Rapid development and mass production of SARS-CoV-2 neutralizing chicken egg yolk antibodies with protective efficacy in hamsters.

Despite the record speed of developing vaccines and therapeutics against the SARS-CoV-2 virus, it is not a given that such success can be secured in future pandemics. In addition, COVID-19 vaccination and application of therapeutics remain low in developing countries. Rapid and low cost mass production of antiviral IgY antibodies could be an attractive alternative or complementary option for vaccine and therapeutic development. In this article, we rapidly produced SARS-CoV-2 antigens, immunized hens and purified IgY antibodies in 2 months after the SARS-CoV-2 gene sequence became public. We further demonstrated that the IgY antibodies competitively block RBD binding to ACE2, neutralize authentic SARS-CoV-2 virus and effectively protect hamsters from SARS-CoV-2 challenge by preventing weight loss and lung pathology, representing the first comprehensive study with IgY antibodies. The process of mass production can be easily implemented in most developing countries and hence could become a new vital option in our toolbox for combating viral pandemics. This study could stimulate further studies, optimization and potential applications of IgY antibodies as therapeutics and prophylactics for human and animals.

Immunogenicity of Tetravalent Protein Vaccine SCTV01E-2 against SARS-CoV-2 EG.5 Subvaraint: A Phase 2 Trial.

The Omicron EG.5 lineage of SARS-CoV-2 is currently on a trajectory to become the dominant strain. This phase 2 study aims to evaluate the immunogenicity of SCTV01E-2, a tetravalent protein vaccine, with a specific emphasis on its immunogenicity against Omicron EG.5, comparing it with its progenitor vaccine, SCTV01E (NCT05933512). As of 12 September 2023, 429 participants aged ≥18 years were randomized into the groups SCTV01E (N = 215) and SCTV01E-2 (N = 214). Both vaccines showed increases in neutralizing antibody (nAb) against Omicron EG.5, with a 5.7-fold increase and a 9.0-fold increase in the SCTV01E and SCTV01E-2 groups 14 days post-vaccination, respectively. The predetermined statistical endpoints were achieved, showing that the geometric mean titer (GMT) of nAb and the seroresponse rate (SRR) against Omicron EG.5 were significantly higher in the SCTV01E-2 group than in the SCTV01E group. Additionally, SCTV01E and SCTV01E-2 induced a 5.5-fold and a 5.9-fold increase in nAb against XBB.1, respectively. Reactogenicity was generally mild and transient. No vaccine-related serious adverse events (SAEs), adverse events of special interest (AESIs), or deaths were reported. In summary, SCTV01E-2 elicited robust neutralizing responses against Omicron EG.5 and XBB.1 without raising safety concerns, highlighting its potential as a versatile COVID-19 vaccine against SARS-CoV-2 variants.

Efficacy, safety and genomic analysis of SCT200, an anti-EGFR monoclonal antibody, in patients with fluorouracil, irinotecan and oxaliplatin refractory RAS and BRAF wild-type metastatic colorectal cancer: a phase â ¡ study.

BACKGROUND: Limited therapeutic options are available for metastatic colorectal cancer (mCRC) patients after failure of first- and second-line therapies, representing an unmet medical need for novel therapies. METHODS: This is an open-label, single arm, multicenter, phase Ⅱ study aiming to perform the efficacy, safety and genomic analysis of SCT200, a noval fully humanized IgG1 anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in patients with fluorouracil, irinotecan and oxaliplatin refractory RAS and BRAF wild-type mCRC. SCT200 (6 mg/kg) was given weekly for the first six weeks, followed by a higher dose of 8 mg/kg every two weeks until disease progression or unacceptable toxicity. Primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR) and secondary endpoints included ORR in patients with left-sided tumor, disease control rate (DCR), duration of response (DoR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and safety. FINDINGS: From February 12, 2018 to December 1, 2019, a total of 110 patients aged between 26 and 77 years (median: 55; interquartile range [IQR]: 47-63) with fluorouracil, oxaliplatin, and irinotecan refractory RAS and BRAF wild-type mCRC were enrolled from 22 hospitals in China. As the data cut-off date on May 15, 2020, the IRC-assessed ORR and DCR was 31% (34/110, 95% confidence interval [CI] 22-40%) and 75% (82/110, 95% CI 65-82%), respectively. Thirty one percent (34/110) patients achieved confirmed partial response (PR). The median PFS and median OS were 5.1 months (95% CI 3.4-5.2) and 16.2 months (95% CI 11.1-not available [NA]), respectively. The most common ≥ grade 3 treatment-related adverse events (TRAEs) were hypomagnesemia (17%, 19/110) and acneiform dermatitis (11%, 12/110). No deaths occurred. Genomic analysis suggested positive association between MYC amplification and patients' response (P = 0.0058). RAS/RAF mutation and MET amplification were the most frequently detected resistance mechanisms. Patients with high circulating tumor DNA (ctDNA) at baseline or without ctDNA clearance at the 7th week after the first dose of SCT200 administration before receiving SCT200 had worse PFS and OS. INTERPRETATION: SCT200 exhibited promising clinical efficacy and manageable safety profiles in RAS and BRAF wild-type mCRC patients progressed on fluorouracil, irinotecan and oxaliplatin treatment. The baseline ctDNA and ctDNA clearance status at the 7th week after the first dose of SCT200 administration before receiving SCT200 could be a potential prognostic biomarker for RAS and BRAF wild-type mCRC patients with SCT200 therapy. FUNDING: This study was sponsored by Sinocelltech Ltd., Beijing, China and partly supported by the National Science and Technology Major Project for Key New Drug Development (2019ZX09732001-006, 2017ZX09304015).

Phase Ib study of anti-EGFR antibody (SCT200) in combination with anti-PD-1 antibody (SCT-I10A) for patients with RAS/BRAF wild-type metastatic colorectal cancer.

OBJECTIVE: This study evaluated the safety and efficacy of an anti-epidermal growth factor receptor (EGFR) antibody (SCT200) and an anti-programmed cell death 1 (PD-1) antibody (SCT-I10A) as third-line or subsequent therapies in patients with rat sarcoma viral oncogene (RAS)/v-raf murine sarcoma viral oncogene homolog B (BRAF) wild-type (wt) metastatic colorectal cancer (mCRC). METHODS: We conducted a multicenter, open-label, phase Ib clinical trial. Patients with histologically confirmed RAS/BRAF wt mCRC with more than two lines of treatment were enrolled and treated with SCT-I10A and SCT200. The primary endpoints were the objective response rate (ORR) and safety. The secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). RESULTS: Twenty-one patients were enrolled in the study through January 28, 2023. The ORR was 28.57% and the DCR was 85.71% (18/21). The median PFS and OS were 4.14 and 12.84 months, respectively. The treatment-related adverse events (TRAEs) were tolerable. Moreover, compared with the monotherapy cohort from our previous phase I study evaluating SCT200 for RAS/BRAF wt mCRC in a third-line setting, no significant improvements in PFS and OS were observed in the combination group. CONCLUSIONS: SCT200 combined with SCT-I10A demonstrated promising efficacy in previously treated RAS/BRAF wt mCRC patients with an acceptable safety profile. Further head-to-head studies with larger sample sizes are needed to validate whether the efficacy and safety of combined anti-EGFR and anti-PD-1 therapy are superior to anti-EGFR monotherapy in the third-line setting. (Registration No. NCT04229537).

Antitumor activity of pegylated human interferon ß as monotherapy or in combination with immune checkpoint inhibitors via tumor growth inhibition and dendritic cell activation.

Type I interferons (IFN), especially human IFN alpha (IFNα), have been utilized for antitumor therapy for decades. Human interferon beta (IFNß) is rarely used for cancer treatment, despite advantages over IFNα in biological activities such as tumor growth inhibition and dendritic cell (DC) activation. The utilization of pegylated human IFNß (PEG-IFNß), as monotherapy or in combination with immune checkpoint inhibitors (ICIs) was evaluated in this study through in vivo efficacy studies in syngeneic mouse melanoma, non-small cell lung cancer (NSCLC), and colon adenocarcinoma (COAD) models resistant to immune checkpoint inhibitors (ICIs). In vitro comparative study of PEG-IFNß and pegylated IFNα-2b was performed in terms of tumor growth inhibition against human melanoma, NSCLC and COAD cell lines and activation of human monocyte-derived DCs (MoDCs). Our data demonstrate that the in vivo antitumor effects of PEG-IFNß are partially attributable to tumor growth-inhibitory effects and DC-activating activities, superior to pegylated IFNα-2b. Our findings suggest that utilizing PEG-IFNß as an antitumor therapy can enhance the therapeutic effect of ICIs in ICI-resistant tumors by directly inhibiting tumor growth and induction of DC maturation.

Safety and immunogenicity of multivalent SARS-CoV-2 protein vaccines: a randomized phase 3 trial.

Background: COVID-19 vaccines that offer broad-spectrum protection are needed. We aimed to evaluate the safety and immunogenicity of multivalent vaccines, SCTV01E and SCTV01C, and compare them with an inactivated vaccine. Methods: In the phase 3 trial (ClinicalTrials.gov: NCT05323461), adult participants previously vaccinated with Sinopharm's inactivated SARS-CoV-2 vaccine (BBBIP-CorV) were assigned to receive one booster dose of BBBIP-CorV, 20 µg SCTV01C, or 30 µg SCTV01E. The primary endpoint was to evaluate the geometric mean titers (GMT) of neutralizing antibody (nAb) against the Delta and Omicron BA.1 variants on day 28 after injection. Additional endpoints included GMTs of nAb against Delta (B.1.617.2) and Omicron BA.1 variants on day 180, GMTs against BA.5 on day 28, as well as solicited adverse events (AEs) within seven days, unsolicited AEs within 28 days, and serious AEs, AEs of special interest within 180 days after vaccination. Findings: Between May 30, 2022 and October 28, 2022, a total of 1351 participants were randomized to BBBIP-CorV, SCTV01C, or SCTV01E in a 1:1:1 ratio, with immunogenicity assessments performed on the first 300 participants. For BBBIP-CorV, SCTV01C, and SCTV01E groups, the day 28 GMTs of neutralizing antibody against Omicron BA.1 were a 2.38-, 19.37-, and 28.06-fold increase from baseline; the GMTs against Omicron BA.5 were 2.07-, 15.89- and 21.11-fold increases; the GMTs against Delta variants were 1.97-, 12.76-, and 15.88-fold increases, respectively. The day 28 geometric mean ratio (GMR) of SCTV01C/BBIBP-CorV for Omicron BA.1 was 6.49 (95% CI: 4.75, 8.88), while the GMR of SCTV01E/BBIBP-CorV was 9.56 (95% CI: 6.85, 13.33). For the Delta variant, the day 28 GMR of SCTV01C/BBIBP-CorV was 6.26 (95% CI: 4.78, 8.19), and the day 28 GMR of SCTV01E/BBIBP-CorV was 7.26 (95% CI: 5.51, 9.56). On Day 180, the GMTs against Omicron BA.1 were 2.80-, 9.51-, and 15.56-fold increase from baseline, while those against Delta were 1.58-, 5.49-, and 6.63-fold for BBBIP-CorV, SCTV01C, and SCTV01E groups, respectively. Subgroup analyses showed that SCTV01C and SCTV01E induced uniformly high GMTs against both BA.1 and BA.5, demonstrating its superiority over BBIBP-CorV, regardless of baseline GMT levels. Safety and reactogenicity were similar among the three vaccines. Most AEs were Grade 1 or 2. There were 15 ≥Grade 3 AEs: 6 in the BBIBP-CorV group, 4 in the SCTV01C group and 5 in the SCTV01E group. No SAE was reported and one grade 1 AESI (Bell's palsy) was observed in SCTV01C group. Interpretation: A booster dose of the tetravalent vaccine SCTV01E consistently induced high neutralizing antibody responses against Omicron BA.1, BA.5, and Delta variants, demonstrating superiority over inactivated vaccine. There is evidence to suggest that SCTV01E may have GMT superiority over bivalent vaccine SCTV01C against Delta, BA.1 and BA.5 variants. Funding: This study was sponsored by Sinocelltech Ltd., and funded by the Beijing Science and Technology Planning Project [Z221100007922012] and the National Key Research and Development Program of China [2022YFC0870600].

Validation of Luminex immunological and competitive Luminex immunological assays for clinical immunogenicity assessment of a 14-valent recombinant human papillomavirus vaccine.

A novel virus-like particle (VLP)-based multivalent recombinant human papillomavirus (HPV) vaccine was developed and evaluated in human, including 14 HPV-type specific VLP antigens (HPV6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59). The pseudovirus-based neutralizing assay (PBNA) method is widely used for immunogenicity assessment of HPV vaccine in clinical trials. However, as many as 14 antigen-specific antibody levels need be determined, PBNA is, for many reasons, challenging and time-consuming. In this study, we developed a Luminex immunological assay (LIA) and a competitive Luminex immunological assay (cLIA). These methods increase the throughput, reproducibility and precision, as well as reduce the complexity. All assay parameters showed good characteristics in the validation of both methods, benefiting from highly purified and structurally correct VLPs, high specific antibodies, standard VLP-microspheres and PE-mAbs conjugating process, adequate assay development and stable system. Validation data support the use of both methods for immunogenicity assessment in clinical trials. LIA showed higher sensitivity than cLIA, and due to limited epitopes of mAb, cLIA detected lower antibody responses, and therefore, fewer antibodies. This work not only supports clinical trials of 14-valent HPV vaccines more efficiently and reliably, but also provides a set of validation strategies and usable standards for general vaccine immunogenicity testing.

Safety and immunogenicity of a tetravalent and bivalent SARS-CoV-2 protein booster vaccine in men.

The safety and immunogenicity of a protein-based tetravalent vaccine SCTV01E that contains spike protein ectodomain (S-ECD) of Alpha, Beta, Delta and Omicron BA.1 are assessed and compared with bivalent protein vaccine SCTV01C (Alpha and Beta variants) and monovalent mRNA vaccine (NCT05323461). The primary endpoints are the geometric mean titers (GMT) of live virus neutralizing antibodies (nAb) to Delta (B.1.617.2) and Omicron BA.1 at day 28 post-injection. The secondary endpoints include the safety, day 180 GMTs against Delta and Omicron BA.1, day 28 GMTs to BA.5, and seroresponse rates of neutralizing antibodies and T cell responses at day 28 post-injection. 450 participants, comprising of 449 males and 1 female, with a median age (range) of 27 (18-62) years, are assigned to receive one booster dose of BNT162b2, 20 µg SCTV01C or 30 µg SCTV01E and completed 4-week follow-up. All SCTV01E related adverse events (AEs) are mild or moderate and no Grade ≥3 AE, serious AE or new safety concerns are identified. Day 28 GMT of live virus neutralizing antibodies and seroresponse against Omicron BA.1 and BA.5 with SCTV01E are significantly higher than those with SCTV01C and BNT162b2. These data indicate an overall neutralization superiority with tetravalent booster immunization in men.

A Randomized, Double-Blind, Parallel-Controlled Phase I Study Comparing the Pharmacokinetics, Safety, and Immunogenicity of SCT510 to Bevacizumab (Avastin®) in Healthy Chinese Males.

BACKGROUND: SCT510 is a recombinant humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF), which is intended as a candidate biosimilar of bevacizumab that is approved for various metastatic cancers.Please confirm change in wording to match definition for VEGF belowYes. OBJECTIVE: This study aimed to compare the pharmacokinetics profiles, safety, and immunogenicity of SCT510 to bevacizumab (Avastin®) in healthy Chinese males. METHODS: This was a single-center, double-blind, parallel-group phase I study. A total of 84 participants were randomly assigned (1:1) to receive a single 3 mg/kg infusion of either SCT510 or bevacizumab and followed up for 99 days. Primary endpoints were area under the serum concentration-time curve from time 0 extrapolated to infinity (AUC0-∞), area under the serum concentration-time curve from time 0 to last quantifiable concentration (AUC0-t), and the maximum observed concentration (Cmax). Secondary endpoints included safety and immunogenicity.Kindly check and confirm the edit made in the article title.Yes. RESULTS: A total of 82 subjects completed the study. Geometric means ratios (GMR) for AUC0-∞, AUC0-t, and Cmax were 0.88, 0.89, and 0.97, respectively, for SCT510 versus bevacizumab (USA). The 90% confidence intervals for GMRs of AUC0-∞, AUC0-t, and Cmax were all within the prespecified criteria (80-125%). No adverse events (AEs) led to study termination, and no serious adverse events (SAEs) were reported. None of the anti-drug antibodies (ADAs) identified were found to be neutralizing antibodies (NAbs), and only one subject from the SCT510 group tested positive for the ADA at the day 99 visit. CONCLUSION: This study demonstrated that the pharmacokinetics, safety, and immunogenicity of SCT510 were equivalent to bevacizumab (Avastin®). As a proposed biosimilar drug to bevacizumab, SCT510 was well tolerated in healthy Chinese males. CLINICAL TRIALS REGISTRATION: NCT05113511.

A Polysaccharide-RBD-Fc-Conjugated COVID-19 Vaccine, SCTV01A, Showed High Immunogenicity and Low Toxicity in Animal Models.

We previously developed a polysaccharide--RBD-conjugated nanoparticle vaccine which induced protective efficacy against SARS-CoV-2 in a mouse model. Here, we newly developed a vaccine, SCTV01A, by chemically conjugating recombinant SARS-CoV-2 RBD-Fc and PPS14 (Streptococcus pneumoniae serotype type 14 capsular polysaccharide). The immunogenicity and toxicity of SCTV01A were evaluated in animal models. The PPS14 conjugation enhanced the immunogenicity of RBD-Fc in C57BL/6 mice whether formulated with SCT-VA02B or Alum adjuvant. SCTV01A also induced high opsonophagocytic activity (OPA) against S. pneumoniae serotype 14. In addition, SCTV01A stimulated potent neutralizing titers in rhesus macaques and effectively reduced lung inflammation after SARS-CoV-2 infection with neither antibody-dependent enhancement (ADE) nor vaccine-enhanced diseases (VED) phenomenon. Importantly, the long-term toxicity study of SCTV01A in rhesus macaques did not cause any abnormal toxicity and was tolerated at the highest tested dose (120 µg). The existing immunogenicity and toxicological evaluation results have demonstrated the safety and efficacy of SCTV01A, which will be a promising and feasible vaccine to protect against SARS-CoV-2 infection.

A spike-trimer protein-based tetravalent COVID-19 vaccine elicits enhanced breadth of neutralization against SARS-CoV-2 Omicron subvariants and other variants.

Multivalent vaccines combining crucial mutations from phylogenetically divergent variants could be an effective approach to defend against existing and future SARS-CoV-2 variants. In this study, we developed a tetravalent COVID-19 vaccine SCTV01E, based on the trimeric Spike protein of SARS-CoV-2 variants Alpha, Beta, Delta, and Omicron BA.1, with a squalene-based oil-in-water adjuvant SCT-VA02B. In the immunogenicity studies in naïve BALB/c and C57BL/6J mice, SCTV01E exhibited the most favorable immunogenic characteristics to induce balanced and broad-spectrum neutralizing potencies against pre-Omicron variants (D614G, Alpha, Beta, and Delta) and newly emerging Omicron subvariants (BA.1, BA.1.1, BA.2, BA.3, and BA.4/5). Booster studies in C57BL/6J mice previously immunized with D614G monovalent vaccine demonstrated superior neutralizing capacities of SCTV01E against Omicron subvariants, compared with the D614G booster regimen. Furthermore, SCTV01E vaccination elicited naïve and central memory T cell responses to SARS-CoV-2 ancestral strain and Omicron spike peptides. Together, our comprehensive immunogenicity evaluation results indicate that SCTV01E could become an important COVID-19 vaccine platform to combat surging infections caused by the highly immune evasive BA.4/5 variants. SCTV01E is currently being studied in a head-to-head immunogenicity comparison phase 3 clinical study with inactivated and mRNA vaccines (NCT05323461).

A highly efficient needle-free-injection delivery system for mRNA-LNP vaccination against SARS-CoV-2.

Despite the various vaccines that have been developed to combat the coronavirus disease 2019 (COVID-19) pandemic, the persistent and unpredictable mutations of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) require innovative and unremitting solutions to cope with the resultant immune evasion and establish a sustainable immune barrier. Here we introduce a vaccine-delivery system with a combination of a needle-free injection (NFI) device and a SARS-CoV-2-Spike-specific mRNA-Lipid Nanoparticle (LNP) vaccine. The benefits are duller pain and a significant increase of immunogenicity compared to the canonical needle injection (NI). From physicochemical and bioactivity analyses, the structure of the mRNA-LNP maintains stability upon NFI, contradictory to the belief that LNPs are inclined towards destruction under the high-pressure conditions of NFI. Moreover, mRNA-LNP vaccine delivered by NFI induces significantly more binding and neutralizing antibodies against SARS-CoV-2 variants than the same vaccine delivered by NI. Heterogeneous vaccination of BA.5-LNP vaccine with NFI enhanced the generation of neutralizing antibodies against Omicron BA.5 variants in rabbits previously vaccinated with non-BA.5-specific mRNA-LNP or other COVID-19 vaccines. NFI parameters can be adjusted to deliver mRNA-LNP subcutaneously or intramuscularly. Taken together, our results suggest that NFI-based mRNA-LNP vaccination is an effective substitute for the traditional NI-based mRNA-LNP vaccination.

Safety and immunogenicity of a bivalent SARS-CoV-2 protein booster vaccine, SCTV01C, in adults previously vaccinated with mRNA vaccine: a randomized, double-blind, placebo-controlled phase 1/2 clinical trial.

BACKGROUND: Booster vaccination is an efficient way to address the waning protection of vaccines and immune escape of SARS-CoV-2 variants. We aimed to assess the safety and immunogenicity of SCTV01C, a novel bivalent protein vaccine as a booster for people who previously received two doses of mRNA vaccine. METHODS: In this randomized, phase 1/2 trial, adults fully vaccinated with mRNA vaccines 3-24 month earlier were enrolled. Participants received SCTV01C at 20 µg, 40 µg or placebo. The primary endpoints were adverse reactions within 7 days and immunogenicity on Day 28 after vaccination. This trial was registered with ClinicalTrials.gov (NCT05043311). FINDINGS: Between January 27 and April 28, 2022, 234 adults were randomly assigned to receive SCTV01C or placebo. The most common solicited adverse events (AEs) were Grade 1 injection-site pain (10.7%) and pyrexia (6.3%). There were no reports of Grade 3 or above solicited AE, serious AEs or AEs of special interests. On Day 28 post the booster, the geometric mean concentrations (GMCs) of the specific binding IgG antibodies to spike protein for placebo, 20 µg and 40 µg SCTV01C were 1649, 4153 and 5354 BAU/mL, with fold of increase from baseline of 1.0, 2.8 and 3.4-fold, respectively. GMTs of neutralizing antibodies against live Delta variant were 1280, 3542, and 4112, with fold of increase of 1.1, 3.9 and 4.1-fold, respectively; GMTs of neutralizing antibodies against live Omicron variant were 218, 640, and 1083, with fold of increase of 1.1, 4.4 and 5.1-fold, respectively. Participants with low neutralizing antibody titers at baseline (below the lower limit of quantitation) had 64.0 and 49.4-fold of increase in GMTs for Delta and Omicron, respectively. INTERPRETATION: The heterologous booster of SCTV01C was safe, and induced uniformly high cross-neutralization antibody responses against Delta and Omicron variants. FUNDING: Beijing Science and Technology Plan Project (Z221100007922012) and the National Key Research and Development Program of China (2022YFC0870600) supported this study.

Novel hKDR mouse model depicts the antiangiogenesis and apoptosis-promoting effects of neutralizing antibodies targeting vascular endothelial growth factor receptor 2.

Vascular endothelial growth factor receptor 2 (VEGFR2)/KDR plays a critical role in tumor growth, diffusion, and invasion. The amino acid sequence homology of KDR between mouse and human in the VEGF ligand-binding domain was low, thus the WT mice could not be used to evaluate Abs against human KDR, and the lack of a suitable mouse model hindered both basic research and drug developments. Using the CRISPR/Cas9 technique, we successfully inserted different fragments of the human KDR coding sequence into the chromosomal mouse Kdr exon 4 locus to obtain an hKDR humanized mouse that can be used to evaluate the marketed Ab ramucirumab. In addition, the humanized mAb VEGFR-HK19 was developed, and a series of comparative assays with ramucirumab as the benchmark revealed that VEGFR-HK19 has higher affinity and superior antiproliferation activity. Moreover, VEGFR-HK19 selectively inhibited tumor growth in the hKDR mouse model but not in WT mice. The most important binding epitopes of VEGFR2-HK19 are D257, L313, and T315, located in the VEGF binding region. Therefore, the VEGFR2-HK19 Ab inhibits tumor growth by blocking VEGF-induced angiogenesis, inflammation, and promoting apoptosis. To our best knowledge, this novel humanized KDR mouse fills the gaps both in an animal model and the suitable in vivo evaluation method for developing antiangiogenesis therapies in the future, and the newly established humanized Ab is expected to be a drug candidate possibly benefitting tumor patients.

An antibody cocktail with broadened mutational resistance and effective protection against SARS-CoV-2.

Neutralizing antibodies have been proven to be highly effective in treating mild and moderate COVID-19 patients, but continuous emergence of SARS-CoV-2 variants poses significant challenges. Antibody cocktail treatments reduce the risk of escape mutants and resistance. In this study, a new cocktail composed of two highly potent neutralizing antibodies (HB27 and H89Y) was developed, whose binding epitope is different from those cocktails that received emergency use authorization. This cocktail showed more potent and balanced neutralizing activities (IC50 0.9-11.3 ng mL-1) against a broad spectrum of SARS-CoV-2 variants over individual HB27 or H89Y antibodies. Furthermore, the cocktail conferred more effective protection against the SARS-CoV-2 Beta variant in an aged murine model than monotherapy. It was shown to prevent SARS-CoV-2 mutational escape in vitro and effectively neutralize 61 types of pseudoviruses harbouring single amino acid mutation originated from variants and escape strains of Bamlanivimab, Casirivimab and Imdevimab with IC50 of 0.6-65 ng mL-1. Despite its breadth of variant neutralization, the HB27+H89Y combo and EUA cocktails lost their potencies against Omicron variant. Our results provide important insights that new antibody cocktails covering different epitopes are valuable tools to counter virus mutation and escape, highlighting the need to search for more conserved epitopes to combat Omicron.

Safety, pharmacokinetics and efficacy of SCT200, an anti-EGFR monoclonal antibody in patients with wild-type KRAS/NRAS/BRAF metastatic colorectal cancer: a phase I dose-escalation and dose-expansion study.

BACKGROUND: An over-expression of the epidermal growth factor receptor (EGFR) has been observed in colorectal cancer and is associated with aggressive disease and poor prognosis. SCT200 is a newly developed recombinant, fully humanized, anti-EGFR monoclonal antibody. This study aimed to evaluate its safety, tolerability, pharmacokinetics (PK), and efficacy in patients with wild-type KRAS/NRAS/BRAF metastatic colorectal cancer (mCRC).  METHODS: This phase I study comprising dose-escalation phase and dose-expansion phase. SCT200 was administrated intravenously to groups of three to six patients. An every 3-week dosing cycle (0.5-15.0 mg/kg) and multiple dosing schedule were evaluated. Blood samples were collected at preset intervals for PK assessment, radiological imaging was used for efficacy assessment, and continuous safety monitoring was performed in each group during the study.  RESULTS: From December 16, 2014 to December 31, 2018, fifty-six patients with wild-type KRAS/NRAS/BRAF mCRC receiving ≥ 1 dose of SCT200 were evaluated. Among them, 44.6% (25/56) of the patients failed at least two prior lines of chemotherapy. No dose-limiting toxicities occurred in any group. All of the patients experienced treatment-emergent adverse events (TEAEs). 96.4% (54/56) of patients experienced treatment-related adverse events (TRAEs), and 26.8% (15/56) of patients with Grade ≥ 3 TRAEs. No serious TRAEs were observed. The most common TRAEs were dermotoxicity and hypomagnesemia. PK analysis showed non-linear PK in the range of 0.5 - 8.0 mg/kg of single dose SCT200, the clearance decreased, and the elimination half-life (T1/2) prolonged following dose increase. In the multiple-dose period, the clearance decreased, peak concentration increased, and T1/2 prolonged during prolonged drug administration, and a steady state was reached after five consecutive dose of 6.0 mg/kg quaque week (QW). The objective response rate (ORR) was 30.4% (17/56, 95% confidence interval [CI], 18.8%-44.1%). The ORR in the dose-expansion group (6.0 mg/kg QW) was 48.0% (12/25, 95% CI, 27.8%-68.7%), the median progression-free survival was 5.2 months (95%CI, 3.6-5.5), and the median overall survival was 20.2 months (95%CI, 12.1-not reached). CONCLUSIONS: SCT200 showed favorable safety, PK profile, and preliminary efficacy for patients with wild-type KRAS/NRAS/BRAF mCRC. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov ( NCT02211443 ).