DP-303c

Investigational

DP303c; DP 303c

Target

HER2 (Receptor tyrosine-protein kinase erbB-2) · ERBB2

Sponsor

CSPC Pharmaceutical Group (CSPC Zhongqi Pharmaceutical Technology Shijiazhuang)

Indication

HER2-positive advanced solid tumors (predominantly breast cancer; also gastric, ovarian)

Target family

Receptor tyrosine kinase

RP2D dose

3.0 mg/kg

Q3W (every 3 weeks)RP2D

Multi-organ toxicity

Fingerprint & organ drill-down

Also reported

0%severity100%

Assessed · clear

true 0%

No data

never assessed

10 adverse-event terms

Ocular

Any-grade

94.7%

G3+

21.3%

RP2D

sagittal schematic · Reversible

↳

Tissues shaded by reported adverse-event rate.

Cornea

87.2%

Express.

46.2%

Limbus

Express.

61.99%

Conjunctiva

Express.

61.13%

Lens

Express.

Retina / RPE

Express.

5.48%

7.5 nTPM

Off-target signature

87.2% corneal toxicity, yet the HER2 (Receptor tyrosine-protein kinase erbB-2) target is detected in only 46.2% of central cornea - toxicity is not explained by target expression.

Dominant tissue

Cornea

Surface subtype

Corneal (off-target)

Reversibility

Reversible

Reported ocular events

Any ocular TRAE (composite)94.7%

G3+ 21.3%

Corneal disease (keratopathy/epitheliopathy)87.2%

G3+ 2.1%

Blurred vision61.7%

G3+ 16%

Dry eye57.4%

G3+ 6.4%

Eye pain19.1%

G3+ 1.1%

Lacrimation increased18.1%

Photophobia18.1%

Eye discharge14.9%

Foreign body sensation in eyes13.8%

Visual acuity reduced (decreased visual acuity)1.1%

Construct

Molecular anatomy

Antibody

IgG1

Humanized

Linker

Peptide

Cleavable

DAR

Payload

Monomethyl auristatin E (MMAE)

Microtubule polymerization inhibitor (anti-mitotic; tubulin binder)

Linker structureC26H44N6O8

CC(C)[C@H](NC(=O)COCCOCCOCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)Nc1ccc(CO)cc1

Payload structureC39H67N5O7

CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@@H]([C@@H](C)C(=O)N[C@H](C)[C@H](C2=CC=CC=C2)O)OC)OC)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC

Antibody

Antibody & Fc engineering

Antibody

Trastuzumab (anti-HER2)

Isotype

IgG1

Origin

Humanized

Fc modifications

None

Glycoengineering

Effector silencing

None reported (native human IgG1 Fc)

FcγR binding

Retained

C1q binding

Retained

Linker & conjugation

Linker chemistry

Linker profile

Linker

NH2-PEG3-Val-Cit-PABC

Class

Peptide

Cleavage

Cleavable

Attachment

Site-specific (enzymatic/non-natural AA)

Conjugation

Site-specific via microbial transglutaminase (mTG) transamidation to heavy-chain Q295 (ADCdb lists 'reactive cysteines' - contradicted by primary publication)

Symmetry

Site-specific (paired)

DAR (mean)

DAR homogeneity

Homogeneous

Plasma t½

Cleavage trigger

Cathepsin B (lysosomal cysteine protease); Val-Cit (valine-citrulline) dipeptide

Release control

Conditional

Hydrophilicity mask

Discrete-PEG-spacer

Formula

C26H44N6O8

Linker MW

568.67 Da

Linker TPSA

216.36 Å²

Linker xLogP

-0.8

ADCdb linker

LIN0YLYYC

In-vitro stability

Payload

Payload & physicochemistry

Payload profile

Payload

Monomethyl auristatin E (MMAE)

Class

Auristatin

Mechanism

Microtubule polymerization inhibitor (anti-mitotic; tubulin binder)

Released catabolite

Free MMAE (monomethyl auristatin E), released after cathepsin B cleavage of Val-Cit and 1,6-elimination of the PABC self-immolative spacer

Mechanistic subtype

Tubulin-auristatin

Stereochem / salt

Bystander

Yes

PAMPA rank

717.98 Da

XLogP3

4.1

logD₇.₄

TPSA

150 Å²

pKa

Charge pH 7.4

H-bond donors

H-bond acceptors

IC50 (HCEC)

Formula

C39H67N5O7

PubChem CID

11542188

ADCdb payload

PAY0FSXOW

Bioactivity note

ADCdb reports ADC cytotoxicity IC50 ranging 0.07-3.39 nM across HER2-positive cell lines (lowest 0.07 nM in SK-BR-3 and BT-474); >1000 nM in HER2-negative cells (e.g., MDA-MB-468), confirming HER2-dependent potency. Source: ADCdb DRG0CRYVT.

Dosing & regimen

Dosing

RP2D dose

3.0 mg/kg

Schedule

Q3W (every 3 weeks)

Route

Fractionated

n at RP2D

72 (dose-expansion cohort at RP2D 3.0 mg/kg); 94 total safety population

Dose basis

TBW

Trial phase

Phase 1

Dose-OAE available

Partial

Tox summary basis

RP2D

Ocular & expression

Ocular profile & eye-tissue target expression

Target profile

OAE any-grade

94.7 %

OAE grade 3+

21.3 %

OAE data status

reported

Severity (weighted)

43.32

Keratopathy

87.2 %

Conjunctival

Dry eye

57.4 %

Blurred vision

61.7 %

Dominant tissue

Cornea

Surface subtype

Corneal (off-target)

Grading scale

CTCAE v5

Reversibility

Reversible

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

Cornea (central)

46.2 %

Cornea (limbal)

61.99 %

Conjunctiva

61.13 %

RPE

5.48 %

Retina (HPA)

7.5 nTPM

Cross-trial comparability

Ascertainment: Partial / unspecified monitoringScale: CTCAE v5Denominator: RP2D

Identity & registry

Identifiers, registry & notes

ADC id

dp-303c

Approval status

Investigational

Approval year

UniProt

P04626

ADCdb ADC

DRG0CRYVT

ADCdb antibody

ANI0FIZAK

ADCdb target

TAR0THKZD

Primary source

Zhang J, et al. First-in-human study of DP303c, a HER2-targeted ADC. npj Precis Oncol 2024; doi:10.1038/s41698-024-00687-7; PMID 39266619 (NCT04146610, Phase 1 FIH). Composition cross-refs from ADCdb DRG0CRYVT/LIN0YLYYC.

Aliases & development codes

DP303c; DP 303c

Notes

DP-303c is a HER2 (trastuzumab-based, humanized IgG1) MMAE ADC, DAR 2, site-specific via microbial transglutaminase (mTG) to heavy-chain Gln295 (Q295) using the amine-terminated linker NH2-PEG3-Val-Cit-PABC (cathepsin B-cleavable Val-Cit). NOTE/DISCREPANCY: ADCdb lists conjugation as "Reactive Cysteines," but the primary publication explicitly describes mTG transamidation to Q295; the publication (Tier B) is authoritative and is consistent with the amine-terminated linker + DAR2 (homogeneous), so conjugation is recorded as mTG/Q295 site-specific. Sponsor CSPC Pharmaceutical Group. FIH Phase 1 (NCT04146610): IV Q3W, dose levels 0.5/1.0/2.0/3.0/4.0 mg/kg; RP2D = 3.0 mg/kg Q3W; N=94 safety population (escalation n=22, expansion n=72 at RP2D; 68 breast cancer); ORR 42.9%; CTCAE v5.0. OCULAR is the defining toxicity: any ocular TRAE 89/94 = 94.7% (G1 26.6%, G2 46.9%, G3 21.3%; NO G4/5). I recorded oae_any_pct as the explicit composite 94.7% (the single highest PT is corneal disease 87.2%, placed in ae_corneal_pct). All grade-3 ocular events occurred at >=3.0 mg/kg after the 2nd dose (median onset 5.29 wk); 18/20 (90%) G3 ocular events fully recovered with dose interruption + artificial tears (median recovery 5.57 wk); NO ocular discontinuations. Prophylactic artificial tears recommended after a Sep 2020 protocol amendment. Pattern = off-target MMAE corneal epitheliopathy (corneal disease + blurred vision + dry eye). REPORTING-THRESHOLD CAVEAT: Table 2 only lists TRAEs occurring in >=10% of patients, so GI PTs (nausea/vomiting/diarrhoea), infusion-related reactions, and thrombocytopenia/platelet-decrease were NOT tabulated -> left blank (NOT zero; below the 10% reporting threshold). The only GI-adjacent term meeting threshold was decreased appetite 16.0% (G1-2) [MedDRA SOC Metabolism & nutrition, so not coded as a GI organ row]; other non-tracked TRAEs >=10%: asthenia/fatigue 19.1% (G1-2), alopecia 36.2% (G1-2). ILD: 4 patients (4.3%) all CTCAE grade 1 (stated in text narrative, below the 10% table threshold). Anaemia and leucopenia had 0 grade-3+ events (documented 0 in the grade>=3 column). All toxicity rows are pooled across the N=94 safety population (expansion at RP2D 3.0 mg/kg), tagged line_context=RP2D. Payload physchem are standard MMAE values (PubChem CID 11542188); payload_logd_7_4 and payload_pka left blank (not firmly sourced).