Background: BDC-1001 is a HER2-targeted immune-stimulating antibody conjugate (ISAC), designed to trigger local activation of the innate immune system and generate a durable tumor-targeted adaptive immune response. BDC-1001 incorporates a trastuzumab biosimilar (EG12014) conjugated to a proprietary TLR7/8 agonist using a non-cleavable linker and a cell membrane-impermeable payload. An international phase 1/2 study was initiated to evaluate the safety of BDC-1001 ± nivolumab (nivo) and to identify the recommended phase 2 dose (RP2D) considering PK/PD analyses and preliminary efficacy. Methods: Dose-escalation (3+3, +backfills) enrolled patients (pts) with HER2-positive (amplified, or IHC 3+) or HER2 low (IHC 2+ and not amplified) solid tumors who had progressed after standard therapies. BDC-1001 was given IV q3w, q2w, or q1w as monotherapy (mono; n=91) and q2w or q1w with nivo 240 mg q2w (combo; n=27). Results: As of Nov 23, 2022, 118 pts with 16 different tumor types, were enrolled with BDC-1001 doses ranging from 0.15 to 20 mg/kg. Mean age was 61 yrs with a median of 4 and 5 prior lines of therapy (range, 1-11; 1-14; prior anti-HER2 therapy (HER2Tx) [66%/70%], immunotherapy (IO) [23%/22%]) for mono and combo, respectively. Median follow-up time was 5.0-6.1 months. Treatment was well tolerated with only 1 DLT (Gr3 supraventricular tachycardia) at 8 mg/kg q1w combo cohort. Low-grade IRRs were the most common related TEAEs (mono, 26.5%; combo, 25.9%). A related SAE (Gr4, bronchopulmonary hemorrhage) was seen in 1 pt (mono, 1.1%). Antitumor activity was observed at a range of doses and malignancies. There were 4 confirmed (RECIST 1.1) durable PRs (all in MSS tumors with low/intermediate TMB, prior Tx: 1 HER2Tx, 1 IO) including 1 pt with colon cancer (CRC) in the 5 mg/kg q3w mono cohort, and 3 in the 20 mg/kg q2w cohorts (mono 1/7; combo 2/7; ovarian, biliary, and rectal cancers). After the data cut, an additional PR (unconfirmed) was reported at week 6 in a pt with CRC receiving 12m/kg 1qw combo. Ten additional pts had SD lasting ≥6 months (8 mono; 2 combo; prior Tx: 6 HER2Tx; 1 IO; e.g., ovarian, endometrial, colorectal, gastric). Durable SDs were most frequent in the q2w cohorts. BDC-1001 exposure (e.g., C_min) correlated with activity among pts in q2w cohorts. Increases in myeloid and T cell infiltration markers in post-Tx tumor biopsies align with mechanism of action (MoA). No anti-drug antibodies were detected. Conclusions: BDC-1001 mono and combo were well-tolerated. Targeted serum exposure levels were achieved, and encouraging clinical activity was noted in heavily pretreated pts with various HER2 positive tumors, especially in the 20 mg/kg q2w cohorts. Immune biomarker changes from plasma and tumor were consistent with MoA of this ISAC. These data support further development of BDC-1001 with phase 2 expansion in HER2-expressing solid tumors at the RP2D. Clinical trial information: NCT04278144.