: H. Läubli, G. Alonso, J. Lopez, E. Calvo, M. Jörger, V. Sanchez, D. Di Blasi, A. Nair, K. Richter, Ch Huber, J Mouton, S. Costanzo, S. Jethwa, Ch Bucher and E. Garralda
Date/Time: 12 September 2022 at 9:00 CEST – 18:30 CEST

Abstract Title: "ANV419 is a novel CD122-biased IL-2/anti-IL-2 fusion protein with potent CD8 T cell and NK cell stimulating capacity that shows additive efficacy in combination with checkpoint inhibitors and treatments acting through antibody dependent cellular cytotoxicity"
Presentation Number: 39P (pdf)
Location: Poster Area Hall 4
Authors: K. Richter, N. Egli, L. Petersen, P. Murer, A. Katopodis and Ch. Huber
Date/Time: 11 September 2022 at 9:00 CEST – 18:30 CEST

Anaveon is undertaking a Phase I/II study to evaluate the safety, dosing and clinical activity of its lead program, ANV419, a powerful and selective interleukin-2 (IL-2) agonist in patients with solid tumors. The Company is pursuing multiple parallel Phase II programs in order to explore the full therapeutic potential of ANV419. In addition, Anaveon continues its work in developing follow-on compounds to expand on the success of ANV419 by delivering the IL-2 agonist to tumor fighting cells and thus expand the therapeutic potential into less immunogenic tumors. Alongside this, the Company is building on its cytokine engineering expertise with preclinical-stage programs harnessing the power of cytokines for therapeutic purposes.

On September 10, 2022 Immatics N.V. (NASDAQ: IMTX, "Immatics"), a clinical-stage biopharmaceutical company active in the discovery and development of T cell-redirecting cancer immunotherapies, reported a comprehensive preclinical data set for its T cell engaging receptor (TCER) product candidate IMA402 at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 held in Paris, France, from September 9 to 13, 2022 (Press release, Immatics, SEP 10, 2022, View Source [SID1234619356]). IMA402 is the company’s second program in its TCR Bispecifics pipeline and is directed against an HLA-A*02:01-presented peptide derived from PRAME, a cancer target broadly expressed in many solid tumors. The data are available as an ePoster on the ESMO (Free ESMO Whitepaper) platform at 9 AM on Saturday, September 10, and will be presented during the poster session from noon to 1 PM CEST on Monday, September 12.

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Immatics TCER molecules are "off-the-shelf" TCR Bispecifics engineered with two binding regions: a TCR domain and a T cell recruiter domain.

1) Clinical Trial Application (CTA) is the equivalent of an Investigational New Drug (IND) application in Europe

Data Highlights:
TCER format is optimized for efficacy and safety

The IMA402 TCER utilizes a high-affinity TCR designed to specifically bind to an HLA-A*02:01-presented peptide derived from PRAME on tumor cells
The T cell recruiter domain is a proprietary low-affinity T cell recruiter against the TCR/CD3 complex that demonstrates superior in vivo tumor control compared to analogous TCER molecules designed with higher-affinity variants of a widely used antibody recruiter
The IMA402 TCER is optimized to reduce T cell engager-associated toxicities in patients, which is demonstrated by reduced recruiter-mediated cytokine release in vitro

Compelling preclinical data

IMA402 showed potent and selective activity against PRAME-positive tumor cell lines in vitro
In vivo studies in mice demonstrated dose-dependent anti-tumor activity of IMA402. Sufficiently high drug doses were key to achieving the desired anti-tumor effects over a prolonged period
In vitro safety assessment including toxicity screening against 20 normal tissue types, whole blood cytokine release assessment and alloreactivity evaluation confirmed favorable safety profile for IMA402
The half-life extended format of IMA402 confers a serum half-life of >1 week in mice suggesting a favorable dosing regimen and prolonged drug exposure at therapeutic levels when compared to TCR Bispecifics lacking half-life extension strategies

Clinical trial evaluating IMA402 in patients with solid tumors to start in 2023

IMA402 is designed to allow high dosing not limited by toxicities with the goal of reaching relevant therapeutic doses in tumor tissue and achieve a meaningful clinical benefit in patients

"Improving drug safety, efficacy and dosing schedule are key considerations in the field of bispecific T cell engaging molecules. The promising preclinical results for our next-generation, half-life extended TCER IMA402 reflect the potential of our TCR Bispecific approach for patients with solid tumors," commented Carsten Reinhardt, M.D., Ph.D., Chief Development Officer at Immatics. "We look forward to initiating the IMA402 Phase 1/2 clinical trial in 2023 as part of our strategy to tackle PRAME with two distinct therapeutic modalities. We believe PRAME is the most promising, clinically validated T cell target for solid cancers to date and with our cell therapy and bispecific approaches, we are well positioned to provide innovative treatment options for a variety of cancer patient populations with different medical needs."

To enable the start of the Phase 1/2 trial in 2023, Immatics has completed the manufacturing process development for IMA402 and manufacturing of the clinical batch is on track for 2H 2022. The Phase 1 part of the trial will start with a minimal anticipated biological effect level (MABEL) dose of IMA402 and will have an adaptive design aimed at accelerating dose escalation to determine the recommended Phase 2 dose (RP2D). HLA-A*02:01-positive patients with different solid tumors expressing PRAME will initially receive weekly infusions of IMA402. Pharmacokinetics data will be assessed throughout the trial and might provide an opportunity to adapt the treatment interval. The Phase 2a dose expansion part of the trial will be designed to comprise several cohorts to further evaluate IMA402 in specific indications and combination therapies. Submission of the IND1 application is planned for Q2 2023.

The ESMO (Free ESMO Whitepaper) Congress 2022 poster presentation is available on Immatics’ website using this link.

About TCER
Immatics’ half-life extended TCER molecules are next-generation, antibody-like "off-the-shelf" biologics that leverage the body’s immune system by redirecting and activating T cells towards cancer cells expressing a specific tumor target. The design of the TCER molecules enables the activation of any T cell in the body to attack the tumor, regardless of the T cells’ intrinsic specificity. Immatics proprietary biologics are engineered with two binding regions: a TCR domain and a T cell recruiter domain. The TCER format is designed to maximize efficacy while minimizing toxicities in patients. It contains a high-affinity TCR domain that is designed to bind specifically to the cancer target peptide on the cell surface presented by an HLA molecule. The antibody-derived, low-affinity T cell recruiter domain is directed against the TCR/CD3 complex and recruits a patient’s T cells to the tumor to attack the cancer cells. With a low-affinity recruiter aiming for optimized biodistribution and enrichment of the molecule at the tumor site instead of the periphery, TCER are engineered to reduce the occurrence of immune-related adverse events, such as cytokine release syndrome. In addition, the TCER format consists of an Fc-part conferring half-life extension, stability, and manufacturability. TCER are "off-the-shelf" biologics and thus immediately available for patient treatment. They can be distributed through standard pharmaceutical supply chains and provide the opportunity to reach a large patient population without the need of specialized medical centers.