BYON-3521

Investigational

BYON3521; BYON 3521

Target

Hepatocyte growth factor receptor (MET / c-MET) · MET

Sponsor

Byondis BV (originated Syntarga BV)

Indication

c-MET-expressing locally advanced or metastatic solid tumors

Target family

Receptor tyrosine kinase

RP2D dose

Every 3 weeks (Q3W)Pooled

Multi-organ toxicity

Fingerprint & organ drill-down

Also reported

0%severity100%

Assessed · clear

true 0%

No data

never assessed

3 adverse-event terms

Ocular

Any-grade

G3+

Pooled

sagittal schematic · Reversible

↳

Tissues shaded by reported adverse-event rate.

Cornea

Express.

26.59%

Limbus

Express.

37.08%

Conjunctiva

Express.

67.14%

Lens

Express.

Retina / RPE

Express.

59.48%

3.6 nTPM

Dominant tissue

None

Surface subtype

None

Reversibility

Reversible

Reported ocular events

Eye disorder (unspecified; 2 distinct events in 1 patient)3.2%

Eye disorder (unspecified)-

G3+ 3.2%

Keratitis0%

n=31

Per-trial detail

Adverse events by trial

BYON3521.001 (NCT05323045)Phase 10.8–6.4 mg/kg IV every 3 weeks (Q3W)n=31PooledC

UK HRA end-of-study research summary, NCT05323045 (final cohort N=31): "tiredness (12 out of 31 patients [38.7%])"; ct.gov NCT05323045 hasResults=FALSE

8 adverse-event terms · 6 systems · expand a system below

General3

Adverse event (any TEAE)

93.5%

29/31

Fatigue

38.7%

12/31

Decreased appetite

35.5%

11/31

GI1

Hematologic1

Infections1

Pulmonary1

Dermatologic1

Construct

Molecular anatomy

Antibody

IgG1

Humanized

Linker

Peptide

Cleavable

1.8

DAR

Payload

seco-DUBA (duocarmycin)

DNA minor-groove alkylation; seco-DUBA activated to DUBA causing irreversible DNA alkylation

Linker structureC28H40N6O7

CC(C)[C@@H](C(=O)N[C@@H](CCCNC(=O)N)C(=O)NC1=CC=C(C=C1)CO)NC(=O)CCCCCN2C(=O)C=CC2=O

Payload structureC29H23ClN4O4

CC1=C2C(=CC=C1)C(=CC3=C2[C@@H](CN3C(=O)C4=CN5C=C(C=CC5=N4)NC(=O)C6=CC=C(C=C6)O)CCl)O

Antibody

Antibody & Fc engineering

Antibody

Humanized cysteine-engineered IgG1 anti-MET (clone mAb3b / SYD2884)

Isotype

IgG1

Origin

Humanized

Fc modifications

None

Glycoengineering

None / standard glycosylation

Effector silencing

Not Fc-silenced

FcγR binding

Retained

C1q binding

No CDC activity

Target KD (nM)

0.01

Dev code

mAb3b / SYD2884

Linker & conjugation

Linker chemistry

Linker profile

Linker

vc-seco-DUBA (valine-citrulline-seco-DUBA / SYD980; Mc-Val-Cit-PABC)

Class

Peptide

Cleavage

Cleavable

Attachment

Site-specific (engineered Cys)

Conjugation

Site-specific via reactive engineered cysteines

Symmetry

Site-specific (paired)

DAR (mean)

1.8

DAR homogeneity

Homogeneous

Plasma t½

Cleavage trigger

Cathepsin B (lysosomal protease; valine-citrulline cleavage)

Release control

Conditional

Hydrophilicity mask

None

Platform

Byondis vc-seco-DUBA

Conjugation site

HC-41C

DAR distribution

Predominantly DAR1/DAR2 species

Formula

C28H40N6O7

Linker MW

572.7 Da

Linker TPSA

200 Å²

Linker xLogP

0.68

ADCdb linker

LIN0SQEDQ

In-vitro stability

Stable in CES1c KO mouse, cynomolgus, and human plasma (37C, 0-96 h); percent not quantified in accessible text

Stability note

Stable in human/cyno/CES1c-KO mouse plasma to 96h; low circulating free DUBA in cyno PK

Payload

Payload & physicochemistry

Payload profile

Payload

seco-DUBA (duocarmycin)

Class

Duocarmycin

Mechanism

DNA minor-groove alkylation; seco-DUBA activated to DUBA causing irreversible DNA alkylation

Released catabolite

seco-DUBA, activated to DUBA (duocarmycin)

Mechanistic subtype

DNA-alkylator

Stereochem / salt

Free base

Bystander

Yes

PAMPA rank

527 Da

XLogP3

5.3

logD₇.₄

3.7

TPSA

107 Å²

pKa

~6 pKa

Charge pH 7.4

H-bond donors

H-bond acceptors

IC50 (HCEC)

Formula

C29H23ClN4O4

PubChem CID

46240929

ADCdb payload

PAY0SOSMQ

Potency IC50 (nM)

1.5

Hydrophobicity · logD₇.₄

hydrophilic −2+3.7+4 lipophilic

Bioactivity note

Free DUBA payload is highly potent (ADCdb-reported cell IC50 ~0.09 nM SK-BR-3 / SW620, 0.43 nM SK-OV-3). BYON3521 ADC showed good potency and full efficacy in MET-amplified/high-MET cell lines (publication IC50 ~1.5-18.2 ng/mL across MET-expressing lines) with target- and bystand

Dosing & regimen

Dosing

RP2D dose

Schedule

Every 3 weeks (Q3W)

Route

Fractionated

n at RP2D

Dose basis

TBW

Trial phase

Phase 1

Dose-OAE available

Yes

Tox summary basis

dose-escalation

HNSTD / NOAEL

15 mg/kg Q3W

Ocular & expression

Ocular profile & eye-tissue target expression

Target profile

OAE any-grade

0 %

OAE grade 3+

0 %

OAE data status

documented-absent

Severity (weighted)

Keratopathy

Conjunctival

Dry eye

Blurred vision

Dominant tissue

None

Surface subtype

None

Grading scale

CTCAE (unversioned)

Reversibility

Reversible

Target expression in eye tissues (HCA detection · HPA bulk)

Cornea (central)

26.59 %

Cornea (limbal)

37.08 %

Conjunctiva

67.14 %

RPE

59.48 %

Retina (HPA)

3.6 nTPM

Cross-trial comparability · source-verified

Ascertainment: Systematic eye examsScale: CTCAE (unversioned)Denominator: RP2D

Dose & schedule → ocular toxicity · keratopathy (any-grade) by cohort

0.8-4.8 mg/kg

Q3W IV

n=31 · NCT05323045 (FIH Phase 1)

6.4 mg/kg

3.2%

6.4 mg/kg

3.2%

Per-cohort rates from the per-trial extraction, sorted by dose. Cross-trial comparison is subject to ascertainment / scale differences (see comparability above) — e.g. an early symptom-driven trial can read lower than a later systematic-exam trial at a higher dose.

Ocular AE grading reference — interspecialty consensus · 6 scales + dose modification

Identity & registry

Identifiers, registry & notes

ADC id

byon-3521

Approval status

Investigational

Approval year

UniProt

P08581

ADCdb ADC

DRG0SZKXH

ADCdb antibody

ADCdb target

TAR0AIJKM

Primary source

AACR 2023 Abstract CT185 (Cancer Res 2023;83(8_suppl):CT185); NCT05323045

Aliases & development codes

BYON3521; BYON 3521

Notes

c-MET (MET/HGFR) targeting ADC from Byondis (originated by Syntarga). Humanized cysteine-engineered IgG1 (clone mAb3b / SYD2884) conjugated site-specifically via engineered cysteine (HC-41C, Kabat) to the cleavable valine-citrulline-seco-DUBA (vc-seco-DUBA / SYD980; ADCdb linker "Mc-Val-Cit-PABC", LIN0SQEDQ) duocarmycin linker-drug, DAR ~1.8 (ADCdb lists 2). Payload seco-DUBA is a DNA-alkylating duocarmycin activated to DUBA, with bystander activity. Clinical evidence is the AACR 2023 dose-escalation abstract CT185 (FIH Phase 1 NCT05323045, n=8 as of data cutoff Jan 1, 2023; doses 0.8/1.6/3.2/4.8 mg/kg IV Q3W). No Grade 3/4 TRAEs and no DLTs at cutoff; most common related AEs were decreased appetite/weight, fatigue, abdominal pain, back pain, vomiting and chills. OCULAR: explicit-zero - the abstract states "Typical ADC associated adverse events as keratitis and pneumonitis have not been observed so far," consistent with the triage. "History or presence of keratitis" is a trial exclusion criterion (ctv.veeva.com / NCT05323045). The ClinicalTrials.gov registry summary now lists the study as Completed with 31 patients enrolled, but no primary publication beyond the n=8 CT185 abstract was retrievable, so dosing/toxicity reflect the Jan 2023 cutoff. NOTE: duocarmycin/seco-DUBA is the same payload class as trastuzumab duocarmazine (SYD985), which is ocular-prone; the preclinical paper (Mol Cancer Ther 2023, PMC10233350) characterizes BYON3521's eye toxicity as "modest" in the nonclinical (cynomolgus) setting only - that is preclinical, not clinical. A secondary/unverified suggestion that eye disorders may emerge at higher doses (>4.8 mg/kg) in later data could not be confirmed in any primary source. No RP2D/MTD was defined at the data cutoff (escalation ongoing), so dosing.rp2d fields left blank. Payload physchem reported at the seco-DUBA/DUBA duocarmycin level (Tier C; exact computed PubChem values for the specific seco-DUBA structure not separately retrieved, so left blank where uncertain rather than imputed).