Phase I/II Clinical Study of 1A46 Drug Substance

Inclusion Criteria:

1. Male or female patients aged 18 years or older; 2. Be able to sign informedconsent form voluntarily and understand the study, incuding the purpose and theprocedure and be able to comply with protocol requirements; 3. Patientpopulations:

Dose Escalation:

1. Aggressive NHL (aNHL) : MCL, each subtype of DLBCL and FL3b, PMBCL, high level of Bcell lymphoma, etc.

2. Indolent NHL (iNHL) : including FL1-3 a grade, MZL, small lymphocytic lymphoma, etc.

3. all NHL patients should must: relapsed after or failed to respond to at least twoprior systemic treatment regimens, including at least one containing ananti-CD20-directed therapy,, received or be ineligible for autologous SCT , there isno other standard treatment is thought to have clinical benefit Dose Expansion: Cohort 1: FL patients who are refractory to or relapsed after ≥ 2 prior regimens andhave no other standard of care with clinical benefit. Cohort 2: r/r DLBCL patients who have progressed after or refractory to 2 or morelines of systemic therapy and have not received prior therapy with CAR-T, and do nothave standard treatment with clinical benefit. Cohort 3: r/r DLBCL patients who have progressed after or refractory to 2 or moreregimens which consisted of a CAR-T therapy that has been approved by a healthauthority, and do not have standard treatment with clinical benefit.

4. NHL patients must have expression of CD20 and/or CD19-expression as determinedby immunohistochemistry (IHC) at a certified laboratory within 6 months beforestudy entry without intervening treatment of NHL, otherwise a fresh biopsy mustbe obtained to determine if CD19 and/or CD20 continue to be expressed by tumorcells.

5. ≥ 1 measurable target lesion as defined by Lugano 2014 criteria (> 15 mm in itslargest dimension for nodal lesions, or > 10 mm in its largest dimension forextranodal lesion).

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; Lifeexpectancy> 3 months.

7. Subjects with fertility must take effective contraceptive measures aftersigning the ICF until at least 12 months after the last administration of 1A46.

8. Clinical laboratory values as specified below during the screening period.

① Total bilirubin must be < 1.5 x the upper limit of the normal range (ULN). Totalbilirubin may be elevated up to 3 x ULN if their elevation can be reasonablyascribed to patients with documented Gilbert's Syndrome.

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) must be < 3x ULN. AST and ALT may be elevated up to 5 x ULN if their elevation can bereasonably ascribed to the presence of metastatic disease in liver.
• Calculated creatinine clearance > 50 mL/min (the Cockcroft-Gault formula). ④ Hemoglobin (Hb) must be ≥ 80 g/L. No transfusion of red blood cells oruse of hematopoietic stimulating factors such as TPO within 14 days beforethe study.
• Neutrophil count must be >1.0×10^9/L, No granulocyte or granulocytemacrophage colony-stimulating factor and other hematopoieticstimulating factors were used within 14 days before the study.
• Platelet count must be >75×10^9/L, No platelet transfusion oruse of hematopoietic stimulating factors such as TPO and IL-11within 14 days prior to testing. ⑦ Prothrombin time-international normalized ratio (PT-INR) mustbe ≤ 1.5. Patients who are appropriately anticoagulated for apreexisting medical condition [e.g., atrial fibrillation] may beeligible with documented and evaluated by investigators andsponsor approval.

9. Recovery to Grade 0-1 from AEs related to prior anticancertherapy except alopecia, < Grade 2 sensory neuropathy,lymphopenia, and endocrinopathies controlled with hormonereplacement therapy.

Exclusion Criteria:

1. Patient has brain metastasis or other significant neurological conditions.
2. Female patients who are lactating and breastfeeding or have a positiveserum pregnancy test during the screening period, or intending to becomepregnant during the study.
3. At the time of enrollment, there are active infections, includingbacteria, viruses (including EB virus, cytomegalovirus, etc.), fungi,mycobacteria, parasites, or other infections (excluding nail bed fungalinfections), or there are any serious infections that require antibioticintravenous injection treatment or hospitalization treatment (relating tothe completion of the course of antibiotics) within the first 4 weeksprior to enrollment.
4. Treatment with corticosteroids (> 10 mg daily prednisone or equivalent) orimmunosuppressive medication( including but not limited tocyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumornecrosis factor drugs) ≤ 7 days before the first dose of 1A46, with thefollowing exceptions: local, ocular, intra-articular, nasal, or inhaledcorticosteroids, and those who receive corticosteroid replacement therapydue to adrenal insufficiency.
5. Treatment with any investigational products (including cell or genetherapy) within 5 half-lives of the agent or 4 weeks prior to the firstdose of 1A46, whichever is shorter.
6. Received Systemic anticancer therapy (including I/O therapies) within 5half-lives of the agent or 4 weeks prior to the first dose of 1A46,whichever is shorter.
7. Treatment with radiotherapy within 2 weeks before the study entry. If thepatients have received radiotherapy within 4 weeks before enrollment,there must be at least one measurable lesion outside the radiotherapyarea, or if the patient only has measurable lesion progression afterradiotherapy, they can be enrolled.
8. Treatment with CAR-T within 30 days before the study entry. 9. Treatmentwith autologous stem cell transplantation therapy within 100 days beforethe study entry.
9. Prior allogeneic hematopoietic stem cell transplantation . 11. Priorsolidorgan transplantation. 12. Positive human immunodeficiency virus (HIV)antibodies; positive EB virus nucleic acid ; positive Cytomegalovirusnucleic acid positive; Hepatitis C virus (HCV) antibody is positive, andthe result of HCV RNA detection is positive; Hepatitis B surface antigen [HBsAg] is positive, and hepatitis B virus DNA test result is positive orgreater than the upper limit of normal value.
10. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
11. Have ischemic or hemorrhagic cerebrovascular disease, epilepsy,dementia, or ≥ grade 3 gastrointestinal bleeding within the first 6 months (CTCAE, version 5.0) before screening.
12. Unstable cardiovascular function:

• Myocardial infarction occurred within 6 months prior to enrollment;
• Have experienced unstable angina pectoris within 3 months prior toenrollment; ③ Uncontrolled and clinically significant arrhythmias (such as persistent ventricular tachycardia, ventricularfibrillation, and torsion of the apex);
• Mobitz type II degree or III degree atrioventricular block; ⑤Congestive heart failure with a New York Heart Associationrating of ≥ 3; ⑥ Left ventricular ejection fraction<50%. 16.Received major surgery < 4 weeks prior to enrollment; (minorsurgeries such as catheter insertion and biopsy required by theprotocol are not considered as exclusion criteria).

17. Inoculate with live virus vaccine within 28 days beforeenrollment (attenuated live vaccine is not allowed duringthe study period or until B cells return to normal rangeafter the last trial drug administration).
18. Have a history of grade 3-4 allergic reactions to othermonoclonal antibody treatments; Or known to be allergic toany component or excipient of the investigational drug.Patients with Level 3 reactions lasting less than 24 hoursmay be eligible for inclusion after comprehensiveevaluation by the researchers.
19. Have a history of 3-4 levels of immune related adverseevents or a history of immune related adverse eventsrequiring discontinuation of medication, except for level 3endocrine diseases treated with hormone replacementtherapy. Subjects who have experienced levels 3-4 ICANSafter previous CAR-T treatment.
20. Any other serious underlying diseases that researchersbelieve may interfere with treatment, affect patientcompliance, or put patients at high risk oftreatment-related complications (such as active gastriculcers, uncontrolled seizures, cerebrovascular events,gastrointestinal bleeding, severe signs and symptoms ofcoagulation disorders, heart disease), mental,psychological, familial, or geographic conditions.
21. Have had other malignant tumors within the past 5 years,excluding cured cervical carcinoma in situ, basal cellcarcinoma, or squamous cell skin cancer.
22. Autoimmune, liver, and lung diseases that may worsen underimmune activation, such as certain autoimmune diseases,cirrhosis, hepatitis, interstitial pneumonia, systemiclupus erythematosus, rheumatoid arthritis, inflammatorybowel disease, multiple sclerosis, antiphospholipidantibody syndrome, vasculitis, psoriasis history, etc.
23. Thoracic effusion, pericardial effusion, or ascites thatrequire frequent drainage or medical intervention (recurrence within 2 weeks after intervention requiresadditional intervention).
24. Previous T-cell engaging treatment regimens (includingbispecific antibody, CAR-T therapy, etc.) targeting CD19and CD20, either successively or simultaneously (those whohave only received T-cell engaging therapy targeting one ofthe targets CD19 or CD20can be included).
25. Use Fredericia's QT correction formula to correct heartrate for QT interval (QTCF)>480msec.
26. During the dose increase phase, the body weight is lessthan 40kg. 27. Subjects judged by the investigator to beunsuitable for participation in this study.