Whitehawk Therapeutics : Preclinical Assessment of HWK-016, a Next-Generation, MUC16-Targeting ADC with Novel Bioconjugation and Linker-Payload Technology

WHWK

Published on 04/19/2026 at 11:48 pm EDT

Kathleen S. Keegan1; Shihe Hou1; Ashwini B. Pai1; Enrico Bellomo1; Erik Kratzer1; VictorPeykov1; Bryan Ball1; Yifeng Wang2; Yaohua Hu2; Xia Wang2; Zhuozhi Wang2; Siwei Nie2; Yunying Chen2; Jijie Gu2; David J. Lennon1; David Dornan1

1Whitehawk Therapeutics, Morristown, NJ, USA; 2WuXi Biologics, Shanghai, China

‌David Dornan, PhD

I have the following relevant financial relationships to disclose: Employee of Whitehawk Therapeutics

Stockholder in Whitehawk Therapeutics

Disclosure Information

CA125

MUC16

Non-shed

MUC16 ECD

MUC16 is a heavily glycosylated cell-surface protein that plays a key role in cancer

progression by facilitating tumor cell proliferation, invasion, and immune evasion1,2

CA125, the well-known cancer antigen and biomarker, is a proteolytic cleavage product of MUC16 that is shed into the blood stream. Non-shed MUC16 extracellular domain (ECD) remains on the tumor cell surface1,2

MUC16 SLC34A2 (NaPi2b)

PTK7 ERBB2 (HER2) FOLR1 (FRα) TACSTD2

VTCN1 (B7-H4)

CDH6 CLDN6

7.8

7.2

7.1

7

6.9

5.2

5.2

2.1

MUC16 Expression Relative to Other ADC Targets in OC4

MUC16

SLC34A2 (NaPi2b)

PTK7

ERBB2 (HER2)

FOLR1 (FRalpha)

9.1

TACSTD2 (TROP2)

VTCN1 (B7-H4)

(TROP2)

CDH6

CLDN6

0 2 4 6 8 10

Expression (log2[TPM+1])

MUC16 Expression in Cancer

MUC16 is highly expressed in multiple tumor types, including ovarian, endometrial, cervical, pancreatic, and lung cancers, and has relatively low expression in normal tissues1-3

In ovarian cancer (OC), MUC16 expression is 2- to >100-fold higher than that of clinically validated and emerging ADC targets4

Previous ADCs targeting MUC16 (DMUC4064A and DMUC5754A) demonstrated response rates of 14% to 42% in patients with high MUC16 expression5,6

- Higher MUC16 expression correlated with greater clinical activity5,6

Common TRAEs included fatigue, nausea, and peripheral neuropathy; grade ≥3

TRAEs included neutropenia, fatigue, and ocular toxicity5,6

However, since these ADCs bound shed CA125, higher dosing was required to overcome target-mediated drug disposition5-8

1. Zhang XY, et al. Clin Exp Med. 2024;24:101. 2. Chen X, et al. Front Immunol. 2024;15:1356913. 3. Wang AJ, et al. Front Pharmacol. 2022;13:1093666. 4. O'Malley M, et al. Presented at SGO Annual Meeting on Women's Cancer 2026; Poster 1544. 5. Liu J, et al. Gynecol Oncol. 2021;163:473-80.

6. Liu JF, et al. Ann Oncol. 2016;27:2124-30. 7. Chen Y, et al. Cancer Res. 2007;67:4924-32. 8. Zhang XY, et al. Clin Chim Acta. 2025;565:119981.

CPT116

TOP1i

inhibitor

Carbon

bridge

Cleavable

linker

Fc-effector attenuated

PEG masking

Intracellular triple peptide cleavage site

Proprietary TOP1i payload

Linker-Payload (CPT113)

Carbon bridge cysteine re-pairing

Optimized DAR6 configuration

Stability-enhancing hydrolysis

Bioconjugation

Antibody targeting membrane-bound ECD of MUC16 for improved tumor targeting

Attenuated Fc region

Targeting

‌HWK-016 mAb Binding

(MUC16 ECD Engineered SK-OV-3)

DMUC5457A mAb Binding

(MUC16 ECD Engineered SK-OV-3)

40,000

30,000

20,000

10,000

0

0.0001 0.01 1 100

(302 × ULN)

1,000

800

600

400

200

0

0.0001 0.01 1 100

(302 × ULN)

‌OVCAR-3 (OV, MUC16high)

SW1990 (PAAD, MUC16medium)

SK-OV-3 (OV, MUC16low)

5,000

4,000

MFI

3,000

2,000

2,000

2,000

1,500

MFI

1,000

500

2,000

1,500

MFI

1,000

500

0

0.0001 0.01 1 100

Antibody (nM)

10,000

0

0.0001 0.01 1 100

Antibody (nM)

10,000

0

0.0001 0.01 1 100

Antibody (nM)

10,000

HWK-016 binding is dependent on MUC16 expression

HWK-016

Isotype-CPT113

Cell Line

EC50 (nM)

Max MFI

EC50 (nM)

Max MFI

OVCAR-3 (MUC16high)

0.51

4200

NA

39

SW1990 (MUC16medium)

0.18

1708

NA

52

SK-OV-3 (MUC16low)

NA

172

NA

159

‌HWK-016 mAb Binding

SW1990

DMUC5754A mAb Binding

SW1990

HWK-016 mAb

SW1990

DMUC5754A mAb

SW1990

3-fold

22-fold

8,000 1,500

6,000

MFI

4,000

2,000

1,000

MFI

500

0

0.0001 0.01 1 100

Antibody (nM)

10,000

0

0.0001 0.01 1 100

Antibody (nM)

10,000

CA125

Concentration

HWK-016 mAb

EC50 (nM)

Fold Change

0 U/mL

0.22

N/A

10,623 U/mL (304 × ULN)

0.67

3.0

CA125

Concentration

DMUC5754A mAb EC50 (nM)

Fold Change

0 U/mL

0.56

N/A

10,623 U/mL (304 × ULN)

12.4

22.2

3-fold shift in EC50 for HWK-016 mAb binding vs 22-fold shift in EC50 for DMUC5754 mAb indicates minimal potential for high levels of CA125 to affect HWK-016 cell surface binding

Note: In patients with cancer, high CA125 is defined as 2 × ULN (>70 U/mL).

‌HWK-016 mAb Internalization

SW1990

DMUC5754A mAb Internalization

SW1990

HWK-016 mAb

SW1990

2.6-fold

8,000

6,000

MFI

4,000

2,000

0

0.01 0.1 1 10

Antibody (nM)

100

25,000

DMUC5754A mAb

SW1990

10-fold

20,000

MFI

15,000

10,000

5,000

0

0.01 0.1 1 10

Antibody (nM)

100

CA125

Concentration

HWK-016 mAb

EC50 (nM)

Fold Change

0 U/mL

0.34

N/A

10,623 U/mL (304 × ULN)

0.89

2.6

CA125

Concentration

DMUC5754A mAb EC50 (nM)

Fold Change

0 U/mL

1.6

N/A

10,623 U/mL (304 × ULN)

~15.8

10.1

2.6-fold shift in EC50for HWK-016 mAb internalization vs 10-fold shift in EC50for DMUC5754 mAb indicates minimal potential for high levels of CA125 to affect HWK-016-mediated cancer cell internalization

Note: In patients with cancer, high CA125 is defined as 2 × ULN (>70 U/mL).

20.5%

18.8%

26.6%

HWK-016

Isotype-CPT113

Untreated

48h

‌Average % area/nucleus is shown Blue: Hoescht; Green: γ-H2AX

γ-H2AX Activation by HWK-016 (% Area / Nucleus)

γH2AX

H2AX

Cleaved PARP

5 days post-treatment

30 β-Actin

20

10

0

Isotype-CPT113 HWK-016

*, p<0.05, paired t-test

‌HWK-016 Cell Viability

OVCAR-3

DMUC5754A-mAb-CPT113 Cell Viability

OVCAR-3

HWK-016 mAb

SW1990

DMUC5754A mAb

SW1990

2.5-fold

120

Cell Viability %

100

80

60

40

20

0

0.0001 0.01 1 100

Concentration (nM)

CA125

Concentration

HWK-016 mAb

EC50 (nM)

Fold Change

0 U/mL

1.86

N/A

10,623 U/mL (304× ULN)

4.57

2.5

2.5-fold shift in EC50for HWK-016 induced inhibition of cell viability vs 146-fold shift in EC50for DMUC5754-mAb-CPT113 indicates minimal potential for high levels of CA125 to affect HWK-016-mediated cancer cell killing

Note: In patients with cancer, high CA125 is defined as 2× ULN (>70 U/mL).

120

146-fold

Cell Viability %

100

80

60

40

20

0

0.0001 0.01 1 100

Concentration (nM)

CA125

Concentration

DMUC5754A-mAb-CPT113 EC50 (nM)

Fold Change

0 U/mL

0.02

N/A

10,623 U/mL (304× ULN)

2.93

146.5

‌HWK-016

MUC16positive OVCAR-3

HWK-016

MUC16negative Raji-Luc

HWK-016

3:1 Co-Culture OVCAR-3:Raji-Luc

Isotype-CPT113 HWK-016

OVCAR-3 Cell Viability (%)

120

100

80

60

40

20

0

0.01 0.1 1 10 100

Concentration (nM)

120

Isotype-CPT113 HWK-016

Raji.luc Cell Viability (%)

100

80

60

40

20

0

0.01 0.1 1 10 100 1000

Concentration (nM)

120

Isotype-CPT113 HWK-016

Raji.luc Cell Viability (%)

100

80

60

40

20

0

0.01 0.1 1 10 100

Concentration (nM)

+

+

+ +

HWK-016

ADC

+

+

+

+

+

+

-

-

- -

-

-

-

- -

-

+

-

+

+

+

+

-

+

HWK-016

ADC

+

+

-

+

-

+ +

+

HWK-016 ADC

+

-

MUC16positive cell MUC16negative cell

HWK-016 Reduced Viability of MUC16negative Cells After Co-Culture with MUC16positive Cells Demonstrating Bystander Effect

‌HWK-016 Efficacy in OVCAR-3 (MUC16high)

HWK-016 Efficacy in CTG-3423 (MUC16high)

2,500

Tumor Volume (mm3)

2,000

1,500

1,000

DPBS

Isotype-CPT113 1 mg/kg

DMUC5754A 1 mg/kg

DMUC5754A-mAb-CPT113 1 mg/kg

HWK-016 1 mg/kg

750

Tumor Volume (mm3)

500

250

HWK-016 (6 mg/kg)

500

0

108% TGI;

4/7 CRs

0 7 14 21 28 35

0

0 7 14 21

103% TGI;

1/8 CR

28 35

Time (days) Time (days)

HWK-016 shows greater antitumor activity relative to DMUC5754A and DMUC5754A mAb conjugated to CPT113

Note: OVCAR-3 sheds large amounts of CA125 (>600 ULN)

‌HWK-016 In Vitro Plasma Stability

Dato-DXd In Vitro Plasma Stability1

Human plasma

Cynomolgus monkey plasma

Human plasma Monkey plasma Rat plasma Mouse plasma PBS + 1% BSA

10 10

8 8

% CPT116 Release

% Drug Release

6 6

4 4

2 2

0

0 5 10 15 20 25

CPT116 release in human and cyno plasma is minimal (≤0.4%)

Time (days)

0

0 7 14 21

Time (days)

1. Okajima D et al., Mol Cancer Ther. 2021 Dec;20(12):2329-2340.

‌Species

HNSTD

Findings

Cynomolgus monkey

60 mg/kg

(highest dose tested)

No mortalities, all findings consistent with TOP1i

payload class of ADC

HWK-016 60 mg/kg

HWK-016

CPT116

HWK-016 T1/2 consistent with highly

stable ADC (~10-13 days)

Very low levels of CPT116 payload (<0.01%) released from HWK-016 into circulation

Mean Concentration (ng/mL)

1,000,000

100,000

10,000

10

1

0.1

0.01

0 200 400

Time (hrs)

‌HWK-016 is a promising next generation MUC16-targeting ADC that leverages novel bioconjugation and linker-payload technologies to minimize off-target effects and increase the therapeutic index

HWK-016 selectively binds to the non-shed, ECD of MUC16 to ensure delivery to the tumor instead

of circulating CA125

HWK-016 demonstrated potent binding, internalization, and reduced cancer cell viability that are minimally impacted by addition of high levels of exogenous CA125

HWK-016 has bystander activity and robust anti-tumor activity in models of ovarian cancer with

tumor regressions observed at doses as low as 1 mg/kg

In a repeat dose toxicology study, HWK-016 was well tolerated with an HNSTD of 60 mg/kg, the highest dose tested, and minimal levels of released payload were observed

HWK-016 is currently being evaluated in a phase 1 study of patients living with advanced ovarian

and endometrial cancers (NCT07470853)

Disclaimer

Whitehawk Therapeutics Inc. published this content on April 19, 2026, and is solely responsible for the information contained herein. Distributed via Public Technologies (PUBT), unedited and unaltered, on April 20, 2026 at 03:47 UTC.