HDP-101

Investigational

HDP-101; J22.9-amanitin ADC; anti-BCMA amanitin ADC

Target

B-cell maturation antigen (BCMA) · TNFRSF17

Sponsor

Heidelberg Pharma

Indication

Relapsed/refractory multiple myeloma

Target family

TNF receptor superfamily

RP2D dose

Selected April 2026

Q3WRP2D

Multi-organ toxicity

Fingerprint & organ drill-down

Also reported

0%severity100%

Assessed · clear

true 0%

No data

never assessed

1 adverse-event term

Ocular

Any-grade

G3+

RP2D

sagittal schematic · Reversible

↳

Tissues shaded by reported adverse-event rate.

Cornea

Express.

0.4%

Limbus

Express.

0.6%

Conjunctiva

Express.

0.06%

Lens

Express.

Retina / RPE

Express.

0.1 nTPM

Dominant tissue

Hematologic

Surface subtype

None

Reversibility

Reversible

Reported ocular events

Ocular disorders0%

Per-trial detail

Adverse events by trial

HDP-101-01 (NCT04879043)Phase 1/2a20-100 ug/kg (dose-escalation cohorts 1-5 pooled) IV once every 3 weeks (21-day cycle)n=18CTCAE not reported in open cPooledDto verify

HDP-101-01 IMS 2024 / ASH 2024 (Blood 2024;144 Suppl 1:3381) dose-escalation cut, reported verbatim in CancerNetwork Blood 2024;144(Suppl 1):3381 / IMS 2024 / CancerNetwork

5 adverse-event terms · 3 systems · expand a system below

Hematologic3

Thrombocytopenia

56%G3+ 39%

10/18

Anemia

33%G3+ 22%

6/18

Neutropenia

22%G3+ 17%

4/18

General1

Musculoskeletal1

Construct

Molecular anatomy

Antibody

IgG1

Humanized

Linker

Peptide

Cleavable

DAR

Payload

HDP 30.2115 (alpha-amanitin derivative)

RNA polymerase II inhibitor (transcription inhibition; POLR2A poison)

Linker structureC22H28N4O6

CC(NC(=O)C(NC(=O)CCN1C(=O)C=CC1=O)C(C)C)C(=O)Nc1ccc(CO)cc1

Payload structureC40H58N10O11S

CCC(C)C1NC(=O)CNCC2Cc3c([nH]c4ccccc34)SCC(NC(=O)CNCC1=O)C(=O)NC(CC(N)=O)C(=O)N1CC(O)CC1C(=O)NC(C(C)C(O)CO)C(=O)N2

Antibody

Antibody & Fc engineering

Antibody

J22.9-ISY

Isotype

IgG1

Origin

Humanized

Fc modifications

Engineered cysteine introduced at position 265 for site-specific conjugation

Glycoengineering

Effector silencing

FcgammaR binding reduced/silenced via the D265C conjugation substitution

FcγR binding

Reduced

C1q binding

Retained

Target KD (nM)

2.0

Epitope / domain

BCMA extracellular DxL loop

Linker & conjugation

Linker chemistry

Linker profile

Linker

Mal-Val-Ala-PAB

Class

Peptide

Cleavage

Cleavable

Attachment

Cysteine

Conjugation

Site-specific (engineered cysteine at position 265)

Symmetry

Site-specific (paired)

DAR (mean)

DAR homogeneity

Homogeneous

Plasma t½

Cleavage trigger

Cathepsin B / Val-Ala dipeptidase-mediated cleavage

Release control

N/A

Hydrophilicity mask

None

Platform

ATAC

Conjugation site

HC-D265C

Intact ADC mass (Da)

6464

Formula

C22H28N4O6

Linker MW

444.488 Da

Linker TPSA

144.91 Å²

Linker xLogP

0.078

ADCdb linker

LIN0BSKSQ

In-vitro stability

Payload

Payload & physicochemistry

Payload profile

Payload

HDP 30.2115 (alpha-amanitin derivative)

Class

Amatoxin

Mechanism

RNA polymerase II inhibitor (transcription inhibition; POLR2A poison)

Released catabolite

alpha-amanitin derivative (HDP 30.2115)

Mechanistic subtype

Other

Stereochem / salt

Bystander

Low/Minimal

PAMPA rank

919 Da

XLogP3

-4.4

logD₇.₄

TPSA

400 Å²

pKa

Charge pH 7.4

H-bond donors

H-bond acceptors

IC50 (HCEC)

Formula

C40H58N10O11S

PubChem CID

ADCdb payload

PAY0VZNCV

CAS no.

2925692-67-5

Bioactivity note

ADCdb reports HDP-101 / HDP 30.2115 cytotoxicity IC50 across 11 cell-line experiments ranging from ~0.01 nM (highest potency, U266B1 myeloma line) to >1000 nM (non-target HS-5 and U2OS lines), demonstrating selective killing of BCMA-expressing multiple myeloma cells. Mechanism: a

Dosing & regimen

Dosing

RP2D dose

Selected April 2026

Schedule

Q3W

Route

Fractionated

Yes

n at RP2D

Dose basis

TBW

Trial phase

Phase 1/2

Dose-OAE available

Yes

Tox summary basis

RP2D

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

0 %

Conjunctival

Dry eye

Blurred vision

Dominant tissue

Hematologic

Surface subtype

None

Grading scale

CTCAE v5.0

Reversibility

Reversible

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

Cornea (central)

0.4 %

Cornea (limbal)

0.6 %

Conjunctiva

0.06 %

RPE

0 %

Retina (HPA)

0.1 nTPM

Cross-trial comparability · source-verified

Ascertainment: Symptom-driven reportingScale: CTCAE (unversioned)Denominator: RP2D⚠ Not comparable: symptom-driven ascertainment

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

20-100 ug/kg (dose-escalation cohorts 1-5 pooled)

IV once every 3 weeks (21-day cycle)

n=18 · HDP-101-01

20-80 µg/kg

· HDP-101-01

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

hdp-101

Approval status

Investigational

Approval year

UniProt

Q02223

ADCdb ADC

DRG0WIBDT

ADCdb antibody

ANI0OBRWR

ADCdb target

PATR0QBNMQ

Primary source

ASH 2024 abstract (FIH NCT04879043), Blood 2024;144(Suppl 1):3381

Aliases & development codes

HDP-101; J22.9-amanitin ADC; anti-BCMA amanitin ADC

Notes

HDP-101 (Heidelberg Pharma) is an anti-BCMA (TNFRSF17) ADC with the fully human IgG1 antibody J22.9-ISY, a Mal-Val-Ala-PAB cathepsin-cleavable linker, site-specific conjugation at an engineered cysteine (position 265), DAR 2, and a novel synthetic alpha-amanitin derivative payload (HDP 30.2115) that inhibits RNA polymerase II — a distinct mechanism from antimicrotubule/maytansinoid ADCs. OCULAR: Triage-confirmed explicit-zero. The FIH Phase 1/2a (NCT04879043; ASH 2024, Blood 2024;144(Suppl 1):3381; also AACR 2024 CT067) states the initial four dose cohorts were well tolerated with explicit absence of hepatic/renal toxicities, infusion reactions, or ocular disorders; oae_any_pct=0, subtype None. The dose-limiting/dominant toxicity is transient thrombocytopenia (all patients in the 100 µg/kg cohort; 3 DLTs; nadir C1D5, recovery by D15), with mild transient ALT/AST elevations at the same cohort. As of July 2024, 19 patients enrolled across 20/30/60/80/100 µg/kg cohorts plus a 90 µg/kg dose-optimization cohort (premedication/split-dosing arms); RP2D/MTD not yet established, so no RP2D dose/schedule reported (left blank). Route is IV. Free amanitin payload not detected in serum (LOD 30 ng/mL); no ADA/immunogenicity. Confidence: conference-abstract granularity (Tier D) for clinical/toxicity; composition Tier B (ADCdb + preclinical PMC10802748); linker physchem from ADCdb LIN0BSKSQ; payload physchem from PubChem alpha-amanitin (CID 9543442) as proxy for the HDP 30.2115 derivative (Tier C). Linker plasma t1/2, RP2D, dosing schedule, payload logD/pKa/charge, and AE reversibility/CTCAE version left blank (not in accessible literature).