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Riccardo Vergaro @drvergaro.bsky.social · 18h

US20260308264A1 describes an IL-5Rα×CD3 bispecific for eosinophil depletion via T-cell redirection. Its scFv-Fc achieved 0.037 pM EC50 in vitro versus 1.330 pM for a benralizumab-derived comparator. Key unknowns: cytokine release, tissue efficacy and safety.

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Riccardo Vergaro @drvergaro.bsky.social · 15/10/2026

(WO2026213608A1) discloses Cytodigm’s retargetable Cytofinity LNPs, using a ganglioside-docked bispecific to direct mRNA to T cells. Anti-GD2×CD5 achieved ~100% reporter transfection and ~55% CAR-positive T cells; cell-resolved in-vivo delivery remains unproven.

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Riccardo Vergaro @drvergaro.bsky.social · 14/10/2026

US20260295067A1: Novartis develops B7-H3/EphA2-targeted ADCs delivering pan-RAS inhibitors via cleavable linkers. Constructs achieved subnanomolar potency in several cell models, suggesting antigen-directed delivery could broaden RAS inhibition while limiting systemic exposure.

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Riccardo Vergaro @drvergaro.bsky.social · 13/10/2026

US20260297150A1 defines IL-22-Fc glycoforms by 8–12 mol/mol sialylation and site-specific N-glycan occupancy, linking glycosylation to PK and epithelial REG3β induction. Despite improved exposure, efmarodocokin alfa failed Phase II UC efficacy endpoints.

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Riccardo Vergaro @drvergaro.bsky.social · 12/10/2026

(WO2026206803A1) describes a swallowable capsule that deploys a hollow member through the GI wall to systemically deliver RT-114, a GLP-1RA/GLP-2RA fusion. Canine PK/PD studies compare oral and SC dosing; key uncertainties are absolute bioavailability, tissue injury and repeat-dose safety.

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Riccardo Vergaro @drvergaro.bsky.social · 11/10/2026

(WO2026207331A1) discloses aminoglycoside-, glucosamine- and polymyxin-related ligands for renal siRNA/ASO delivery. S003 and S005–S014 achieved >50% SLC6A19 knockdown in vitro. Key question: whether systemic dosing achieves proximal-tubule selectivity with limited off-target exposure.

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Riccardo Vergaro @drvergaro.bsky.social · 10/10/2026

WO2026205975A1 - a TROP2-targeted IFNβ fusion designed to bypass ADC resistance and stimulate antitumour immunity. ABN202 induced complete responses; 3/5 responders resisted tumour rechallenge, suggesting durable immune memory. Tumour selectivity and normal-tissue toxicity remain key questions.

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Riccardo Vergaro @drvergaro.bsky.social · 09/10/2026

WO2026201138A1 describes an EGFR-VHH/HER3 bispecific ADC with optimised drug loading. In SW620 xenografts, a single 10 mg/kg dose achieved 93.45% TGI, with regression in all six animals and partial responses in two at endpoint. Added EGFR-arm benefit over HER3-only ADCs remains unproven.

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Riccardo Vergaro @drvergaro.bsky.social · 08/10/2026

(US20260297207A1) discloses a bispecific antibody targeting TL1A and IL-23 for IBD. BiAb25/29 improved weight loss versus equimolar parental-antibody combinations in mice. Key question: tissue exposure and biomarkers proving bispecific pharmacology beyond PK differences.

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Riccardo Vergaro @drvergaro.bsky.social · 07/10/2026

(WO2026200927A1) discloses an EGFR×cMET bispecific ADC with site-specific glycan conjugation of topoisomerase-I payloads. ADC1 showed activity in NCI-H1975 CDX and 12 osimertinib-resistant NSCLC PDX models, addressing heterogeneous resistance.

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Riccardo Vergaro @drvergaro.bsky.social · 06/10/2026

WO2026207254A1: engineered CD98hc antibodies cross-reactive with mouse/cyno/human orthologues enable BBB shuttling. Leads achieved 3.1–3.6 nM brain levels at day 1 and 1.8–2.7 nM at week 1, with 31–144× brain:blood gains. Parenchymal/cell-specific cargo exposure remains key.

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Riccardo Vergaro @drvergaro.bsky.social · 05/10/2026

(US20260297208A1) discloses an anti-Aβ×TfR bispecific designed to enhance brain delivery and reduce anti-Aβ dosing. In APP/human-TfR mice, BR282 achieved plaque reduction comparable to 10 mg/kg BR11 at lower doses; BR838 used 0.3–3 mg/kg. ARIA/vascular safety remains key.

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Riccardo Vergaro @drvergaro.bsky.social · 04/10/2026

(US20260285908A1) discloses cyclic IL-23R peptides for oral IBD therapy. Compound C inhibited pSTAT3 at 4 nM, bound IL-23R at 2.4 nM and showed gut-biased exposure (355 vs 0.3 µg·h/g/mL plasma). Key question: intestinal target engagement and efficacy vs parenteral IL-23 blockade.

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Riccardo Vergaro @drvergaro.bsky.social · 03/10/2026

(WO2026198950A1) describes synNotch-controlled autolL2, linking IL-2 to intracellular receptor machinery without measurable secretion. In bilateral CD19+/− tumours, the circuit promoted T-cell persistence selectively at CD19+ sites. Key questions: leakage and antigen-loss persistence.

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Riccardo Vergaro @drvergaro.bsky.social · 02/10/2026

(WO2026194744A1) discloses LILRB4×CD3 bispecifics for myeloid malignancies. HB134-074/-079 showed sub-nM LILRB4 binding vs weaker CD3 engagement (58.7–178.9 nM) and activity in a single-dose THP-1 model. Key gap: cytokines and killing vs antigen density.

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Riccardo Vergaro @drvergaro.bsky.social · 01/10/2026

(WO2026194813A1) discloses a MUC16×CD3 bispecific targeting SEA15/16 epitopes. It showed higher in-vitro cytotoxicity than REGN4018 and activity in OV90-MUC16 and CFPAC-1 PBMC-humanised models. Key questions remain soluble MUC16 interference, cytokine release and normal-tissue binding.

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Riccardo Vergaro @drvergaro.bsky.social · 30/09/2026

(WO2026194865A1) discloses an ADAM9-directed ADC for ADAM9-positive solid tumours, with activity in breast and colorectal xenografts and a pancreatic PDX. Key gaps are matched comparator data, normal-tissue cross-reactivity and exposure-based safety.

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Riccardo Vergaro @drvergaro.bsky.social · 29/09/2026

(US20260274966A1) discloses a cetuximab–CD137 affibody bispecific designed to localise T-cell costimulation to EGFR+ tumours. Affinity optimisation improved CD137 EC50 to 0.092–0.128, but reduced purity in some formats. Key: EGFR-dependent agonism and systemic safety.

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Riccardo Vergaro @drvergaro.bsky.social · 28/09/2026

(WO2026193162A1) discloses an IL-31 analogue-Fc immunogen designed to induce endogenous neutralising antibodies against IL-31. Key questions are titre durability, epitope specificity, native IL-31 cross-reactivity, reversibility and sustained control of pruritus.

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Riccardo Vergaro @drvergaro.bsky.social · 27/09/2026

US20260274961A1 discloses dual-variable-domain IgGs targeting FcRn and activating FcγR to redirect immune-complex handling. FcRn/FCGR2A knockout and transgenic models, including K/B×N arthritis, test receptor dependence. Key risk: immune-complex clearance may amplify myeloid inflammation.

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Riccardo Vergaro @drvergaro.bsky.social · 26/09/2026

(WO2026192887A1) discloses trispecific T-cell engagers targeting #CD79B, #CD20 and #CD3. Dual B-cell antigen recognition aims to overcome antigen heterogeneity/escape. Key questions are added potency versus bispecifics, cytokine release and normal B-cell depletion.

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Riccardo Vergaro @drvergaro.bsky.social · 25/09/2026

(WO2026178229A1) describes CD71-targeted FN3 domains delivering IFIH1/MDA5 siRNA, with optional albumin-binding FN3 for persistence. In-vitro knockdown suppresses interferon signalling, but systemic biodistribution, productive cytosolic delivery and tissue knockdown remain unproven.

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Riccardo Vergaro @drvergaro.bsky.social · 24/09/2026

(WO2026189421A1) discloses CLDN-targeted conjugates combining PBD, MMAE or Dxd with a protease-activatable IL-2 prodrug. CLDN-ProIL-2-PBD induced complete regressions in some MC38-CLDN tumours and outperformed separate ADC+ProIL-2; mixed-antigen models tested bystander effects.

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Riccardo Vergaro @drvergaro.bsky.social · 23/09/2026

US20260256934A1 discloses site-specific STING agonist ADCs using Fc LALA-DG antibodies. Conjugation increased FcγRI binding in WT/LALA constructs, while LALA-DG maintained low binding near the parent antibody, supporting reduced FcγR engagement after conjugation.

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Riccardo Vergaro @drvergaro.bsky.social · 22/09/2026

Cpd 5 achieves >12,000-fold p38δ selectivity by inducing an ~11 Å P-loop remodeling stabilized by unique His30. This self-encapsulating conformation creates a selective pocket, validated by structural and phosphoproteomic data, highlighting conformational remodeling as a kinase-selectivity strategy.

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Riccardo Vergaro @drvergaro.bsky.social · 21/09/2026

WO2026184613A1 discloses tandem masking peptides for coordinated cleavage and simultaneous exposure of CD3/CD19 binding domains, with optional anti-HSA VHH. Shared cleavage may simplify activation, but complete, synchronized unmasking remains to be demonstrated.

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Riccardo Vergaro @drvergaro.bsky.social · 20/09/2026

US20260265359A1 discloses Fc fusion proteins combining VEGF-A trapping, Ang-2 binding and IL-6R blockade. Lead B21138002 showed sub-nanomolar binding to all three targets and advanced to rabbit/cynomolgus ocular models; IL-6R’s incremental benefit remains unproven.

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Riccardo Vergaro @drvergaro.bsky.social · 19/09/2026

(US20260265396A1) discloses bispecifics using scFvs targeting the protease-like domain of #TfR1 for brain delivery, including amyloid-β cargo. Affinity-varied shuttles show brain/plasma exposure in human-TfR1 KI mice after equimolar dosing.

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Riccardo Vergaro @drvergaro.bsky.social · 18/09/2026

US20260265379A1 discloses BTN3A×PD-1/PD-L1 bispecifics to activate Vγ9Vδ2 T cells while blocking checkpoints. 69 constructs screened; several enhanced degranulation and SKOV3 killing vs ICT01. In-vivo and parental-combination comparisons remain key.

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Riccardo Vergaro @drvergaro.bsky.social · 17/09/2026

US20260265390A1 discloses hexavalent BCMA×GPRC5D×CD3 trispecifics with paired binding domains. 18 designs showed NFAT activation and PBMC killing across varied antigen densities. Key gap: antigen-loss mixtures, cytokine release and normal-tissue GPRC5D reactivity.

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Riccardo Vergaro @drvergaro.bsky.social · 16/09/2026

(US20260263625A1) discloses N297Q-directed antibody–camptothecin conjugates targeting PRLR, EGFRvIII, MET and STEAP2, with tumour regression in xenografts and antigen dependence shown for STEAP2. Cross-target PK, linker catabolism and therapeutic windows remain unresolved.

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Riccardo Vergaro @drvergaro.bsky.social · 15/09/2026

(US20260263614A1) discloses CDCP1 ADCs with exatecan- or MMAE-class payloads. A DAR8 ADC showed ~25% linker-payload loss vs ~60–75% for DAR4 in mouse, human and cynomolgus plasma. ADC3 inhibited MDA-MB-231 growth; cynomolgus PK was also assessed.

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Riccardo Vergaro @drvergaro.bsky.social · 14/09/2026

(WO2026183142A2) discloses anti-CD5-targeted LNPs delivering circRNA encoding a CD19 CAR for in-vivo T-cell programming. Targeting increased splenic CAR+ T cells and B-cell depletion versus base LNPs in mice.

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Riccardo Vergaro @drvergaro.bsky.social · 13/09/2026

WO2026178657A1 describes pH-responsive amphipathic peptides that become cationic in acidic endosomes, promoting cytosolic cargo release. In mRNA-LNPs, 1% FSP003D-CLS increased liver/spleen reporter output ~18×/~20×, with no obvious distribution shift. Escape and toxicity remain to be confirmed.

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Riccardo Vergaro @drvergaro.bsky.social · 12/09/2026

WO2026180989A1 combines CH3 P374/CH1 P151 and heterodimerisation mutations with BiP-mediated ER retention and IRE1/RIDD control to reduce mispaired chains and half-antibodies, with stability, FcRn and mouse-PK validation.

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Riccardo Vergaro @drvergaro.bsky.social · 11/09/2026

US20260258083A1 discloses separate CD3-paratope-binding peptide-PEG masks that transiently suppress T-cell engager cytotoxicity and cytokine release. Four-arm PEG enhanced blockade vs linear masks. Key question: in-vivo dissociation timing without prolonged loss of antitumour activity.

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Riccardo Vergaro @drvergaro.bsky.social · 10/09/2026

WO2026179945A1 discloses a HER3×TROP2 multispecific ADC for NSCLC, tested in xenografts and an osimertinib-resistant PDX. Claims include PD-1 blockade ± platinum, with Q3W ADC dosing of 3–8 mg/kg.

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Riccardo Vergaro @drvergaro.bsky.social · 09/09/2026

HER2×CD3 bispecifics use site-specific, cleavable ~20 kDa masks on CD3 CDRs to suppress T-cell engagement until cleavage. Masked constructs retained dose-responsive xenograft activity comparable to unmasked controls, supporting conditional activation.

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Riccardo Vergaro @drvergaro.bsky.social · 08/09/2026

Last week’s filings span ADCs, multispecific proteins, CNS delivery and in-vivo cell engineering: EGFR×B7-H3 ADCs, FGFR3 S249C×CD3 engagers, orthogonal IL-21 signalling, brain-targeted progranulin/AAVs and CRISPR CAR-T generation, with preclinical data highlighting key translational caveats.

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Riccardo Vergaro @drvergaro.bsky.social · 07/09/2026

(WO2026178423A2) discloses CD3/CD5/CD7/CD27-targeted particles delivering CRISPR-Cas9 RNPs for in-vivo T-cell reprogramming. CD3 targeting generated CAR+ T cells and B-cell depletion, with in-vivo/in-vitro performance rank reversal.

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Riccardo Vergaro @drvergaro.bsky.social · 06/09/2026

US20260250342A1 discloses an orthogonal IL-21/IL-21R pair engineered for selective signaling in receptor-modified cells. RV13 with IL-21 R9K/K73V restored STAT3 signaling while reducing native IL-21R activation.

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Riccardo Vergaro @drvergaro.bsky.social · 05/09/2026

US20260250345A1 discloses protease-activated IL-2, IL-12 and interferon cytokines masked by albumin/albumin-binding domains. MMP9 cleavage restores activity and may remove the half-life module, linking tumour activation to pharmacokinetics.

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Riccardo Vergaro @drvergaro.bsky.social · 04/09/2026

US20260248911A1 discloses multispecific pMHC-based molecules that selectively target antigen-specific TCR clonotypes, with CD28 co-stimulation or CD20 binding. GP33/OVA systems showed clonotype-selective proliferation and antigen-specific lytic activity in vitro and in vivo.

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Riccardo Vergaro @drvergaro.bsky.social · 03/09/2026

US20260248935A1 discloses branched conjugate precursors that attach two identical or different payloads to one antibody-reactive unit, enabling controlled-ratio multidrug ADCs. Exatecan/MMAE constructs showed tumour inhibition in xenografts, including selected activity at 1 mg/kg.

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Riccardo Vergaro @drvergaro.bsky.social · 02/09/2026

US20260242510A1 discloses MUC17×CD3×CD28 trispecific antibodies combining tumour targeting, T-cell recruitment and localized CD28 co-stimulation. Reported sub-30-pM potency and >85% killing, with in vivo activity in MUC17+ xenografts.

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Riccardo Vergaro @drvergaro.bsky.social · 01/09/2026

WO2026175911A1 discloses a four-chain trispecific antibody targeting IL-4, IL-13 and NKG2D. It combines type-2 cytokine neutralisation with blockade of MICA/MICB/ULBP6–NKG2D interactions, aiming to address mixed inflammatory pathways in one molecule.

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Riccardo Vergaro @drvergaro.bsky.social · 31/08/2026

Centanafadine (Simtriyo), Otsuka’s investigational ADHD therapy, is a first-in-class triple monoamine reuptake inhibitor (NET>DAT>SERT). Phase 3 trials showed significant symptom improvement, with priority FDA review targeting July 24, 2026.

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Riccardo Vergaro @drvergaro.bsky.social · 30/08/2026

(WO2026174105A1) discloses EPLEx-1, an antibody excipient that reversibly binds chelate-bearing radiotheranostics to extend circulation. Tested across PSMA-617 and DOTATATE systems, it offers a non-covalent half-life extension strategy while preserving eventual ligand release.

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Riccardo Vergaro @drvergaro.bsky.social · 29/08/2026

US20260241010A1 discloses bicyclic peptide–PMO conjugates for intracellular/CNS delivery of splice-modulating oligonucleotides. Functional splice correction is shown in reporters and mice, but CNS efficacy followed ICV dosing—not evidence of systemic BBB crossing.

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Riccardo Vergaro @drvergaro.bsky.social · 28/08/2026

US20260241023A1 discloses 3E10-D31N antibody–oligonucleotide conjugates for intracellular siRNA/ASO delivery. Covalent and non-covalent formats show target knockdown and tumour activity, including c-MYC cargo, highlighting cell penetration and endosomal escape as key challenges.

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